Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

Abstract

In recent years, natural products, which originate from plants, animals, and fungi, together with their bioactive compounds have been intensively explored and studied for their therapeutic potentials for various diseases such as cardiovascular, diabetes, hypertension, reproductive, cancer, and neurodegenerative diseases. Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis are characterized by the progressive dysfunction and loss of neuronal structure and function that resulted in the neuronal cell death. Since the multifactorial pathological mechanisms are associated with neurodegeneration, targeting multiple mechanisms of actions and neuroprotection approach, which involves preventing cell death and restoring the function to damaged neurons, could be promising strategies for the prevention and therapeutic of neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases. This review focused on the therapeutic potential of natural products and their bioactive compounds to exert a neuroprotective effect on the pathologies of neurodegenerative diseases.

1. Introduction

Neurodegeneration is the progressive dysfunction and loss of neuronal structure and function that resulted in neuronal cell death [1, 2]. Neurodegeneration occurs in various diseases affecting the central nervous system (CNS). The loss of specific populations of neurons related to the functional neuronal networks determines the clinical presentation of acute and chronic neurodegenerative diseases. Neurodegenerative disease is a general term for a range of neurological disorder which primarily affects neurons in the CNS that are characterized by the gradual loss of neurons in the CNS, leading to deficits in specific brain functions (memory, movement, and cognition) [3].

Acute neurodegeneration is a condition in which neurons are rapidly damaged and usually die in response to a sudden insult or traumatic event such as head injury, strokes, traumatic brain injury, cerebral or subarachnoid hemorrhage, and ischemic brain damage [4]. Meanwhile, chronic neurodegeneration is a chronic state in which neurons in the nervous system undergo neurodegenerative process that usually starts slowly and worsen over time with multifactorial causes, resulting in the progressive and irreversible destruction of specific neuron populations [3, 5–7]. The chronic neurodegenerative diseases include Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

Various types of biological mechanisms have been associated with neurodegeneration including oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, abnormal protein misfolding and aggregation, and apoptosis [8–16]. These biological processes have been implicated in the progression and pathogenesis of neurodegenerative diseases. To date, extensive studies have attempted to elucidate the mechanism and potential therapeutic targets to combat neurodegenerative diseases. Therefore, neuroprotection strategies and relative mechanisms work best to prevent or delay the process of neurodegeneration through the interaction with the pathophysiological change process.

Natural products are known and employed since ancient times for their therapeutic properties. In recent years, biological activities, nutritional values, and potential health and therapeutic benefits of natural products and their bioactive compounds have been intensively explored and investigated. Within the past decades, many studies have reported the protective effect of natural products and its bioactive compounds against various diseases such as cardiovascular, diabetes, reproductive, cancer, and neurodegenerative diseases. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases. This review focused on the therapeutic potential of natural products and their bioactive compounds to exert neuroprotective effects on the pathologies of neurodegenerative diseases.

2. Neurodegeneration and Neurodegenerative Diseases: Mechanisms and Potential Therapeutic Targets

Neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, are a group of disorders that are characterized by progressive and specific loss of cell in specific vulnerable neuronal populations of the CNS [6, 17]. Alzheimer’s disease is an age-related and chronic, progressive neurodegenerative disease, which is associated with memory and cognitive impairments and behavioral changes. It is characterized by two major neuropathological hallmarks: (i) the formation and deposition of the extracellular amyloid-beta (Aβ) plaques and (ii) the protein accumulation of intracellular hyperphosphorylated tau proteins known as neurofibrillary tangles in the brain [18].

Parkinson’s disease is a chronic and progressive neurodegenerative disease caused by a progressive loss of dopaminergic nigrostriatal neurons and diminishes the motor function, including resting tremor, postural imbalance, bradykinesia, and muscular rigidity [19]. The neuropathological hallmark of Parkinson’s disease is the accumulation of intracellular protein aggregates, Lewy bodies, and Lewy neurites, which are predominantly formed of misfolded and aggregated forms of the presynaptic protein alpha (α)-synuclein and the progressive loss of dopaminergic nigrostriatal neurons [19].

Another progressive neurodegenerative disease, amyotrophic lateral sclerosis is characterized by progressive degeneration and death of upper and lower motor neurons, resulting in paralysis and death from respiratory failure. The mechanisms that underlie amyotrophic lateral sclerosis remain unknown, but several factors have been considered including genetic factors, excitotoxicity, oxidative stress, autoimmune response, impaired axonal transport, neurofilament aggregation, environmental factors, and mitochondrial dysfunction [20]. Amyotrophic lateral sclerosis is associated with mutation in the gene that produces the copper/zinc superoxide dismutase-1 (SOD1) enzyme.

Meanwhile, Huntington’s disease is characterized pathologically by excessive dopaminergic activity and diminished gamma-aminobutyric acid (GABA) functions in the basal ganglia and clinically by abnormal movements, psychiatric disturbance, and cognitive deficits [21]. It is caused by a trinucleotide repeat expansion of the nucleotides cytosine, adenine, and guanine (a CAG expansion) in the Huntingtin (HTT) gene, located at the short arm of chromosome 4 [22].

Various types of biological processes have been implicated in the progression and pathogenesis of neurodegenerative diseases, including oxidative stress, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and apoptosis [8–16] (refer Figure 1).

Figure 1 

Various types of mechanisms have been associated with the neurodegeneration that implicated in the progression and pathogenesis of neurodegenerative diseases.

Oxidative stress plays a contributory role in the pathophysiology of common neurodegenerative diseases [9–11]. The imbalance of the production of reactive oxygen species (ROS) and insufficient antioxidant defense capacity, causing oxidative stress to occur, results in cellular damage, DNA repair system impairment, and mitochondrial dysfunction. These will accelerate the neurodegenerative process and progression of neurodegenerative disease.

Moreover, it has been postulated that neuroinflammation may also play a role in the pathophysiology of neurodegenerative diseases [13, 23–25]. Neuroinflammation is an inflammatory process that involved in both innate and adaptive immune system in the CNS and has been associated with neurodegeneration. The mechanisms of neuroinflammation could contribute to the development of the normal brain and the neuropathological events. In the CNS, microglia are the major component of innate immune defense. Following the pathological changes within the nervous system, microglia rapidly acquired the morphology changes and activated microglia secrete several inflammatory mediators, such as cytokines, chemokines, and cytotoxic molecules (cyclooxygenase-2 (COX-2), ROS, glutamate, and prostaglandins). These inflammatory mediators will trigger astrocytes to induce secondary inflammatory or growth factor repair response as well as trigger neurons to respond for its survival.

Another biological process, excitotoxicity may also involve in the pathogenesis of neurodegenerative diseases [7]. It is defined as the pathological process of neuronal death caused by the over- or prolonged activation of glutamate receptors by excitatory amino acids or excitotoxins in the CNS [5]. Excitotoxins which bind to the glutamate receptors, as well as pathologically high levels of glutamate release, can cause excitotoxicity by allowing rapid entry of calcium ions (Ca²⁺) to enter the cell. Ca²⁺ influx into cells activates several Ca²⁺-dependent enzymes, including phospholipases, lipases, endonucleases, xanthine oxidase, protein phosphatases, proteases, protein kinase, and inducible nitric oxide synthase (iNOS). These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA [5, 26–30]. The excessive Ca²⁺ influx could also result in ROS production, mitochondrial dysfunction, oxidative stress, and inflammatory responses. These processes ultimately lead to neuronal cell death.

Neuronal apoptosis also plays a role in the neurodegenerative process. It is a highly regulated form of cell death and characterized by cell shrinkage, chromatin condensation, DNA fragmentation, and membrane cell death. This energy-dependent process requires ATP for protein synthesis and signal activation [31]. Apoptosis is a complex process which is triggered by intrinsic and extrinsic signal. The extrinsic pathway involves the activation of death receptors upon ligand binding and downstream signaling through cascade of protein-protein interactions. Meanwhile, the intrinsic pathway involves the release of proapoptotic factors located in the mitochondrial intermembrane space via mitochondrial permeability transition into cytosol and subsequently triggers caspase-dependent apoptosis or caspase-independent apoptosis (see [32]).

Mitochondria are the site of oxidative phosphorylation and cellular respiration and play a role in maintaining a low concentration of Ca²⁺ in the cytosol [28]. Excessive uptake of Ca²⁺ and generation of ROS cause the collapse of mitochondrial membrane potential and the opening of mitochondrial permeability transition pores [31]. The opening of mitochondrial permeability transition pores causes swelling of the mitochondrial matrix, which result in mitochondrial uncoupling, the rupture of the mitochondrial outer membrane, and the release of mitochondrial factors (cytochrome-c and apoptotic-inducing factor) located in the mitochondrial intermembrane space via mitochondrial permeability transition pores into cytosol [29, 32]. In caspase-dependent mechanism, cytochrome-c binds to apoptotic protease-activating factor-1 and procaspase-9 to form apoptosome complex and the activation of caspase-3 pathway. The activation of caspase is responsible for the activation of apoptotic neuronal death. This leads to the cleavage of essential cellular substrates such as poly (ADP-ribose) polymerase-1 (PARP-1). These alterations in the mitochondrial function could be an early event prior to neuronal cell death. In caspase-independent mechanism, apoptotic-inducing factor translocates to the nucleus and induces DNA fragmentation and chromatin condensation [32].

Since the multifactorial pathological mechanisms are associated with neurodegeneration, targeting multiple mechanisms of actions is a promising strategy for the prevention and therapeutic of neurodegenerative diseases. Several potential therapeutic targets to combat neurodegenerative diseases could be explored (see Figure 2).

Figure 2 

The potential therapeutic targets on various mechanisms of neurodegeneration.

3. Neuroprotective Activities of Natural Products and Their Bioactive Compounds

The therapeutic potential of natural products and their bioactive compounds to exert a neuroprotective effect on the pathologies of neurodegenerative diseases will be discussed in more detail in this section.

3.1. Honey

Honey, a beehive product, is the natural sweet substance with therapeutic and nutritional values. It is highly rich in bioactive compounds and antioxidants such as polyphenols. It is widely used as a nutrient supplementation and in traditional medicine. Since the last two decades, honey has been explored for its gastroprotective, hepatoprotective, reproductive, hypoglycemic, antioxidant, antihypertensive, antibacterial, antifungal, anti-inflammatory, immunomodulatory, wound healing, cardioprotective, and antitumor effects [33–40]. In general, pure honey contains over 200 compounds, consisting mainly of carbohydrates (monosaccharides: glucose and fructose; disaccharides: sucrose and maltose), protein (amino acids and enzymes), minerals, vitamins (vitamin B6, riboflavin, niacin, and thiamine), phenolic compounds (flavonoids and phenolic acids), and volatile substance (responsible for the characteristic aroma of honey) [41–46].

In kainic acid-induced excitotoxicity animal model, pretreatment with honey significantly attenuated oxidative stress, neuroinflammation, and apoptosis in the cerebral cortex, cerebellum, and brainstem as well as progression of neuronal damage in the piriform cortex of kainic acid-induced rats [47–49]. Hence, honey confers its neuroprotection against the deleterious effect of kainic acid through its antioxidants and anti-inflammatory and antiapoptotic properties, thereby protecting brain from neuronal loss and neurodegeneration. In addition, honey has been reported to reduce brain oxidative stress and improve morphological impairment of the hippocampus and medial prefrontal cortex in stressed rats [50–55]. Honey also attenuates the cognitive impairment caused by chronic cerebral hypoperfusion-induced neurodegeneration [56] and ameliorates oxidative stress in the rat midbrain against repeated paraquat exposure [57]. Meanwhile, in normal rats, consumption of honey could prevent morphological impairment of the hippocampus and improve the spatial memory performance of adult male rats [58]. These findings were clinically supported by a study done in healthy postmenopausal women [59] reporting the improvement in total learning and immediate memory observed in healthy postmenopausal women after receiving the supplementation of honey for 16 weeks. Among the compounds found in these honeys are phenolic acids (gallic, syringic, coumaric, benzoic, cinnamic, caffeic, ferulic, and chlorogenic acids), flavonoids (catechin, naringenin, kaempferol, pinobanksin-3-O-propionate, pinobanksin-3-O-butyrate, and quercetin), minerals (potassium, calcium, sodium, and magnesium), amino acids (aspartic acid, serine, glutamic acid, glycine, threonine, alanine, proline, tyrosine, valine, methionine, lysine, isoleucine, and leucine), and vitamins (vitamin B3 and vitamin C) [43, 60–62]. Hence, the neuroprotective effects of honey are likely to be exerted at different stages of neurodegeneration and play prominent roles in early events. Therefore, honey could be considered as a potential candidate in mitigating the oxidative stress, inflammation, and apoptosis in neurodegenerative diseases as well as improving spatial memory performance and attenuating the cognitive impairment.

These protective effects of honey could be resulting from the presence of flavonoids and phenolic acids as well as other bioactive compounds in honey. Furthermore, the synergistic effect of these bioactive compounds present in honey could also contribute to the neuroprotection action of honey against neurodegeneration. Several important constituents including polyphenols found in honey have been suggested to play the neuroprotective role by reduction of oxidative stress, attenuation of neuroinflammation, the improvement of memory, learning and cognitive function, and protection against neuronal injury and neurodegeneration [63–66].

3.2. Propolis

Another bee product, propolis is a complex resinous mixture produced by bees and is used for defense against intruders and reconstruction of beehive. Propolis is mainly composed of resins, balms, wax, essential oils, pollen, amino acids, micronutrients, and vitamins and other organic compounds [67–70]. These organic compounds found in the propolis include phenolic compounds, flavonoids, terpenes, aromatic aldehydes, and alcohols [71]. The properties and chemical composition of propolis differ depending on various factors including the geographical origin, the season and time of collection, and types of plant sources [67, 68]. Propolis possesses numerous biological and pharmacological properties, such as antifungal, anticancer, antidiabetic, antibacterial, anti-inflammatory, and antioxidant activities [67, 68, 70, 72, 73]. These beneficial effects of propolis could have been attributed to its bioactive compounds as well as the combined actions of these compounds [69].

Propolis has been reported to attenuate nitric oxide level, glutamine synthetase activity, oxidative stress, tumor necrosis factor-alpha (TNF-α), and caspase-3 activity, reduce seizures, and prevent neuronal loss in kainic acid-induced excitotoxicity rat model [74–76]. These findings suggested that propolis exhibits its inhibitory effect on the oxidative stress, proinflammatory cytokines, and apoptosis as well as protection against neuronal damage through its anti-inflammatory, antioxidant, and antiapoptotic properties. The beneficial action of propolis might be due to the presence of phenolic compounds and flavonoids [76].

Moreover, Ni et al.’s study [77] has reported that Brazilian green propolis reduced the hydrogen peroxide-induced mitochondria-derived ROS generation and nuclear DNA oxidative damage marker, 8-oxo-2′-deoxyquanosine in human neuroblastoma (SH-SY5Y) cell line. This indicated that the propolis could attenuate the oxidative stress in neuronal cells. In addition, propolis also showed to reverse the interleukin-1 beta- (IL-1β-) induced and fibrillar Aβ-induced impairment of brain-derived neurotrophic factor- (BDNF-) induced activity-regulated cytoskeleton-associated protein (Arc) mRNA and protein expressions, upregulate the mRNA expression of BDNF through phosphoinositide 3-kinase- (PI3K-) dependent pathways, and increase the expression of critical factors of synapse efficacy. Hence, this study indicated that propolis may have the ability to prevent neurodegenerative damaged synapse efficacy, which could relate to cognitive impairment in neurodegenerative diseases, through antioxidant property. This finding supported the previous studies [78, 79] that reported the neuroprotective effect of Brazilian green propolis and its main components (caffeoylquinic acid derivatives, artepillin C, and p-coumaric acid) against retinal damage in vitro [78] and against oxygen-glucose deprivation/reoxygenation-induced neuronal damage [79]. The Brazilian green propolis displays its neuroprotective effect through its antioxidant mechanism of actions, which could be attributed to the synergistic effect of its main components (caffeoylquinic acid derivates, artepillin C, and p-coumaric acid).

Moreover, Ueda et al. work [80] reported that ethanol extract of Brazilian green propolis protected N2a cells against amyotrophic lateral sclerosis-associated mutant SOD1^G85R-mediated neurotoxicity and reduced intracellular aggregates of mutant SOD1^G85R by autophagy induction. This neuroprotective effect could be due to the role of its active ingredients, like flavonols, against mutant SOD1^G85R-induced neurotoxicity. In addition, Ueda et al. [80] also reported that its active ingredients, such as kaempferide and kaempferol, also prevented mutant SOD1^G85R-induced toxicity and reduced aggregated mutant SOD1^G85R as well as suppressed mutant SOD1^G85R-induced superoxide in mitochondria. This study suggested that both kaempferide and kaempferol exert an antioxidant activity which involved in the neuroprotection against mutant SOD1^G85R-induced toxicity. However, only kaempferol could reduce intracellular aggregate and induced autophagy through adenosine monophosphate- (AMP-) activated protein kinase (AMPK)—the mammalian target of rapamycin (mTOR) pathway. Subsequently, kaempferol inhibited mutant SOD1^G85R-induced toxicity. These results suggested that ethanol extract of Brazilian green propolis as well as kaempferol may have a potential to be neuroprotective agents.

Another study done by Nanaware et al. [81] on the macerated ethanolic extract of Indian propolis in an animal model of Alzheimer’s disease reported that treatment with propolis could reverse the cognitive impairment, inhibit acetylcholinesterase, and increase brain monoamine level as well as improve memory deficits by increasing plasma BDNF level in Aβ (25–35)-induced rats. From this study, it indicated there could be multiple mechanisms of actions participated in the neuroprotection of propolis against Aβ (25–35)-induced neurodegeneration.

In the cerebral ischemia-induced oxidative injury stroke mouse model, water-extracted brown propolis was reported to restore the endogenous enzymatic antioxidant activity and subsequently reduce lipid peroxidation and infarct volume [82]. The treatment with water-extracted brown propolis also improved sensory-motor impairment and neurological deficits [82]. These findings indicated that propolis confers its neuroprotective effect against neuronal oxidative damage following stroke via its antioxidant mechanism which is mediated by the endogenous antioxidant enzyme system.

Taken together, all these findings suggest that propolis displays neuroprotective through multiple pathways which might be attributed by the presence of bioactive compounds in propolis as well as their combination of multitarget compound acting on the different pathways. Several studies have reported on the neuroprotective effect of compounds present in the propolis in various study models of neurodegenerative diseases; for example, kaempferol [80, 83], chrysin [84], pinocembrin [85–96], and caffeic acid phenethyl ester [97–108]. These studies reported and suggested that these bioactive compounds may protect against neurodegenerative characteristics of neurodegenerative diseases and the multiple mechanisms of the neuroprotective effect of compounds tested could be potentially involved. Those suggested mechanisms included counteracting oxidative damage, modulating events associated with apoptosis, inhibiting glial activation, and suppressing the production of proinflammatory mediators as well as improving the cognitive impairment and motor performances.

3.3. Withania somnifera

Withania somnifera, commonly known as Indian ginseng or Ashwagandha, is an important medicinal plant being used in Ayurveda and belongs to family Solanaceae. It is a perennial herb covered with hairs. The characterization of phytochemicals has revealed the presence of different chemical constituents extracted and isolated from the different parts of Withania somnifera plant, which include steroidal lactones, alkaloids, flavonoids, tannin, withanolides, and several sitoindosides [109].

In an animal model of Parkinson’s disease, study has shown that pretreatment with ethanolic crude extract of Withania somnifera reduced oxidative stress and increased catecholamine content in 6-hydroxydopamine- (6-OHDA-) induced rats [110]. In another animal model of Parkinson’s disease, administration of Withania somnifera root extract improved behavioral alternations of mice in the rotarod test, hang test, and stride length measurement, restored the antioxidant status, and reduced lipid peroxidation as well as increase striatal catecholamine contents in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced mice [111, 112]. In a rotenone-induced mouse model of Parkinson’s disease, Withania somnifera extract restored the reduced glutathione (GSH) level and activity level of antioxidant enzymes, reduced lipid peroxidation, and normalized nitric oxide levels [113]. The extract of Withania somnifera also attenuated the increase of acetylcholinesterase activity and restored dopamine level and mitochondrial electron transport chain enzyme complex activities [113]. Hence, these findings suggested that Withania somnifera extracts reduced oxidative stress and mitochondrial dysfunction and the beneficial role of Withania somnifera extracts seems to be primarily based on its antioxidant property.

In 3-nitropropionic acid-induced Huntington’s like mouse model, administration of Withania somnifera root extracts decreased lipid peroxidation and levels of nitrite and lactate dehydrogenase and restored the antioxidant enzymes levels and adenosine triphosphate (ATP) synthesis as well as attenuated mitochondrial enzyme complex activities in the striatum and cortex of 3-nitropropionic acid-induced rats [114]. This indicated that Withania somnifera root extracts could reduce oxidative stress and mitochondrial dysfunction. Besides, Withania somnifera root extracts improved motor function assessed by locomotor and rotarod tests and improved muscle activity as observed in the rotarod and limb withdraw test [114]. This finding suggested that the neuroprotective action of Withania somnifera could be partly attributed due to its free radical scavenging and antioxidant activities and its ability to decrease the loss of ATP from mitochondria as well as beneficial effect on improving motor performance.

In amyotrophic lateral sclerosis-associated mutant SOD1^G93A-induced mice, Withania somnifera root extract ameliorated the motor performance and delayed the disease progression rate [115]. Besides, the extract reduced misfolded SOD1 species levels and upregulated heat-shock protein in the spinal cord of SOD1^G93A-induced mice [115]. This finding suggested that Withania somnifera root extracts could inhibit SOD1 misfolding through induction of molecular chaperons and reduction of oxidative stress. The extract also attenuated glial activation (glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (Iba-1)) and NF-κB phosphorylation in the spinal cord of SOD1^G93A-induced mice and promoted autophagy [115]. This indicated that the extract could modulate inflammation to minimize neuronal damage through the inhibition of NF-κB activation and thereby induced the activity of autophagy.

In a clinical application, Withania somnifera has shown promising results in a randomized, double-blind, placebo-controlled clinical pilot study in enhancing immediate and general memory and improving cognitive function in adult with mild cognitive impairment [116]. Another randomized, double-blind, placebo-controlled adjunctive study reported that Withania somnifera extract could ameliorate cognitive dysfunction in adults with bipolar disorder [117]. Other than that, a clinical study has suggested that Withania somnifera could improve cognitive and psychomotor performance in healthy human participants [118].

Collectively, the possible mechanism underlying the neuroprotective actions of Withania somnifera could be mediated through several pathways. Several studies have suggested that the protective effect of withanoside IV [119], withanone [120–122], withaferin A [123–125], and withanolide A [126–130] and other compounds as well as the synergistic action of multiple compounds present in Withania somnifera extract could contribute towards beneficial effect of Withania somnifera in the pathogenesis of neurodegenerative diseases.

3.4. Ginseng

Ginseng is a perennial herb belonging to the Panax genus of the Araliaceae family. It has been used as a traditional herbal medicine, especially in China, Korea, and Japan. The most frequently studied ginseng is Panax ginseng C. A. Meyer (Asian ginseng or Korean ginseng) [131]. Ginseng and its chemical constituents have exhibited various beneficial effects, which include antioxidant, anti-inflammatory, antiapoptotic, anticancer, antifatigue, antidiabetic, and antiaging [132–139]. Apart from that, ginseng and its constituents are also known to have a beneficial effect on the central nervous system [140–143]. The major active constituents of ginseng are ginsenosides, which are derivatives of the triterpenoid dammarane. The most extensively investigated ginsenosides are ginsenoside Rb1, Rd, Re, and Rg1 [144, 145].

In an animal model of Parkinson’s disease, Korean red ginseng could improve the behavioral impairment of mice in the pole test, inhibit dopaminergic neuronal death, and decrease cyclin-dependent kinase 5 (Cdk5) and p25 expressions as well as increase p35 expression in the substantia nigra and striatum of MPTP-induced mice [146]. Further study was done by the same group reporting that Korean red ginseng restored the MPTP-induced proteomic changes in the striatum [147]. These changes were related to the energy metabolism, oxidative phosphorylation, and neurodegenerative diseases. A separate study done by the same group reported that Korean red ginseng also alleviated the protein expression profile in the substantia nigra that involved in the neuronal development and energy metabolism for the neuronal survival as well as neuroprotection [148]. Meanwhile, in the cellular model, Korean red ginseng treatment inhibited 1-methyl-4-phenylpyridinium ion- (MPP⁺-) induced apoptosis on rat pheochromocytoma (PC12) cells by preventing the decrease of cell viability and apoptosis and decreasing mRNA expressions of caspase-3 and caspase-9 [149]. Furthermore, this group also reported that Korean red ginseng treatment alleviated behavioral dysfunction induced by MPTP and enhanced differentiation and proliferation of endogenous neural stem cells in the subventricular zone of MPTP-induced mice [150].

Another research group [151] has reported that administration of Korean red ginseng attenuated MPTP-induced locomotor impairment assessed in the pole test, rotarod test, and nest-building behavior test which was correlated to the reduction of MPTP-induced nigrostriatal dopaminergic neuronal damage [151]. In addition, Korean red ginseng extracts attenuated apoptosis, inhibited microglia and astrocyte activation, and suppressed proinflammatory modulator expressions in the substantia nigra and striatum after MPTP induction. Pretreatment with Korean red ginseng also decreased phosphorylation of extracellular signal-regulated kinase (ERK), Jun-N-terminal kinase (JNK), and p38 protein as well as inhibited blood-brain barrier disruption [151]. Moreover, Korean red ginseng extract increased nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression and consequently increased mRNA expressions of enzymes heme oxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) quinone oxidoreductase-1 (NQO1), and gamma-glutamate cysteine ligase regulatory subunit (GLCs) [151]. These findings suggested the Korean red ginseng could reduce motor deficits and protect dopaminergic neurons against MPTP-induced neurotoxicity possibly through antiapoptotic, antioxidant effect by the activation of Nfr2 pathways and anti-inflammation by inhibition of mitogen-activated protein kinases (MAPKs) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways and maintaining the integrity of blood-brain barrier as well as suppression of overexpression of Cdk5 and cleavage of p35 to p25 in the nigrostriatal system of MPTP-induced mice.

The study done by Hu et al. [152] reported that water extract of Panax ginseng C. A. Meyer protected neuronal cell, prevented the cellular morphological deterioration, reduced DNA fragmentation and percentage of apoptotic cells as well as attenuated the induction of Bax/Bcl-2 ratio, cytosolic cytochrome-c, and cleaved caspase-3 in MPP⁺-induced cytotoxicity in SH-SY5Y cells, indicating the protective effect of ginseng extract against apoptosis. The extract also inhibited the accumulation of intracellular Ca²⁺ and the production of intracellular ROS generation in MPP⁺-induced cytotoxicity in SH-SY5Y cells [152], suggesting the suppression of oxidative stress by the ginseng extract. These findings suggested that water extract of Panax ginseng C. A. Meyer exerts its protective effect against MPP⁺-induced apoptosis and cytotoxicity possibly through its antioxidant property and antiapoptotic activity by suppressing ROS generation and oxidative stress and inhibiting mitochondria-dependent apoptotic pathway [152].

In an animal model of Huntington’s disease, pretreatment with Korean red ginseng extract improved neurological impairment and striatal neuronal cell loss in 3-nitropropionic acid-induced Huntington’s-like mice [153]. Furthermore, Korean red ginseng extract also inhibited microglial activation (Iba-1 immunoreactivity and mRNA expression of OX-42) and proinflammatory mediators (iNOS, IL-1β, IL-6, and TNF-α) mRNA expressions as well as increased the activation of p38, JNK, ERK MAPKs, and NF-κB signaling pathways in striatum of 3-nitropropionic acid-induced Huntington’s-like mice [153]. This finding suggested that Korean red ginseng attenuated 3-nitropropionic acid-induced striatal neurotoxicity possible through anti-inflammatory activity by inhibiting activation of MAPKs and NF-κB signaling pathways and activation of microglial as well as expression of proinflammatory mediators in the striatum.

In an acute autoimmune encephalomyelitis animal model of multiple sclerosis, pretreatment with Korean red ginseng mitigated spinal demyelination, reduced the microglial Iba-1 immunoreactivity of white matter, and suppressed the mRNA expressions of the inflammatory mediators and neurotoxic factors in the spinal cord of experimental autoimmune encephalomyelitis-induced rats [154]. Pretreatment with Korean red ginseng extract also reduced the protein expression levels of p-p38 MAPK and NF-κB/p65 [154]. Hence, this indicated that Korean red ginseng extracts alleviated demyelination in the spinal cord of experimental autoimmune encephalomyelitis-induced rats by inhibiting the phosphorylation of p38 MAPK and NF-κB signaling pathways.

In rat model of Alzheimer’s disease, extract of Panax ginseng has been reported to enhance learning and memory ability, reduce oxidative damage, and inhibit the receptors for advanced glycation end product (RAGE) and NF-κB expressions in the cortex and hippocampus of advanced glycation end product- (AGE-) induced rats [155]. According to a study on fermented ginseng [156], treatment with fermented Panax ginseng extract ameliorated memory impairment in scopolamine-induced amnesia ICR mice as well as in transgenic mice and reduced accumulation of Aβ42 protein in the brain of transgenic mice. This indicated that Panax ginseng improved cognitive impairment and mitigated Alzheimer’s disease-like pathophysiological changes through downregulating RAGE and thus inhibiting NF-κB activation.

Taken together, these findings indicated that ginseng exhibits its neuroprotective properties and improves cognitive and motor functions through various mechanisms. This could be due to the presence of bioactive compound ginsenosides in ginseng. Several studies have reported on the neuroprotective effect of ginsenosides, particularly ginsenosides Rg1, in various neurodegeneration models [157–169]. The neuroprotective effects of these compounds may have been mediated by antiapoptotic, antioxidant, and anti-inflammatory properties, modulating events associated with apoptosis, inhibiting mitochondrial dysfunction well as improving the cognitive impairment and motor performances.

In the clinical application, the clinical efficacy of Panax ginseng was reported to enhance the cognitive performances in patients with Alzheimer’s disease in an open-label study [170]. For the bioactive compounds in ginseng, the pharmacokinetics and safety profile of ginsenoside Rd has been evaluated and reported to have a favorable pharmacokinetics and safety profile in healthy adults [171]. Moreover, the efficacy and safety of ginsenoside Rd for acute ischemic stroke were evaluated in randomized, double-blind, placebo-controlled, phase II, multicenter trial study [172]. They reported that ginsenoside Rd may have some potential benefit, partly improved neurological deficits in patients with acute ischemic stroke [172]. Further study on the effectiveness of ginsenoside Rd for acute ischemic stroke was performed and the study reported ginsenoside Rd improved the primary outcomes of acute ischemic stroke and did not promote severe adverse event profile [173].

3.5. Uncaria rhynchophylla

Uncaria rhynchophylla, which belongs to family Rubiaceae, is a medicinal herb used in the traditional Chinese medicine. Active components found in the extract of Uncaria rhynchophylla are the alkaloids, which are rhynchophylline, isorhynchophylline, hirsutine, hirsuteine, corynanthine, corynoxine, and dihydrocorynantheine [174, 175]. Among these alkaloids, rhynchophylline and isorhynchophylline are the most widely studied and have been known as neuroprotective compounds [176].

In kainic acid-induced excitotoxicity rat model, Uncaria rhynchophylla extract exhibited free radical scavenging activity and suppressed lipid peroxidation [177, 178]. Uncaria rhynchophylla also has been reported to exhibit protection against kainic acid-induced neuronal damage, the reduction of microglial activation, neuronal nitric oxide synthase (nNOS), iNOS, and apoptosis [179], and the attenuation of GFAP and S100 calcium-binding protein B (S100B) expressions [180, 181] in the hippocampal region. Pretreatment with Uncaria rhynchophylla extract before kainic acid administration also has increased the survival of neurons and reduced the epileptiform discharges in the hippocampus [180]. In the experimental model of global ischemia, Uncaria rhynchophylla methanol extract inhibited COX-2 mRNA and protein levels in the hippocampus of rat and inhibited TNF-α and nitric oxide levels in BV-2 microglial cell [182]. Moreover, Uncaria rhynchophylla inhibited the formation of Aβ fibrils and also dissembled preformed Aβ fibrils in Aβ (1–40)- and Aβ (1–42)-induced toxicity of Alzheimer’s disease model [183].

The neuroprotective effect of Uncaria rhynchophylla has been also reported in Parkinson’s disease experimental model. Shim et al. [184] reported that Uncaria rhynchophylla reduced neuronal cell death and ROS generation, restored the GSH level, and prevented the caspase-3 activity in 6-OHDA-induced toxicity in PC12 cells as well as reduced neuronal loss in dopaminergic neurons in the substantia nigra in 6-OHDA-induced rats. This finding was supported by the study done by Pal and Kumar [185] that demonstrated that Uncaria rhynchophylla exhibited anti-Parkinson’s activity in 6-OHDA rat model. In another model of Parkinson’s disease, Uncaria rhynchophylla has been reported to increase cell viability, attenuate dopaminergic neuronal loss of substantia nigra and striatum, inhibit heat-shock protein 90 and apoptosis, and thereby induce autophagy through MAPKs and PI3K-serine/threonine protein kinase (Akt) pathways in MPP⁺-induced SH-SY5Y cells and MPTP-induced mouse model [186].

Taken together, all these findings suggest that Uncaria rhynchophylla display neuroprotective action in protecting neuronal damage through multiple pathways which could be due to the beneficial effect of active compounds as well as the combination effect of those compounds present in Uncaria rhynchophylla. Several studies have reported on the neuroprotective effect of alkaloid in Uncaria rhynchophylla such as hirsutine [187], rhynchophylline [188–191], and isorhynchophylline [192–195]. These compounds exert antioxidant effect by reducing ROS generation and enhancing the antioxidant defense system, anti-inflammatory effect by inhibiting the production of inflammatory mediators and antiapoptotic effect by modulating the event associated with apoptosis and inhibiting caspase activation, and behavioral effect on cognitive functions.

3.6. Marine Macroalgae (Seaweeds)

Marine macroalgae, commonly known as seaweeds, are plant-like organisms that generally live in coastal areas. They can be divided into three groups based on their colors, which are brown algae (Phaeophyceae), red algae (Rhodophyceae), and green algae (Chlorophyceae) [196]. Their colors are associated with the presence of different phytopigments in algae: chlorophyll is for green algae, phycobilin is for red algae, and fucoxanthin for brown algae [197]. They contain diverse bioactive compounds which include phenolic compounds, protein, peptides, amino acids, pigments, and phenols [198]. Several studies have reported the health beneficial effect of algae as well as the bioactive compounds of different algae [196, 198, 199].

Eisenia bicyclis (Kjellman) Setchell, a perennial brown alga, belongs to the Laminariaceae family. This species contains several bioactive compounds, including phlorotannins, polysaccharides, pyropheophytin, sterol, lipids, tripeptides, and oxylipins. Ahn et al.’s study [200] has investigated the neuroprotective effect of Eisenia bicyclis methanol extract and its soluble fractions together with the isolated phlorotannins on Aβ (25–35)-induced cytotoxicity in PC12 cells. In this study, six phlorotannins were isolated from ethyl acetate fraction of Eisenia bicyclis methanol extract which were phloroglucinol, dioxinodehydroeckol, eckol, phlorofucofuroeckol A, dieckol, and 7-phloroeckol [200]. The study also reported that the neuroprotective activity of Eisenia bicyclis methanol extract and its subfractions ethyl acetate and n-butanol fractions together with the isolated phlorotannins from ethyl acetate fraction was due to their ability to reduce intracellular ROS production in Aβ (25–35)-induced cytotoxicity in PC12 cells [200]. In addition, the isolated phlorotannins eckol, phlorofucofuroeckol A, and 7-phloroeckol exert their neuroprotective effect through suppression of intracellular ROS production and restoring intracellular Ca²⁺ level in Aβ (25–35)-induced cytotoxicity in PC12 cells [200]. This study clearly demonstrated that Eisenia bicyclis and its isolated phlorotannins attenuated oxidative damage and neuronal cell death in Aβ (25–35)-induced cytotoxicity in PC12 cells.

Silva et al. [201] have investigated the neuroprotective effect of several seaweeds in 6-OHDA-induced toxicity in SH-SY5Y cells which included Padina pavonica, Sargassum muticum, Saccorhiza polyschides, Codium tomentosum, and Ulva compressa. The study reported that seaweed extracts had increased the cell viability, reduced oxidative stress, protected mitochondrial membrane potential, and reduced caspase-3 activity. This finding indicated that these seaweeds exert their neuroprotective effects through antioxidant activity and antiapoptotic property. Silva et al. [201] suggested that this neuroprotection action could be mediated by the presence of antioxidant compounds in the seaweed extracts. The same research group has also reported the neuroprotective effect of several fractions obtained from brown seaweed, Bifurcaria bifurcata (belongs to Sargassaceae family) against 6-OHDA-induced toxicity in SH-SY5Y cells [202]. Fraction F4 obtained from Bifurcaria bifurcata was reported to exhibit the best neuroprotective effect by protecting mitochondrial membrane potential, reducing hydrogen peroxide production, and inhibiting apoptosis through caspase-3 activity. The authors suggested that this effect could be attributed by the presence of bioactive compounds like eleganolone and eleganonal, which could act on multiple targets through different mechanisms of actions.

Another brown seaweed, Ishige foliacea belongs to the Ishigeaceae family and has known to contain polyphenolic compound known as phlorotannin. Heo et al.’s study [203] has reported that a specific phlorotannin, diphlorethohydroxycarmalol, isolated from Ishige foliacea, increased cell viability and prevented cells from damage induced by hydrogen peroxide in murine hippocampal neuronal cells (HT22). Diphlorethohydroxycarmalol also reported to inhibit caspase-3, caspase-9, and poly (ADP-ribose) polymerase (PARP) cleavage and decrease ROS generation as well as inhibit lipid peroxidation and intracellular Ca²⁺ levels [203]. Another study done by Um et al. [204] demonstrated the effect of phlorotannin-rich fraction from Ishige foliacea in scopolamine-induced memory impairment in mice model. The study reported that it improved memory impairment in mice, reduced brain acetylcholinesterase activity, upregulated the protein expression level of BDNF and tropomyosin-related kinase receptor type B (TrkB), and suppressed oxidative stress by decreasing lipid peroxidation level and increasing the GSH level and superoxide dismutase activity as well as increased the phosphorylation levels of cyclic AMP responsive element binding protein (CREB) and ERK in the cerebral cortex and hippocampus [204]. All these above findings suggested that marine algae display neuroprotective action in protecting neuronal damage and improving memory impairment through multiple pathways which might be attributed due to their bioactive compounds as well as the synergistic effect of these compounds.

Recently, sulfated polysaccharides isolated from marine algae have attracted the interest of scientists for their potential use in pharmaceutical application, mainly in the design of novel drug delivery system [205–208]. Various studies have reported the biological activities of sulfated polysaccharides. Major sulfated polysaccharides found in marine algae include fucoidan from brown seaweed, ulvan from green seaweed, and carrageenan from red seaweed. Several studies have reported on the neuroprotective effect of fucoidan in various neurodegeneration models [209–214]. Luo et al.’s study [209] demonstrated that fucoidan, isolated from Laminaria japonica, attenuated MPTP-induced locomotor activity deficits, prevented depletion of striatal dopamine and its metabolite, dihydroxyphenylacetic acid (DOPAC) level, reduced loss of dopaminergic neurons and tyrosine hydroxylase protein expression, and attenuated the increase of lipid peroxidation level and decreases of antioxidant enzyme activities as well as total antioxidant capacity in the substantia nigra pars compacta of MPTP-induced mice. Fucoidan also protected against MPP⁺-induced neurotoxicity in MN9D cells [209]. In the 6-OHDA rat model of Parkinson’s disease, fucoidan from Laminaria japonica also reduced the dopaminergic neuronal loss in the substantia nigra pars compacta and dopaminergic fibers, inhibited the increase of NADPH oxygenase-1 (NOX1), oxidative stress, and microglial activation in the substantia nigra pars compacta, and attenuated motor dysfunction in 6-ODHA-induced rats [210]. In another rat model of Parkinson’s disease, fucoidan from Laminaria japonica alleviated Parkinson’s disease-like behaviors, reduced nigral dopaminergic neuronal loss and oxidative stress, prevented the reduction on dopamine and its metabolites, and enhanced mitochondrial respiratory function through the peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α)/Nrf2 pathway in rotenone-induced rats [211].

Another fucoidan, isolated from Fucus vesiculosus, inhibited the disruption of mitochondrial membrane potential and attenuated lipid peroxidation and the decrease of glutathione/glutathione disulfide ration as well as the activities of caspase-3/caspase-7 in 6-OHDA-induced neurotoxicity in SH-SY5Y cells [214]. Meanwhile, fucoidan from Undaria pinnatifida improved cell viability, prevented apoptosis through inhibition of caspase-3 activation, and enhanced the antioxidant dense system through superoxide dismutase activity and GSH content, in Aβ (25–35)- and D-galactose-induced neurotoxicity in PC12 cells [212]. This fucoidan from Undaria pinnatifida also regulated cholinergic system, ameliorated spatial learning and memory impairment, improved antioxidant capacity, and decreased Aβ deposition, as well as maintained the density and shape of hippocampus CA1 neurons in D-galactose-induced mice [212]. These findings were supported by the recent study done by Alghazwi et al. [213] that demonstrated the neuroprotective activities of fucoidans from Fucus vesiculosus and Undaria pinnatifida against Aβ (1–42)-induced and hydrogen peroxide-induced cytotoxicity in PC12 cells. These fucoidans decreased Aβ (1–42) aggregation, decreased Aβ (1–42) aggregation, reduced Aβ (1–42)-induced and hydrogen peroxide-induced cytotoxicity in PC12 cells, and reduced Aβ (1–42)-induced apoptosis and enhanced neurite outgrowth activity [213].

3.7. Cyanobacteria

Cyanobacteria, commonly known as blue-green alga, are prokaryotic, photosynthetic, autotrophic organisms closely related to bacteria. They have gained many attentions from researchers for its possible pharmacological properties and therapeutic effects on various medical conditions [199, 215–218]. Spirulina platensis, a cyanobacterium belonging to the Oscillatoriaceae family, is a planktonic multicellular filamentous, alkaliphilic cyanobacterium. It has been widely studied and known to have abundant nutritive elements. Spirulina platensis contains protein, polyunsaturated fatty acids, carotenoids, polysaccharides, vitamins, and minerals [219]. In a study [220], a polysaccharide derived from Spirulina platensis could attenuate the reduction in the immunoreactivity and mRNA expressions of tyrosine hydroxylase and dopamine transporter in the substantia nigra and attenuate the decrease in the dopamine levels and the increase in dopamine metabolism rate as well as increase the antioxidant enzyme activities such as superoxide dismutase and glutathione peroxidase in the serum and midbrain of mice with MPTP-induced Parkinson’s disease. Subsequently, it could protect against MPTP-induced dopaminergic neuronal loss in the substantia nigra. However, no significant change was observed on the monoamine oxidase B activity in the serum and midbrain of mice with MPTP-induced Parkinson’s disease study [220]. This evidence indicated that polysaccharide derived from Spirulina platensis exhibited its neuroprotective effect on dopaminergic neurons and dopamine levels through antioxidant mechanism, but not through the inhibition of monoamine oxidase B.

In another study using 6-OHDA-induced Parkinson’s disease rat model [221], Spirulina platensis attenuate the depletion of striatal dopamine and its metabolite and the increase of nitrite and lipid peroxidation levels as well as reduce the apomorphine-induced rotational behavior. In addition, the authors also reported that Spirulina platensis also blocked the reduction of immunoreactivity of tyrosine hydroxylase and dopamine transporter and reduced the increase of the immunoreactivity of iNOS and COX-2 in the striatal of 6-OHDA-induced rats [221]. From this study, it indicated that Spirulina platensis presented potent anti-inflammatory and antioxidant activities which contribute to its neuroprotective actions against 6-OHDA-induced Parkinson’s disease.

Bermejo-Bescós et al.’s study [222] has reported that Spirulina platensis protean extract and the biliprotein phycocyanin isolated from the extract attenuate the decrease in cell survival and the increase of oxidative stress in SH-SY5Y cells against iron-induced toxicity. The same study also indicated that Spirulina platensis protean extract and phycocyanin exhibited its protection against iron-induced toxicity by increasing the GSH level and the enzymes activities in the glutathione metabolism pathway and decreasing the lipid peroxidation level as well as scavenging ROS [222]. Thus, this finding suggested that Spirulina platensis protean extract, a potent antioxidant which acts through a mechanism related to its antioxidant activity, has the chelating capability and free radical scavenging property, thereby protecting cells against radical-mediated cell death. This protective effect could be also contributed by the presence of the biliprotein C-phycocyanin [222, 223]. The protective effect of Spirulina platensis and C-phycocyanin was further expanded by the study [224] that demonstrated Spirulina platensis water extract and its active compound C-phycocyanin reduced cytotoxicity and inhibited the inflammation-related gene expressions (COX-2, TNF-α, IL-6, and iNOS) of BV-12 microglial cells induced by lipopolysaccharides.

Another cyanobacterium, Spirulina maxima, belonging to the Oscillatoriaceae family, has been known to have many physiologically active substances such as carotenoids, chlorophylls, polysaccharides, vitamins, and C-phycocyanin [225, 226]. In mouse model of Alzheimer’s disease induced by Aβ (1–42), Spirulina maxima extract ameliorated learning and memory impairments in Aβ (1–42)-induced mice (assessed using the passive avoidance and Morris water maze tests), decreased the protein expression levels of hippocampal Aβ (1‐42), amyloid precursor protein (APP), and β-site APP cleaving enzyme 1 (BACE1) and attenuated the increase in acetylcholinesterase activity in the hippocampal oxidative stress of Aβ (1–42)-induced mice [227]. These findings indicated that Spirulina maxima extract ameliorated cognitive impairment through the inhibition of Aβ accumulation and acetylcholinesterase activity. Spirulina maxima extract also suppressed hippocampal oxidative stress of Aβ (1–42)-induced mice through enhancing the antioxidant system in the glutathione metabolism pathway by increasing the GSH level and attenuating the decrease of glutathione peroxidase and glutathione reductase protein expression levels [227]. This suggested that the inhibition of Aβ accumulation and acetylcholinesterase activity by Spirulina maxima extract could contribute to the suppression of oxidative stress. Moreover, Spirulina maxima extract increased the BDNF level, upregulated the phosphorylated PI3K and the phosphorylated Akt, and suppressed the phosphorylated glycogen synthase kinase-3β (GSK3β) in the hippocampal oxidative stress of Aβ (1–42)-induced mice [227]. Therefore, these findings suggested that Spirulina maxima extract inhibited the phosphorylation of hippocampal glycogen synthase kinase-3β through the activation of BDNF/PI3K/Akt signaling pathways. This could contribute to the inhibition of APP processing by regulating BACE1 protein and thereby ameliorate the cognitive impairment in Aβ (1–42)-induced mice.

Another study had demonstrated that the extract of Spirulina maxima could also prevent Aβ-induced oxidative stress and cell death through suppression of PARP cleavage, elevation of GSH levels, and upregulation of antioxidant enzymes and increasing cell viability death as well as reducing cytotoxicity in Aβ (1–42)-induced toxicity in PC12 cells [228]. Furthermore, Spirulina maxima extract increased the expression of BDNF and decreased the expressions of APP and BACE1 [228]. The same study also reported the protective effect of C-phycocyanin and chlorophylls against Aβ (1–42)-induced oxidative stress and cell death in PC12 cells, reporting a similar result was observed as Spirulina maxima extract [228]. Therefore, this study indicated that Spirulina maxima extract confers its neuroprotection action against Aβ-induced oxidative stress and cell death in PC12 cells by promoting the activation of the BDNF pathway. This could be attributed due to the presence of active compounds such as C-phycocyanin and chlorophylls as well as the synergistic effect of all active compounds present in the extract.

In animal model of Parkinson’s disease, Spirulina maxima partially enhanced the content of dopamine and blocked lipid peroxidation in the striatum in MPTP-induced mice [229]. In another study using 6-OHDA-induced Parkinson’s disease rat model, administration of Spirulina maxima improved locomotor activity, decreased 6-OHDA-induced rotational behavior, ROS generation, and nitric oxide level, inhibited the lipid peroxidation and mitochondrial dysfunction in the rat striatum, and prevented the striatal dopamine depletion of 6-OHDA-induced rats [230]. In kainic acid-induced excitotoxicity animal model, Spirulina maxima also reduced lipid peroxidation and the damaging neurobehavioral effect of kainic acid by preventing the spatial memory damage assessed by Morris water maze test [231]. Other study has reported that Spirulina maxima extract ameliorated scopolamine-induced memory impairment in mice [232, 233]. These findings indicated that Spirulina maxima exerts its neuroprotective effect through antioxidant activity.

Collectively, these studies indicated that Cyanobacteria display neuroprotective action against neurodegeneration through multiple mechanisms of actions, mainly through antioxidant activity. This could be attributed due to the presence of active compounds such as phycocyanin, carotenoids, and chlorophylls as well as the synergistic effect of all active compounds present in Cyanobacteria.

3.8. Other Natural Products

There were many other natural products that have been investigated for their neuroprotection potentials against neurodegeneration. A summary of natural products and their bioactive compounds with different neuroprotective activities according to the treating disease is presented in Tables 1–4.

4. Challenges, Limitations, and Recommendations for Future Research

Natural products and their isolated natural compounds have potentials to be neuroprotective and therapeutic agents as well as valuable resource for drug discovery against various neurodegenerative diseases. However, despite their promising neuroprotective activities against neurodegenerative diseases in the preclinical setting, translation of promising preclinical neuroprotective research to clinical application has proven challenging as there are no positive results in human clinical trials of neurodegenerative diseases.

There are a few challenges and limitations about natural products and their isolated natural compounds that could affect their clinical efficacy, which are their low bioavailability and limited water solubility, their physicochemical instability, their rapid metabolism, and their ability to cross blood-brain barrier. Further explanation could be reviewed in these literature studies [282–289]. Several natural compounds, for example, tea catechins [288, 290], resveratrol [287], and curcumin [282, 291–293], have been reported to show low bioavailability and limited stability as these natural compounds are sensitive to the degradation or transformation to inactive derivates [294, 295]. Consequently, this will limit their effectiveness. Moreover, the presence of the blood-brain barrier limits the natural compounds to access to the brain and to reach the action site. Subsequently, this will constrain the distribution to the brain tissues and lead to the low bioavailability.

To overcome these issues, the use of nanotechnology and nanocarrier-based approaches in the delivery of natural products and their isolated compounds may help and improve the therapeutic responses and enhance their effectiveness [296–302]. The incorporation of nanoparticle in the delivery system can increase the bioavailability of natural products and their compounds. The most common types of nanoparticle used are polymeric nanoparticles, nanogels, solid lipid nanoparticle, crystal nanoparticle, liposomes, micelles, and complexes with dendrimers. There have been several studies reported on the use of nanoparticle with natural products and their compound, for example, epigallocatechin-3-gallate for the treatments of Alzheimer’s disease [302], rosmarinic acid in the management of Huntington’s disease [303], and curcumin for brain disease [304].

5. Conclusion

The neuroprotective potentials of natural products and natural bioactive compounds against neurodegenerative diseases were supported by various experimental studies. Natural products and their important bioactive compounds are necessary to prevent and treat various neurodegenerative diseases without harmful side effects. Since the multifactorial involved in the pathological process of neurodegeneration, multiple mechanisms of actions involved are important toward neuroprotection strategies for the prevention and therapeutic of neurodegenerative diseases. Natural products and their bioactive compounds with the multiple mechanisms of actions in exhibiting their neuroprotective effects are preferable. Furthermore, the factor of having the ability to cross blood-brain barrier also plays an important role in the neuroprotective action of natural products and their bioactive compounds. Therefore, the development of new approaches/strategies, such as the application of nanotechnology in the delivery of natural products and compounds, that help to promote the access of neuroprotective to the brain, is needed to boost more neuroprotection action of natural products and their bioactive compounds for the prevention and therapeutic of neurodegenerative diseases.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

The authors acknowledge Universiti Sains Malaysia (USM) for the grants awarded (USM Research University Grant account nos. 1001/PPSP/811203 and 1001/PPSP/8012249).

References

1. A. Yildiz-Unal, S. Korulu, and A. Karabay, “Neuroprotective strategies against calpain-mediated neurodegeneration,” Neuropsychiatric Disease and Treatment, vol. 11, pp. 297–310, 2015. View at: Publisher Site | Google Scholar
2. S. Przedborski, M. Vila, and V. Jackson-Lewis, “Series introduction: neurodegeneration: what is it and where are we?” Journal of Clinical Investigation, vol. 111, no. 1, pp. 3–10, 2003. View at: Publisher Site | Google Scholar
3. H.-M. Gao and J.-S. Hong, “Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression,” Trends in Immunology, vol. 29, no. 8, pp. 357–365, 2008. View at: Publisher Site | Google Scholar
4. S. M. Allan and N. J. Rothwell, “Cytokines and acute neurodegeneration,” Nature Reviews Neuroscience, vol. 2, no. 10, pp. 734–744, 2001. View at: Publisher Site | Google Scholar
5. A. Mehta, M. Prabhakar, P. Kumar, R. Deshmukh, and P. L. Sharma, “Excitotoxicity: bridge to various triggers in neurodegenerative disorders,” European Journal of Pharmacology, vol. 698, no. 1–3, pp. 6–18, 2013. View at: Publisher Site | Google Scholar
6. K. A. Jellinger, “Basic mechanisms of neurodegeneration: a critical update,” Journal of Cellular and Molecular Medicine, vol. 14, no. 3, pp. 457–487, 2010. View at: Google Scholar
7. E. Salińska, W. Danysz, and J. W. Łazarewicz, “The role of excitotoxicity in neurodegeneration,” Folia Neuropathologica, vol. 43, no. 4, pp. 322–339, 2005. View at: Google Scholar
8. A. M. Gorman, “Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling,” Journal of Cellular and Molecular Medicine, vol. 12, no. 6a, pp. 2263–2280, 2008. View at: Publisher Site | Google Scholar
9. A. Singh, R. Kukreti, L. Saso, and S. Kukreti, “Oxidative stress: a key modulator in neurodegenerative diseases,” Molecules, vol. 24, p. 8, 2019. View at: Publisher Site | Google Scholar
10. G. Cenini, A. Lloret, and R. Cascella, “Oxidative stress in neurodegenerative diseases: from a mitochondrial point of view,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 2105607, 18 pages, 2019. View at: Publisher Site | Google Scholar
11. Z. Liu, T. Zhou, A. C. Ziegler, P. Dimitrion, and L. Zuo, “Oxidative stress in neurodegenerative diseases: from molecular mechanisms to clinical applications,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 2525967, 11 pages, 2017. View at: Google Scholar
12. T. Chitnis and H. L. Weiner, “CNS inflammation and neurodegeneration,” Journal of Clinical Investigation, vol. 127, no. 10, pp. 3577–3587, 2017. View at: Publisher Site | Google Scholar
13. W.-W. Chen, X. Zhang, and W.-J. Huang, “Role of neuroinflammation in neurodegenerative diseases (review),” Molecular Medicine Reports, vol. 13, no. 4, pp. 3391–3396, 2016. View at: Publisher Site | Google Scholar
14. C. K. Glass, K. Saijo, B. Winner, M. C. Marchetto, and F. H. Gage, “Mechanisms underlying inflammation in neurodegeneration,” Cell, vol. 140, no. 6, pp. 918–934, 2010. View at: Publisher Site | Google Scholar
15. J. Fan, T. M. Dawson, and V. L. Dawson, “Cell death mechanisms of neurodegeneration,” in Neurodegenerative Diseases: Pathology, Mechanisms, and Potential Therapeutic Targets, P. Beart, M. Robinson, M. Rattray et al., Eds., pp. 403–425, Springer International Publishing, Berlin, Germany, 2017. View at: Google Scholar
16. M. P. Mattson, “Excitotoxicity,” in Neurodegeneration, A. Schapira, Z. Wszolek, T. M. Dawson et al., Eds., Wiley Online Library, Hoboken, NJ, USA, 2017. View at: Google Scholar
17. K. A. Jellinger, “General aspects of neurodegeneration,” Advances in Research on Neurodegeneration, no. 65, Springer, Berlin, Germany, 2003. View at: Publisher Site | Google Scholar
18. L. G. Apostolova, “Alzheimer disease,” Continuum: Lifelong Learning in Neurology, vol. 22, no. 2, pp. 419–434, 2016. View at: Publisher Site | Google Scholar
19. T. R. Mhyre, J. T. Boyd, R. W. Hamill, and K. A. Maguire-Zeiss, “Parkinson’s disease,” Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease, vol. 65, pp. 389–455, 2012. View at: Publisher Site | Google Scholar
20. L. C. Wijesekera and P. N. Leigh, “Amyotrophic lateral sclerosis,” Orphanet Journal of Rare Diseases, vol. 4, p. 3, 2009. View at: Google Scholar
21. Y.-T. Hsu, Y.-G. Chang, and Y. Chern, “Insights into GABA A ergic system alteration in Huntington’s disease,” Open Biology, vol. 8, no. 12, p. 180165, 2018. View at: Publisher Site | Google Scholar
22. M. Macdonald, “A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes,” Cell, vol. 72, no. 6, pp. 971–983, 1993. View at: Google Scholar
23. G. Gelders, V. Baekelandt, and A. Van der Perren, “Linking neuroinflammation and neurodegeneration in Parkinson’s disease,” Journal of Immunology Research, vol. 2018, Article ID 4784268, 12 pages, 2018. View at: Publisher Site | Google Scholar
24. J. Leszek, G. E. Barreto, K. G|siorowski, E. Koutsouraki, M. Ávila-Rodrigues, and G. Aliev, “Inflammatory mechanisms and oxidative stress as key factors responsible for progression of neurodegeneration: role of brain innate immune system,” CNS & Neurological Disorders-Drug Targets, vol. 15, no. 3, pp. 329–336, 2016. View at: Publisher Site | Google Scholar
25. M. Fakhoury, “Role of immunity and inflammation in the pathophysiology of neurodegenerative diseases,” Neurodegenerative Diseases, vol. 15, no. 2, pp. 63–69, 2015. View at: Publisher Site | Google Scholar
26. A. M. Estrada Sánchez, J. Mejía-Toiber, and L. Massieu, “Excitotoxic neuronal death and the pathogenesis of huntington’s disease,” Archives of Medical Research, vol. 39, no. 3, pp. 265–276, 2008. View at: Publisher Site | Google Scholar
27. A. Doble, “The role of excitotoxicity in neurodegenerative disease,” Pharmacology & Therapeutics, vol. 81, no. 3, pp. 163–221, 1999. View at: Publisher Site | Google Scholar
28. X.-x. Dong, Y. Wang, and Z.-h. Qin, “Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases,” Acta Pharmacologica Sinica, vol. 30, no. 4, pp. 379–387, 2009. View at: Publisher Site | Google Scholar
29. Q. Wang, S. Yu, A. Simonyi, G. Y. Sun, and A. Y. Sun, “Kainic acid-mediated excitotoxicity as a model for neurodegeneration,” Molecular Neurobiology, vol. 31, no. 1–3, pp. 3–16, 2005. View at: Publisher Site | Google Scholar
30. X. Y. Zheng, H. L. Zhang, Q. Luo, and J. Zhu, “Kainic acid-induced neurodegenerative model: potentials and limitations,” Journal of Biomedicine and Biotechnology, vol. 2011, Article ID 457079, 10 pages, 2011. View at: Publisher Site | Google Scholar
31. I. Ullah, H. Y. Park, and M. O. Kim, “Anthocyanins protect against kainic acid-induced excitotoxicity and apoptosis via ROS-activated AMPK pathway in hippocampal neurons,” CNS Neuroscience & Therapeutics, vol. 20, no. 4, pp. 327–338, 2014. View at: Publisher Site | Google Scholar
32. M. Okouchi, O. Ekshyyan, M. Maracine, and T. Y. Aw, “Neuronal apoptosis in neurodegeneration,” Antioxidants & Redox Signaling, vol. 9, no. 8, pp. 1059–1096, 2007. View at: Publisher Site | Google Scholar
33. S. Ahmed, S. A. Sulaiman, A. A. Baig et al., “Honey as a potential natural antioxidant medicine: an insight into its molecular mechanisms of action,” Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 8367846, 19 pages, 2018. View at: Publisher Site | Google Scholar
34. L. Porcza, C. Simms, and M. Chopra, “Honey and cancer: current status and future directions,” Diseases, vol. 4, no. 4, p. 30, 2016. View at: Publisher Site | Google Scholar
35. S. Bogdanov, T. Jurendic, R. Sieber, and P. Gallmann, “Honey for nutrition and health: a review,” Journal of the American College of Nutrition, vol. 27, no. 6, pp. 677–689, 2008. View at: Publisher Site | Google Scholar
36. O. O. Erejuwa, S. A. Sulaiman, and M. S. A. Wahab, “Honey-a novel antidiabetic agent,” International Journal of Biological Sciences, vol. 8, no. 6, pp. 913–934, 2012. View at: Publisher Site | Google Scholar
37. O. Bobis, D. S. Dezmirean, and A. R. Moise, “Honey and diabetes: the importance of natural simple sugars in diet for preventing and treating different type of diabetes,” Oxidative Medicine and Cellular Longevity, vol. 2018, Article ID 4757893, 12 pages, 2018. View at: Publisher Site | Google Scholar
38. S. Samarghandian, T. Farkhondeh, and F. Samini, “Honey and health: a review of recent clinical research,” Pharmacognosy Research, vol. 9, no. 2, pp. 121–127, 2017. View at: Google Scholar
39. J. Deng, R. Liu, Q. Lu et al., “Biochemical properties, antibacterial and cellular antioxidant activities of buckwheat honey in comparison to manuka honey,” Food Chemistry, vol. 252, pp. 243–249, 2018. View at: Publisher Site | Google Scholar
40. M. Z. Aumeeruddy, Z. Aumeeruddy-Elalfi, H. Neetoo et al., “Pharmacological activities, chemical profile, and physicochemical properties of raw and commercial honey,” Biocatalysis and Agricultural Biotechnology, vol. 18, Article ID 101005, 2019. View at: Publisher Site | Google Scholar
41. D. W. Ball, “The chemical composition of honey,” Journal of Chemical Education, vol. 84, no. 10, pp. 1643–1646, 1998. View at: Google Scholar
42. J. W. White, “The composition of honey,” Bee World, vol. 38, no. 3, pp. 57–66, 1957. View at: Publisher Site | Google Scholar
43. L. S. Chua and N. A. Adnan, “Biochemical and nutritional components of selected honey samples,” Acta Scientiarum Polonorum Technologia Alimentaria, vol. 13, no. 2, pp. 169–179, 2014. View at: Publisher Site | Google Scholar
44. S. W. Adnan and H. Human, “Bees get a head start on honey production,” Biology Letters, vol. 4, no. 3, pp. 299–301, 2008. View at: Publisher Site | Google Scholar
45. M. Eyer, P. Neumann, and V. Dietemann, “A look into the cell: honey storage in honey bees, Apis mellifera,” PLoS One, vol. 11, no. 8, Article ID e0161059, 2016. View at: Publisher Site | Google Scholar
46. S. Bogdanov, “The book of honey chapter 2: Elaboration and harvest of honey,” 2010, http://www.bee-hexagon.net. View at: Google Scholar
47. N. S. Mohd Sairazi, K. N. S. Sirajudeen, M. A. Asari, S. Mummedy, M. Muzaimi, and S. A. Sulaiman, “Effect of tualang honey against KA-induced oxidative stress and neurodegeneration in the cortex of rats,” BMC Complementary and Alternative Medicine, vol. 17, no. 1, p. 31, 2017. View at: Publisher Site | Google Scholar
48. N. S. M. Sairazi, K. N. S. Sirajudeen, M. Muzaimi, M. Swamy, M. A. Asari, and S. A. Sulaiman, “Tualang honey attenuates kainic acid-induced oxidative stress in rat cerebellum and brainstem,” International Journal of Pharmacy and Pharmaceutical Sciences, vol. 9, no. 12, p. 155, 2017. View at: Publisher Site | Google Scholar
49. N. S. Mohd Sairazi, K. N. S. Sirajudeen, M. Muzaimi, S. Mummedy, M. A. Asari, and S. A. Sulaiman, “Tualang honey reduced neuroinflammation and caspase-3 activity in rat brain after kainic acid-induced status epilepticus,” Evidence-Based Complementary and Alternative Medicine, vol. 2018, Article ID 7287820, 16 pages, 2018. View at: Publisher Site | Google Scholar
50. B. Al-Rahbi, R. Zakaria, Z. Othman, A. Hassan, Z. I. Mohd Ismail, and S. Muthuraju, “Tualang honey supplement improves memory performance and hippocampal morphology in stressed ovariectomized rats,” Acta Histochemica, vol. 116, no. 1, pp. 79–88, 2014. View at: Publisher Site | Google Scholar
51. B. Al-Rahbi, R. Zakaria, Z. Othman, A. Hassan, and A. H. Ahmad, “The effects of Tualang honey supplement on medial prefrontal cortex morphology and cholinergic system in stressed ovariectomised rats,” International Journal of Applied Research in Natural Products, vol. 7, no. 3, pp. 28–36, 2014. View at: Google Scholar
52. B. Al-Rahbi, R. Zakaria, Z. Othman, A. Hassan, and A. H. Ahmad, “Protective effects of Tualang honey against oxidative stress and anxiety-like behaviour in stressed ovariectomized rats,” International Scholarly Research Notices, vol. 2014, Article ID 521065, 10 pages, 2014. View at: Publisher Site | Google Scholar
53. K. Azman, Z. Othman, R. Zakaria, C. AbdAziz, and B. Al-Rahbi, “Tualang honey improves memory performance and decreases depressive-like behavior in rats exposed to loud noise stress,” Noise and Health, vol. 17, no. 75, pp. 83–89, 2015. View at: Publisher Site | Google Scholar
54. K. F. Azman, R. Zakaria, Z. Othman, and C. B. Abdul Aziz, “Neuroprotective effects of Tualang honey against oxidative stress and memory decline in young and aged rats exposed to noise stress,” Journal of Taibah University for Science, vol. 12, no. 3, pp. 273–284, 2018. View at: Publisher Site | Google Scholar
55. K. F. Azman, R. Zakaria, C. B. Abdul Aziz, and Z. Othman, “Tualang honey attenuates noise stress-induced memory deficits in aged rats,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 1549158, 11 pages, 2016. View at: Publisher Site | Google Scholar
56. A. K. Saxena, H. P. Phyu, I. M. Al-Ani, and P. Oothuman, “Improved spatial learning and memory performance following Tualang honey treatment during cerebral hypoperfusion-induced neurodegeneration,” Journal of Translational Science, vol. 2, no. 5, pp. 264–271, 2016. View at: Google Scholar
57. S. P. Tang, S. Kuttulebbai Nainamohamed Salam, H. Jaafar, S. H. Gan, M. Muzaimi, and S. A. Sulaiman, “Tualang honey protects the rat midbrain and lung against repeated paraquat exposure,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 4605782, 12 pages, 2017. View at: Publisher Site | Google Scholar
58. M. A. Kamarulzaidi, M. Y. Z. M. Yusoff, A. M. Mohamed, and D. S. Hasan Adli, “Tualang honey consumption enhanced hippocampal pyramidal count and spatial memory performance of adult male rats,” Sains Malaysiana, vol. 45, no. 2, pp. 215–220, 2016. View at: Google Scholar
59. Z. Othman, N. Shafin, R. Zakaria, N. H. N. Hussain, and W. M. Z. W. Mohammad, “Improvement in immediate memory after 16 weeks of tualang honey (Agro Mas) supplement in healthy postmenopausal women,” Menopause, vol. 18, no. 11, pp. 1219–1224, 2011. View at: Publisher Site | Google Scholar
60. M. I. Khalil, N. Alam, M. Moniruzzaman, S. A. Sulaiman, and S. H. Gan, “Phenolic acid composition and antioxidant properties of Malaysian honeys,” Journal of Food Science, vol. 76, no. 6, pp. C921–C928, 2011. View at: Publisher Site | Google Scholar
61. L. S. Chua, N. L. A. Rahaman, N. A. Adnan, and T. T. Eddie Tan, “Antioxidant activity of three honey samples in relation with their biochemical components,” Journal of Analytical Methods in Chemistry, vol. 2013, Article ID 313798, 8 pages, 2013. View at: Publisher Site | Google Scholar
62. S. Ahmed and N. H. Othman, “Review of the medicinal effects of tualang honey and a comparison with manuka honey,” The Malaysian Journal of Medical Sciences, vol. 20, no. 3, pp. 6–13, 2013. View at: Google Scholar
63. M. Mijanur Rahman, S. H. Gan, and M. I. Khalil, “Neurological effects of honey: current and future prospects,” Evidence-Based Complementary and Alternative Medicine, vol. 2014, Article ID 958721, 13 pages, 2014. View at: Publisher Site | Google Scholar
64. J. P. E. Spencer, K. Vafeiadou, R. J. Williams, and D. Vauzour, “Neuroinflammation: modulation by flavonoids and mechanisms of action,” Molecular Aspects of Medicine, vol. 33, no. 1, pp. 83–97, 2012. View at: Publisher Site | Google Scholar
65. M. S. Hossen, M. Y. Ali, M. H. A. Jahurul, M. M. Abdel-Daim, S. H. Gan, and M. I. Khalil, “Beneficial roles of honey polyphenols against some human degenerative diseases: a review,” Pharmacological Reports, vol. 69, no. 6, pp. 1194–1205, 2017. View at: Publisher Site | Google Scholar
66. C. Ramassamy, “Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: a review of their intracellular targets,” European Journal of Pharmacology, vol. 545, no. 1, pp. 51–64, 2006. View at: Publisher Site | Google Scholar
67. S. I. Anjum, A. Ullah, K. A. Khan et al., “Composition and functional properties of propolis (bee glue): a review,” Saudi Journal of Biological Sciences, vol. 26, no. 7, pp. 1695–1703, 2019. View at: Publisher Site | Google Scholar
68. V. C. Toreti, H. H. Sato, G. M. Pastore, and Y. K. Park, “Recent progress of propolis for its biological and chemical compositions and its botanical origin,” Evidence-Based Complementary and Alternative Medicine, vol. 2013, Article ID 697390, 13 pages, 2013. View at: Publisher Site | Google Scholar
69. M. Viuda-Martos, “Functional properties of honey, propolis, and royal jelly,” Journal of Food Science, vol. 73, no. 9, pp. R117–R124, 2008. View at: Publisher Site | Google Scholar
70. J. M. Sforcin, “Biological properties and therapeutic applications of propolis,” Phytotherapy Research, vol. 30, no. 6, pp. 894–905, 2016. View at: Publisher Site | Google Scholar
71. S. Huang, C.-P. Zhang, K. Wang, G. Li, and F.-L. Hu, “Recent advances in the chemical composition of propolis,” Molecules, vol. 19, no. 12, pp. 19610–19632, 2014. View at: Publisher Site | Google Scholar
72. M. Franchin, D. F. Cólon, F. V. S. Castanheira et al., “Vestitol isolated from Brazilian red propolis inhibits neutrophils migration in the inflammatory process: elucidation of the mechanism of action,” Journal of Natural Products, vol. 79, no. 4, pp. 954–960, 2016. View at: Google Scholar
73. V. R. Pasupuleti, L. Sammugam, N. Ramesh, and S. H. Gan, “Honey, propolis, and royal jelly: a comprehensive review of their biological actions and health benefits,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 1259510, 21 pages, 2017. View at: Publisher Site | Google Scholar
74. Y.-S. Kwon, D.-H. Park, E.-J. Shin et al., “Antioxidant propolis attenuates kainate-induced neurotoxicity via adenosine A1 receptor modulation in the rat,” Neuroscience Letters, vol. 355, no. 3, pp. 231–235, 2004. View at: Publisher Site | Google Scholar
75. M. Swamy, W. Norlina, W. Azman et al., “Restoration of glutamine synthetase activity, nitric oxide levels and amelioration of oxidative stress by propolis in kainic acid mediated excitotoxicity,” African Journal of Traditional, Complementary and Alternative Medicines, vol. 11, no. 2, pp. 458–463, 2014. View at: Publisher Site | Google Scholar
76. M. Swamy, D. Suhaili, K. Sirajudeen, Z. Mustapha, and C. Govindasamy, “Propolis ameliorates tumor nerosis factor-α, nitric oxide levels, caspase-3 and nitric oxide synthase activities in kainic acid mediated excitotoxicity in rat brain,” African Journal of Traditional, Complementary and Alternative Medicines, vol. 11, no. 5, pp. 48–53, 2014. View at: Publisher Site | Google Scholar
77. J. Ni, Z. Wu, J. Meng et al., “The neuroprotective effects of Brazilian green propolis on neurodegenerative damage in human neuronal SH-SY5Y cells,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 7984327, 13 pages, 2014. View at: Publisher Site | Google Scholar
78. Y. Nakajima, M. Shimazawa, S. Mishima, and H. Hara, “Water extract of propolis and its main constituents, caffeoylquinic acid derivatives, exert neuroprotective effects via antioxidant actions,” Life Sciences, vol. 80, no. 4, pp. 370–377, 2007. View at: Publisher Site | Google Scholar
79. Y. Nakajima, M. Shimazawa, S. Mishima, and H. Hara, “Neuroprotective effects of Brazilian green propolis and its main constituents against oxygen-glucose deprivation stress, with a gene-expression analysis,” Phytotherapy Research, vol. 23, no. 10, pp. 1431–1438, 2009. View at: Publisher Site | Google Scholar
80. T. Ueda, M. Inden, K. Shirai et al., “The effects of Brazilian green propolis that contains flavonols against mutant copper-zinc superoxide dismutase-mediated toxicity,” Scientific Reports, vol. 7, no. 1, p. 2882, 2017. View at: Publisher Site | Google Scholar
81. S. Nanaware, M. Shelar, A. Sinnathambi, K. R. Mahadik, and S. Lohidasan, “Neuroprotective effect of Indian propolis in β-amyloid induced memory deficit: impact on behavioral and biochemical parameters in rats,” Biomedicine & Pharmacotherapy, vol. 93, pp. 543–553, 2017. View at: Publisher Site | Google Scholar
82. G. Bazmandegan, M. T. Boroushaki, A. Shamsizadeh, F. Ayoobi, E. Hakimizadeh, and M. Allahtavakoli, “Brown propolis attenuates cerebral ischemia-induced oxidative damage via affecting antioxidant enzyme system in mice,” Biomedicine & Pharmacotherapy, vol. 85, pp. 503–510, 2017. View at: Publisher Site | Google Scholar
83. J. K. Kim, S. J. Choi, H. Y. Cho et al., “Protective effects of kaempferol (3,4′,5,7-tetrahydroxyflavone) against amyloid beta peptide (Aβ)-Induced neurotoxicity in ICR mice,” Bioscience, Biotechnology, and Biochemistry, vol. 74, no. 2, pp. 397–401, 2010. View at: Publisher Site | Google Scholar
84. A. T. R. Goes, C. R. Jesse, M. S. Antunes et al., “Protective role of chrysin on 6-hydroxydopamine-induced neurodegeneration a mouse model of Parkinson’s disease: involvement of neuroinflammation and neurotrophins,” Chemico-Biological Interactions, vol. 279, pp. 111–120, 2018. View at: Publisher Site | Google Scholar
85. J. Tao, C. Shen, Y. Sun, W. Chen, and G. Yan, “Neuroprotective effects of pinocembrin on ischemia/reperfusion-induced brain injury by inhibiting autophagy,” Biomedicine & Pharmacotherapy, vol. 106, pp. 1003–1010, 2018. View at: Publisher Site | Google Scholar
86. R. Liu, J. Z. Li, J. K. Song et al., “Pinocembrin protects human brain microvascular endothelial cells against fibrillar amyloid-beta (1–40) injury by suppressing the MAPK/NF-kappaB inflammatory pathways,” BioMed Research International, vol. 2014, Article ID 470393, 14 pages, 2014. View at: Publisher Site | Google Scholar
87. R. Liu, J.-z. Li, J.-k. Song et al., “Pinocembrin improves cognition and protects the neurovascular unit in Alzheimer related deficits,” Neurobiology of Aging, vol. 35, no. 6, pp. 1275–1285, 2014. View at: Publisher Site | Google Scholar
88. Y. Wang, J. Gao, Y. Miao et al., “Pinocembrin protects SH-SY5Y cells against MPP+ -induced neurotoxicity through the mitochondrial apoptotic pathway,” Journal of Molecular Neuroscience, vol. 53, no. 4, pp. 537–545, 2014. View at: Publisher Site | Google Scholar
89. G. Zhao, W. Zhang, L. Li, S. Wu, and G. Du, “Pinocembrin protects the brain against ischemia-reperfusion injury and reverses the autophagy dysfunction in the penumbra area,” Molecules, vol. 19, no. 10, pp. 15786–15798, 2014. View at: Publisher Site | Google Scholar
90. X. Jin, Q. Liu, L. Jia, M. Li, and X. Wang, “Pinocembrin attenuates 6-OHDA-induced neuronal cell death through Nrf2/ARE pathway in SH-SY5Y cells,” Cellular and Molecular Neurobiology, vol. 35, no. 3, pp. 323–333, 2015. View at: Publisher Site | Google Scholar
91. M. A. Saad, R. M. Abdel Salam, S. A. Kenawy, and A. S. Attia, “Pinocembrin attenuates hippocampal inflammation, oxidative perturbations and apoptosis in a rat model of global cerebral ischemia reperfusion,” Pharmacological Reports, vol. 67, no. 1, pp. 115–122, 2015. View at: Publisher Site | Google Scholar
92. H. Wang, Y. Wang, L. Zhao, Q. Cui, Y. Wang, and G. Du, “Pinocembrin attenuates MPP+ -induced neurotoxicity by the induction of heme oxygenase-1 through ERK1/2 pathway,” Neuroscience Letters, vol. 612, pp. 104–109, 2016. View at: Publisher Site | Google Scholar
93. Y. Wang, Y. Miao, A. Z. Mir et al., “Inhibition of beta-amyloid-induced neurotoxicity by pinocembrin through Nrf2/HO-1 pathway in SH-SY5Y cells,” Journal of The Neurological Sciences, vol. 368, pp. 223–230, 2016. View at: Publisher Site | Google Scholar
94. M. R. de Oliveira, A. Peres, C. S. Gama, and S. M. D. Bosco, “Pinocembrin provides mitochondrial protection by the activation of the erk1/2-nrf2 signaling pathway in SH-SY5Y neuroblastoma cells exposed to paraquat,” Molecular Neurobiology, vol. 54, no. 8, pp. 6018–6031, 2017. View at: Publisher Site | Google Scholar
95. X. Lan, X. Han, Q. Li et al., “Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia,” Brain, Behavior, and Immunity, vol. 61, pp. 326–339, 2017. View at: Publisher Site | Google Scholar
96. Y. Ma, L. Li, L. Kong et al., “Pinocembrin protects blood-brain barrier function and expands the therapeutic time Window for tissue-type plasminogen activator treatment in a rat thromboembolic stroke model,” BioMed Research International, vol. 2018, Article ID 8943210, 13 pages, 2018. View at: Publisher Site | Google Scholar
97. N. A. G. d. Santos, N. M. Martins, R. d. B. Silva, R. S. Ferreira, F. M. Sisti, and A. C. d. Santos, “Caffeic acid phenethyl ester (CAPE) protects PC12 cells from MPP+ toxicity by inducing the expression of neuron-typical proteins,” Neurotoxicology, vol. 45, pp. 131–138, 2014. View at: Publisher Site | Google Scholar
98. S. Akyol, H. Erdemli, F. Armutcu, and O. Akyol, “In vitro and in vivo neuroprotective effect of caffeic acid phenethyl ester,” Journal of Intercultural Ethnopharmacology, vol. 4, no. 3, pp. 192-193, 2015. View at: Publisher Site | Google Scholar
99. J. Bak, H. J. Kim, S. Y. Kim, and Y.-S. Choi, “Neuroprotective effect of caffeic acid phenethyl ester in 3-nitropropionic acid-induced striatal neurotoxicity,” The Korean Journal of Physiology & Pharmacology, vol. 20, no. 3, pp. 279–286, 2016. View at: Publisher Site | Google Scholar
100. L.-Y. Wang, Z.-J. Tang, and Y.-Z. Han, “Neuroprotective effects of caffeic acid phenethyl ester against sevoflurane-induced neuronal degeneration in the hippocampus of neonatal rats involve MAPK and PI3K/Akt signaling pathways,” Molecular Medicine Reports, vol. 14, no. 4, pp. 3403–3412, 2016. View at: Publisher Site | Google Scholar
101. W. Fu, H. Wang, X. Ren, H. Yu, Y. Lei, and Q. Chen, “Neuroprotective effect of three caffeic acid derivatives via ameliorate oxidative stress and enhance PKA/CREB signaling pathway,” Behavioural Brain Research, vol. 328, pp. 81–86, 2017. View at: Publisher Site | Google Scholar
102. M. Kumar, D. Kaur, and N. Bansal, “Caffeic acid phenethyl ester (CAPE) prevents development of STZ-ICV induced dementia in rats,” Pharmacognosy Magazine, vol. 13, pp. 10–15, 2017. View at: Google Scholar
103. R. S. Ferreira, N. A. G. Dos Santos, N. M. Martins, L. S. Fernandes, and A. C. Dos Santos, “Caffeic acid phenethyl ester (CAPE) protects PC12 cells from cisplatin-induced neurotoxicity by activating the NGF-signaling pathway,” Neurotoxicity Research, vol. 34, no. 1, pp. 32–46, 2018. View at: Publisher Site | Google Scholar
104. F. Morroni, G. Sita, A. Graziosi et al., “Neuroprotective effect of caffeic acid phenethyl ester in A mouse model of alzheimer’s disease involves Nrf2/HO-1 pathway,” Aging and Disease, vol. 9, no. 4, pp. 605–622, 2018. View at: Publisher Site | Google Scholar
105. R. Tomiyama, K. Takakura, S. Takatou et al., “3,4-dihydroxybenzalacetone and caffeic acid phenethyl ester induce preconditioning ER stress and autophagy in SH-SY5Y cells,” Journal of Cellular Physiology, vol. 233, no. 2, pp. 1671–1684, 2018. View at: Publisher Site | Google Scholar
106. R. S. Ferreira, N. A. G. Dos Santos, C. P. Bernardes et al., “Caffeic acid phenethyl ester (CAPE) protects PC12 cells against cisplatin-induced neurotoxicity by activating the AMPK/SIRT1, MAPK/erk, and PI3k/akt signaling pathways,” Neurotoxicity Research, vol. 36, no. 1, pp. 175–192, 2019. View at: Publisher Site | Google Scholar
107. S. A. Zaitone, E. Ahmed, N. M. Elsherbiny et al., “Caffeic acid improves locomotor activity and lessens inflammatory burden in a mouse model of rotenone-induced nigral neurodegeneration: relevance to Parkinson’s disease therapy,” Pharmacological Reports, vol. 71, no. 1, pp. 32–41, 2019. View at: Publisher Site | Google Scholar
108. R. Barros Silva, N. A. G. Santos, N. M. Martins et al., “Caffeic acid phenethyl ester protects against the dopaminergic neuronal loss induced by 6-hydroxydopamine in rats,” Neuroscience, vol. 233, pp. 86–94, 2013. View at: Publisher Site | Google Scholar
109. M. Mirjalili, E. Moyano, M. Bonfill, R. Cusido, and J. Palazón, “Steroidal lactones from Withania somnifera, an ancient plant for novel medicine,” Molecules, vol. 14, no. 7, pp. 2373–2393, 2009. View at: Publisher Site | Google Scholar
110. M. Ahmad, S. Saleem, A. S. Ahmad et al., “Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkinsonism in rats,” Human & Experimental Toxicology, vol. 24, no. 3, pp. 137–147, 2005. View at: Publisher Site | Google Scholar
111. S. R. Sankar, T. Manivasagam, A. Krishnamurti, and M. Ramanathan, “The neuroprotective effect of Withania somnifera root extract in MPTP-intoxicated mice: an analysis of behavioral and biochemical variables,” Cellular and Molecular Biology Letters, vol. 12, no. 4, pp. 473–481, 2007. View at: Publisher Site | Google Scholar
112. S. RajaSankar, T. Manivasagam, V. Sankar et al., “Withania somnifera root extract improves catecholamines and physiological abnormalities seen in a Parkinson’s disease model mouse,” Journal of Ethnopharmacology, vol. 125, no. 3, pp. 369–373, 2009. View at: Publisher Site | Google Scholar
113. M. J. Manjunath and Muralidhara, “Effect of Withania somnifera supplementation on rotenone-induced oxidative damage in cerebellum and striatum of the male mice brain,” Central Nervous System Agents in Medicinal Chemistry, vol. 13, no. 1, pp. 43–56, 2013. View at: Google Scholar
114. P. Kumar and A. Kumar, “Possible neuroprotective effect of Withania somnifera root extract against 3-nitropropionic acid-induced behavioral, biochemical, and mitochondrial dysfunction in an animal model of huntington’s disease,” Journal of Medicinal Food, vol. 12, no. 3, pp. 591–600, 2009. View at: Publisher Site | Google Scholar
115. K. Dutta, P. Patel, and J.-P. Julien, “Protective effects of Withania somnifera extract in SOD1G93A mouse model of amyotrophic lateral sclerosis,” Experimental Neurology, vol. 309, pp. 193–204, 2018. View at: Publisher Site | Google Scholar
116. D. Choudhary, S. Bhattacharyya, and S. Bose, “Efficacy and safety of ashwagandha (Withania somnifera (L.) dunal) root extract in improving memory and cognitive functions,” Journal of Dietary Supplements, vol. 14, no. 6, pp. 599–612, 2017. View at: Publisher Site | Google Scholar
117. K. N. R. Chengappa, C. R. Bowie, P. J. Schlicht, D. Fleet, J. S. Brar, and R. Jindal, “Randomized placebo-controlled adjunctive study of an extract of Withania somniferafor cognitive dysfunction in bipolar disorder,” The Journal of Clinical Psychiatry, vol. 74, no. 11, pp. 1076–1083, 2013. View at: Publisher Site | Google Scholar
118. U. Pingali, R. Pilli, and N. Fatima, “Effect of standardized aqueous extract of Withania somniferaon tests of cognitive and psychomotor performance in healthy human participants,” Pharmacognosy Research, vol. 6, no. 1, pp. 12–18, 2014. View at: Publisher Site | Google Scholar
119. T. Kuboyama, C. Tohda, and K. Komatsu, “Withanoside IV and its active metabolite, sominone, attenuate Aβ (25–35)-induced neurodegeneration,” European Journal of Neuroscience, vol. 23, no. 6, pp. 1417–1426, 2006. View at: Publisher Site | Google Scholar
120. A. Konar, N. Shah, R. Singh et al., “Protective role of ashwagandha leaf extract and its component Withanone on scopolamine-induced changes in the brain and brain-derived cells,” PLoS One, vol. 6, no. 11, Article ID e27265, 2011. View at: Publisher Site | Google Scholar
121. A. Pandey, S. Bani, P. Dutt, N. Kumar Satti, K. Avtar Suri, and G. Nabi Qazi, “Multifunctional neuroprotective effect of Withanone, a compound from Withania somnifera roots in alleviating cognitive dysfunction,” Cytokine, vol. 102, pp. 211–221, 2018. View at: Publisher Site | Google Scholar
122. N. J. Dar, J. A. Bhat, N. K. Satti, P. R. Sharma, A. Hamid, and M. Ahmad, “Withanone, an active constituent from Withania somnifera, affords protection against NMDA-induced excitotoxicity in neuron-like cells,” Molecular Neurobiology, vol. 54, no. 7, pp. 5061–5073, 2017. View at: Publisher Site | Google Scholar
123. P. Patel, J.-P. Julien, and J. Kriz, “Early-stage treatment with Withaferin A reduces levels of misfolded superoxide dismutase 1 and extends lifespan in a mouse model of amyotrophic lateral sclerosis,” Neurotherapeutics, vol. 12, no. 1, pp. 217–233, 2015. View at: Publisher Site | Google Scholar
124. F. Martorana, G. Guidotti, L. Brambilla, and D. Rossi, “Withaferin A inhibits nuclear factor-κB-dependent pro-inflammatory and stress response pathways in the astrocytes,” Neural Plasticity, vol. 2015, Article ID 381964, 9 pages, 2015. View at: Publisher Site | Google Scholar
125. K.-j. Min, K. Choi, and T. K. Kwon, “Withaferin A down-regulates lipopolysaccharide-induced cyclooxygenase-2 expression and PGE2 production through the inhibition of STAT1/3 activation in microglial cells,” International Immunopharmacology, vol. 11, no. 8, pp. 1137–1142, 2011. View at: Publisher Site | Google Scholar
126. I. Baitharu, V. Jain, S. N. Deep et al., “Withanolide A prevents neurodegeneration by modulating hippocampal glutathione biosynthesis during hypoxia,” PLoS One, vol. 9, no. 10, Article ID e105311, 2014. View at: Publisher Site | Google Scholar
127. K. R. Kurapati, T. Samikkannu, V. S. Atluri, E. Kaftanovskaya, A. Yndart, and M. P. Nair, “β-Amyloid1-42, HIV-1Ba-L (clade B) infection and drugs of abuse induced degeneration in human neuronal cells and protective effects of ashwagandha (Withania somnifera) and its constituent Withanolide A,” PLoS One, vol. 9, no. 11, Article ID e112818, 2014. View at: Publisher Site | Google Scholar
128. G. Kumar and R. Patnaik, “Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: an in silico study,” Medical Hypotheses, vol. 92, pp. 35–43, 2016. View at: Publisher Site | Google Scholar
129. G. Y. Sun, R. Li, J. Cui et al., “Withania somnifera and its withanolides attenuate oxidative and inflammatory responses and up-regulate antioxidant responses in BV-2 microglial cells,” NeuroMolecular Medicine, vol. 18, no. 3, pp. 241–252, 2016. View at: Publisher Site | Google Scholar
130. E. A. Crane, W. Heydenreuter, K. R. Beck et al., “Profiling withanolide A for therapeutic targets in neurodegenerative diseases,” Bioorganic & Medicinal Chemistry, vol. 27, no. 12, pp. 2508–2520, 2019. View at: Publisher Site | Google Scholar
131. Y.-Z. Xiang, H.-C. Shang, X.-M. Gao, and B.-L. Zhang, “A comparison of the ancient use of ginseng in traditional Chinese medicine with modern pharmacological experiments and clinical trials,” Phytotherapy Research, vol. 22, no. 7, pp. 851–858, 2008. View at: Publisher Site | Google Scholar
132. L. Jiao, B. Li, M. Wang, Z. Liu, X. Zhang, and S. Liu, “Antioxidant activities of the oligosaccharides from the roots, flowers and leaves of Panax ginseng C.A. Meyer,” Carbohydrate Polymers, vol. 106, pp. 293–298, 2014. View at: Publisher Site | Google Scholar
133. H.-D. Yuan, J.-T. Kim, S.-H. Kim, and S.-H. Chung, “Ginseng and diabetes: the evidences from in vitro, animal and human studies,” Journal of Ginseng Research, vol. 36, no. 1, pp. 27–39, 2012. View at: Publisher Site | Google Scholar
134. S. Chen, Z. Wang, Y. Huang et al., “Ginseng and anticancer drug combination to improve cancer chemotherapy: a critical review,” Evidence-Based Complementary and Alternative Medicine, vol. 2014, Article ID 168940, 13 pages, 2014. View at: Publisher Site | Google Scholar
135. Y. Yang, C. Ren, Y. Zhang, and X. Wu, “Ginseng: an nonnegligible natural remedy for healthy aging,” Aging and Disease, vol. 8, no. 6, pp. 708–720, 2017. View at: Publisher Site | Google Scholar
136. A. Ahuja, J. H. Kim, J.-H. Kim, Y.-S. Yi, and J. Y. Cho, “Functional role of ginseng-derived compounds in cancer,” Journal of Ginseng Research, vol. 42, no. 3, pp. 248–254, 2018. View at: Publisher Site | Google Scholar
137. N. M. Arring, D. Millstine, L. A. Marks, and L. M. Nail, “Ginseng as a treatment for fatigue: a systematic review,” Journal of Alternative and Complementary Medicine, vol. 24, no. 7, pp. 624–633, 2018. View at: Google Scholar
138. N. Sathishkumar, S. Sathiyamoorthy, M. Ramya, D.-U. Yang, H. N. Lee, and D.-C. Yang, “Molecular docking studies of anti-apoptotic BCL-2, BCL-XL, and MCL-1 proteins with ginsenosides fromPanax ginseng,” Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 27, no. 5, pp. 685–692, 2012. View at: Publisher Site | Google Scholar
139. L. Bai, J. Gao, F. Wei, J. Zhao, D. Wang, and J. Wei, “Therapeutic potential of ginsenosides as an adjuvant treatment for diabetes,” Frontiers in Pharmacology, vol. 9, p. 423, 2018. View at: Publisher Site | Google Scholar
140. W.-Y. Ong, T. Farooqui, H.-L. Koh, A. A. Farooqui, and E.-A. Ling, “Protective effects of ginseng on neurological disorders,” Frontiers in Aging Neuroscience, vol. 7, p. 129, 2015. View at: Publisher Site | Google Scholar
141. I.-H. Cho, “Effects of Panax ginseng in neurodegenerative diseases,” Journal of Ginseng Research, vol. 36, no. 4, pp. 342–353, 2012. View at: Publisher Site | Google Scholar
142. V. Rastogi, J. Santiago-Moreno, and S. Doré, “Effects of Panax ginseng in neurodegenerative diseases,” Frontiers in Cellular Neuroscience, vol. 8, p. 457, 2015. View at: Google Scholar
143. Z. Cheng, M. Zhang, C. Ling et al., “Neuroprotective effects of ginsenosides against cerebral ischemia,” Molecules, vol. 24, p. 6, 2019. View at: Publisher Site | Google Scholar
144. C. H. Lee and J.-H. Kim, “A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases,” Journal of Ginseng Research, vol. 38, no. 3, pp. 161–166, 2014. View at: Publisher Site | Google Scholar
145. J.-M. Lu, Q. Yao, and C. Chen, “Ginseng compounds: an update on their molecular mechanisms and medical applications,” Current Vascular Pharmacology, vol. 7, no. 3, pp. 293–302, 2009. View at: Publisher Site | Google Scholar
146. Y. L. Jun, C.-H. Bae, D. Kim, S. Koo, and S. Kim, “Korean red ginseng protects dopaminergic neurons by suppressing the cleavage of p35 to p25 in a Parkinson’s disease mouse model,” Journal of Ginseng Research, vol. 39, no. 2, pp. 148–154, 2015. View at: Publisher Site | Google Scholar
147. D. Kim, H. Jeon, S. Ryu, S. Koo, K.-T. Ha, and S. Kim, “Proteomic analysis of the effect of Korean red ginseng in the striatum of a Parkinson’s disease mouse model,” PLoS One, vol. 11, no. 10, Article ID e0164906, 2016. View at: Publisher Site | Google Scholar
148. D. Kim, S. Kwon, H. Jeon, S. Ryu, K.-T. Ha, and S. Kim, “Proteomic change by Korean red ginseng in the substantia nigra of a Parkinson’s disease mouse model,” Journal of Ginseng Research, vol. 42, no. 4, pp. 429–435, 2018. View at: Publisher Site | Google Scholar
149. S. Ryu, S. Koo, K.-T. Ha, and S. Kim, “Neuroprotective effect of Korea red ginseng extract on 1-methyl-4-phenylpyridinium-induced apoptosis in PC12 cells,” Animal Cells and Systems, vol. 20, no. 6, pp. 363–368, 2016. View at: Publisher Site | Google Scholar
150. S. Ryu, H. Jeon, S. Koo, and S. Kim, “Korean red ginseng enhances neurogenesis in the subventricular zone of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice,” Frontiers in Aging Neuroscience, vol. 10, p. 355, 2018. View at: Publisher Site | Google Scholar
151. J. H. Choi, M. Jang, S.-Y. Nah, S. Oh, and I.-H. Cho, “Multitarget effects of Korean Red Ginseng in animal model of Parkinson’s disease: antiapoptosis, antioxidant, antiinflammation, and maintenance of blood-brain barrier integrity,” Journal of Ginseng Research, vol. 42, no. 3, pp. 379–388, 2018. View at: Publisher Site | Google Scholar
152. S. Hu, R. Han, S. Mak, and Y. Han, “Protection against 1-methyl-4-phenylpyridinium ion (MPP+)-induced apoptosis by water extract of ginseng (Panax ginseng C.A. Meyer) in SH-SY5Y cells,” Journal of Ethnopharmacology, vol. 135, no. 1, pp. 34–42, 2011. View at: Publisher Site | Google Scholar
153. M. Jang, M. J. Lee, C. S. Kim, and I. H. Cho, “Korean red ginseng extract attenuates 3-nitropropionic acid-induced huntington’s-like symptoms,” Evidence-Based Complementary And Alternative Medicine, vol. 2013, Article ID 237207, 17 pages, 2013. View at: Publisher Site | Google Scholar
154. M. J. Lee, B. J. Chang, S. Oh, S.-Y. Nah, and I.-H. Cho, “Korean red ginseng mitigates spinal demyelination in a model of acute multiple sclerosis by downregulating p38 mitogen-activated protein kinase and nuclear factor-κB signaling pathways,” Journal of Ginseng Research, vol. 42, no. 4, pp. 436–446, 2018. View at: Publisher Site | Google Scholar
155. X. Tan, J. Gu, B. Zhao et al., “Ginseng improves cognitive deficit via the RAGE/NF-κB pathway in advanced glycation end product-induced rats,” Journal of Ginseng Research, vol. 39, no. 2, pp. 116–124, 2015. View at: Publisher Site | Google Scholar
156. J. Kim, S. H. Kim, D.-S. Lee et al., “Effects of fermented ginseng on memory impairment and β-amyloid reduction in Alzheimer’s disease experimental models,” Journal of Ginseng Research, vol. 37, no. 1, pp. 100–107, 2013. View at: Publisher Site | Google Scholar
157. T.-t. Zhou, G. Zu, X. Wang et al., “Immunomodulatory and neuroprotective effects of ginsenoside Rg1 in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) -induced mouse model of Parkinson’s disease,” International Immunopharmacology, vol. 29, no. 2, pp. 334–343, 2015. View at: Publisher Site | Google Scholar
158. X.-c. Chen, Y.-c. Zhou, Y. Chen, Y.-g. Zhu, F. Fang, and L.-m. Chen, “Ginsenoside Rg1 reduces MPTP-induced substantia nigra neuron loss by suppressing oxidative stress1,” Acta Pharmacologica Sinica, vol. 26, no. 1, pp. 56–62, 2005. View at: Publisher Site | Google Scholar
159. Y.-L. Zhang, Y. Liu, X.-P. Kang et al., “Ginsenoside Rb1 confers neuroprotection via promotion of glutamate transporters in a mouse model of Parkinson’s disease,” Neuropharmacology, vol. 131, pp. 223–237, 2018. View at: Publisher Site | Google Scholar
160. X. C. Chen, Y. Chen, Y. G. Zhu, F. Fang, and L. M. Chen, “Protective effect of ginsenoside Rg1 against MPTP-induced apoptosis in mouse substantia nigra neurons,” Acta Pharmacologica Sinica, vol. 23, no. 9, pp. 829–834, 2002. View at: Google Scholar
161. Y. Heng, Q.-S. Zhang, Z. Mu, J.-F. Hu, Y.-H. Yuan, and N.-H. Chen, “Ginsenoside Rg1 attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting α-synuclein abnormalities in the substantia nigra,” Toxicology Letters, vol. 243, pp. 7–21, 2016. View at: Publisher Site | Google Scholar
162. B.-B. Xu, C.-Q. Liu, X. Gao, W.-Q. Zhang, S.-W. Wang, and Y.-L. Cao, “Possible mechanisms of the protection of ginsenoside Re against MPTP-induced apoptosis in substantia nigra neurons of Parkinson’s disease mouse model,” Journal of Asian Natural Products Research, vol. 7, no. 3, pp. 215–224, 2005. View at: Publisher Site | Google Scholar
163. A. Rajabian, M. Rameshrad, and H. Hosseinzadeh, “Therapeutic potential of Panax ginseng and its constituents, ginsenosides and gintonin, in neurological and neurodegenerative disorders: a patent review,” Expert Opinion on Therapeutic Patents, vol. 29, no. 1, pp. 55–72, 2019. View at: Publisher Site | Google Scholar
164. T. Zhou, G. Zu, X. Zhang et al., “Neuroprotective effects of ginsenoside Rg1 through the Wnt/β-catenin signaling pathway in both in vivo and in vitro models of Parkinson’s disease,” Neuropharmacology, vol. 101, pp. 480–489, 2016. View at: Publisher Site | Google Scholar
165. Y. Liu, R.-Y. Zhang, J. Zhao et al., “Ginsenoside Rd protects SH-SY5Y cells against 1-Methyl-4-phenylpyridinium induced injury,” International Journal of Molecular Sciences, vol. 16, no. 7, pp. 14395–14408, 2015. View at: Publisher Site | Google Scholar
166. B.-S. Zhao, Y. Liu, X.-Y. Gao, H.-Q. Zhai, J.-Y. Guo, and X.-Y. Wang, “Effects of ginsenoside Rg1 on the expression of toll-like receptor 3, 4 and their signalling transduction factors in the NG108-15 murine neuroglial cell line,” Molecules, vol. 19, no. 10, pp. 16925–16936, 2014. View at: Publisher Site | Google Scholar
167. J. Y. Hwang, J. S. Shim, M.-Y. Song, S.-V. Yim, S. E. Lee, and K.-S. Park, “Proteomic analysis reveals that the protective effects of ginsenoside Rb1 are associated with the actin cytoskeleton in β-amyloid-treated neuronal cells,” Journal of Ginseng Research, vol. 40, no. 3, pp. 278–284, 2016. View at: Publisher Site | Google Scholar
168. Y. Zhang, Z. Pi, F. Song, and Z. Liu, “Ginsenosides attenuate d-galactose- and AlCl3-inducedspatial memory impairment by restoring the dysfunction of the neurotransmitter systems in the rat model of Alzheimer’s disease,” Journal of Ethnopharmacology, vol. 194, pp. 188–195, 2016. View at: Publisher Site | Google Scholar
169. L. Song, M.-B. Xu, X.-L. Zhou, D.-p. Zhang, S.-l. Zhang, and G.-q. Zheng, “A preclinical systematic review of ginsenoside-rg1 in experimental Parkinson’s disease,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 2163053, 14 pages, 2017. View at: Publisher Site | Google Scholar
170. S.-T. Lee, K. Chu, J.-Y. Sim, J.-H. Heo, and M. Kim, “Panax ginseng enhances cognitive performance in Alzheimer disease,” Alzheimer Disease & Associated Disorders, vol. 22, no. 3, pp. 222–226, 2008. View at: Publisher Site | Google Scholar
171. X. Zeng, Y. Deng, Y. Feng et al., “Pharmacokinetics and safety of ginsenoside Rd following a single or multiple intravenous dose in healthy Chinese volunteers,” The Journal of Clinical Pharmacology, vol. 50, no. 3, pp. 285–292, 2010. View at: Publisher Site | Google Scholar
172. X. Liu, J. Xia, L. Wang et al., “Efficacy and safety of ginsenoside-Rd for acute ischaemic stroke: a randomized, double-blind, placebo-controlled, phase II multicenter trial,” European Journal of Neurology, vol. 16, no. 5, pp. 569–575, 2009. View at: Publisher Site | Google Scholar
173. X. Liu, L. Wang, A. Wen et al., “Ginsenoside-Rd improves outcome of acute ischaemic stroke-a randomized, double-blind, placebo-controlled, multicenter trial,” European Journal of Neurology, vol. 19, no. 6, pp. 855–863, 2012. View at: Publisher Site | Google Scholar
174. J. S. Shi, J. X. Yu, X. P. Chen, and R. X. Xu, “Pharmacological actions of Uncaria alkaloids, rhynchophylline and isorhynchophylline,” Acta Pharmacologica Sinica, vol. 24, no. 2, pp. 97–101, 2003. View at: Google Scholar
175. Y.-F. Xian, Z.-X. Lin, Q.-Q. Mao et al., “Bioassay-guided isolation of neuroprotective compounds from Uncaria rhynchophylla against beta-amyloid-induced neurotoxicity,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 802625, 8 pages, 2012. View at: Publisher Site | Google Scholar
176. T.-H. Kang, Y. Murakami, K. Matsumoto et al., “Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytes,” European Journal of Pharmacology, vol. 455, no. 1, pp. 27–34, 2002. View at: Publisher Site | Google Scholar
177. C.-L. Hsieh, M.-F. Chen, T.-C. Li et al., “Anticonvulsant effect of Uncaria rhynchophylla (Miq) jack,” The American Journal of Chinese Medicine, vol. 27, no. 2, pp. 257–264, 1999. View at: Publisher Site | Google Scholar
178. C.-L. Hsieh, N.-Y. Tang, S.-Y. Chiang, C.-T. Hsieh, and J.-G. Lin, “Anticonvulsive and free radical scavenging actions of two herbs, Uncaria rhynchophylla (Miq) jack and Gastrodia elata Bl., in kainic acid-treated rats,” Life Sciences, vol. 65, no. 20, pp. 2071–2082, 1999. View at: Publisher Site | Google Scholar
179. N.-Y. Tang, C.-H. Liu, S.-Y. Su et al., “Uncaria rhynchophylla (Miq) Jack plays a role in neuronal protection in kainic acid-treated rats,” The American Journal of Chinese Medicine, vol. 38, no. 2, pp. 251–263, 2010. View at: Publisher Site | Google Scholar
180. Y.-W. Lin and C.-L. Hsieh, “Oral Uncaria rhynchophylla (UR) reduces kainic acid-induced epileptic seizures and neuronal death accompanied by attenuating glial cell proliferation and S100B proteins in rats,” Journal of Ethnopharmacology, vol. 135, no. 2, pp. 313–320, 2011. View at: Publisher Site | Google Scholar
181. C. H. Liu, Y. W. Lin, N. Y. Tang, H. J. Liu, and C. L. Hsieh, “Neuroprotective effect of Uncaria rhynchophylla in kainic acid-induced epileptic seizures by modulating hippocampal mossy fiber sprouting, neuron survival, astrocyte proliferation, and S100B expression,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 194790, 11 pages, 2012. View at: Publisher Site | Google Scholar
182. K. Suk, S. Y. Kim, K. Leem et al., “Neuroprotection by methanol extract of Uncaria rhynchophylla against global cerebral ischemia in rats,” Life Sciences, vol. 70, no. 21, pp. 2467–2480, 2002. View at: Publisher Site | Google Scholar
183. H. Fujiwara, K. Iwasaki, K. Furukawa et al., “Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer’s β-amyloid proteins,” Journal of Neuroscience Research, vol. 84, no. 2, pp. 427–433, 2006. View at: Publisher Site | Google Scholar
184. J. S. Shim, H. G. Kim, M. S. Ju, J. G. Choi, S. Y. Jeong, and M. S. Oh, “Effects of the hook of Uncaria rhynchophylla on neurotoxicity in the 6-hydroxydopamine model of Parkinson’s disease,” Journal of Ethnopharmacology, vol. 126, no. 2, pp. 361–365, 2009. View at: Publisher Site | Google Scholar
185. B. Pal and S. S. Kumar, “Evaluation of anti-Parkinson’s activity of Uncaria rhynchophylla in 6-hydroxy dopamine lesioned rat model,” International Journal of Applied Research, vol. 1, no. 6, pp. 203–206, 2015. View at: Google Scholar
186. Y. L. Lan, J. J. Zhou, J. Liu et al., “Uncaria rhynchophylla ameliorates Parkinson’s disease by inhibiting HSP90 expression: insights from quantitative proteomics,” Cellular Physiology and Biochemistry, vol. 47, no. 4, pp. 1453–1464, 2018. View at: Publisher Site | Google Scholar
187. H. Y. Jung, K. N. Nam, B. C. Woo, K. P. Kim, S. O. Kim, and E. H. Lee, “Hirsutine, an indole alkaloid of Uncaria rhynchophylla, inhibits inflammation-mediated neurotoxicity and microglial activation,” Molecular Medicine Reports, vol. 7, no. 1, pp. 154–158, 2013. View at: Publisher Site | Google Scholar
188. S. Hu, S. Mak, X. Zuo, H. Li, Y. Wang, and Y. Han, “Neuroprotection against MPP (+)-Induced cytotoxicity through the activation of PI3-K/Akt/GSK3beta/MEF2D signaling pathway by rhynchophylline, the major tetracyclic oxindole alkaloid isolated from Uncaria rhynchophylla,” Frontiers in Pharmacology, vol. 9, p. 768, 2018. View at: Publisher Site | Google Scholar
189. Y. Yang, W. G. Ji, Z. R. Zhu, Y. L. Wu, Z. Y. Zhang, and S. C. Qu, “Rhynchophylline suppresses soluble Aβ1-42-induced impairment of spatial cognition function via inhibiting excessive activation of extrasynaptic NR2B-containing NMDA receptors,” Neuropharmacology, vol. 135, pp. 100–112, 2018. View at: Publisher Site | Google Scholar
190. H. Huang, R. Zhong, Z. Xia, J. Song, and L. Feng, “Neuroprotective effects of rhynchophylline against ischemic brain injury via regulation of the Akt/mTOR and TLRs signaling pathways,” Molecules, vol. 19, no. 8, pp. 11196–11210, 2014. View at: Publisher Site | Google Scholar
191. H. Shao, Z. Mi, W. G. Ji et al., “Rhynchophylline protects against the amyloid beta-induced increase of spontaneous discharges in the hippocampal CA1 region of rats,” Neurochemical Research, vol. 40, no. 11, pp. 2365–2373, 2015. View at: Publisher Site | Google Scholar
192. X. M. Li, X. J. Zhang, and M. X. Dong, “Isorhynchophylline attenuates MPP (+)-Induced apoptosis through endoplasmic reticulum stress- and mitochondria-dependent pathways in PC12 cells: involvement of antioxidant activity,” Neuromolecular Medicine, vol. 19, no. 4, pp. 480–492, 2017. View at: Publisher Site | Google Scholar
193. X. Wei, L. P. Jiang, Y. Guo et al., “Indole alkaloids inhibiting neural stem cell from Uncaria rhynchophylla,” Natural Products and Bioprospecting, vol. 7, no. 5, pp. 413–419, 2017. View at: Publisher Site | Google Scholar
194. H. Q. Li, S. P. Ip, G. Q. Zheng, Y. F. Xian, and Z. X. Lin, “Isorhynchophylline alleviates learning and memory impairments induced by aluminum chloride in mice,” Chinese Medicine, vol. 13, p. 29, 2018. View at: Publisher Site | Google Scholar
195. Q. Li, C. Niu, X. Zhang, and M. Dong, “Gastrodin and isorhynchophylline synergistically inhibit MPP(+) -Induced oxidative stress in SH-SY5Y cells by targeting ERK1/2 and GSK-3beta pathways: involvement of Nrf2 nuclear translocation,” ACS Chemical Neuroscience, vol. 9, no. 3, pp. 482–493, 2018. View at: Publisher Site | Google Scholar
196. N. V. Thomas and S.-K. Kim, “Beneficial effects of marine algal compounds in cosmeceuticals,” Marine Drugs, vol. 11, no. 1, pp. 146–164, 2013. View at: Publisher Site | Google Scholar
197. C. Dawczynski, U. Schafer, M. Leiterer, and G. Jahreis, “Nutritional and toxicological importance of macro, trace, and ultra-trace elements in algae food products,” Journal of Agricultural and Food Chemistry, vol. 55, no. 25, pp. 10470–10475, 2007. View at: Publisher Site | Google Scholar
198. S. L. Holdt and S. Kraan, “Bioactive compounds in seaweed: functional food applications and legislation,” Journal of Applied Phycology, vol. 23, no. 3, pp. 543–597, 2011. View at: Publisher Site | Google Scholar
199. R. Singh, P. Parihar, M. Singh et al., “Uncovering potential applications of cyanobacteria and algal metabolites in biology, agriculture and medicine: current status and future prospects,” Frontiers in Microbiology, vol. 8, p. 515, 2017. View at: Publisher Site | Google Scholar
200. B. R. Ahn, H. E. Moon, H. R. Kim, H. A. Jung, and J. S. Choi, “Neuroprotective effect of edible brown alga Eisenia bicyclis on amyloid beta peptide-induced toxicity in PC12 cells,” Archives of Pharmacal Research, vol. 35, no. 11, pp. 1989–1998, 2012. View at: Publisher Site | Google Scholar
201. J. Silva, C. Alves, S. Pinteus, S. Mendes, and R. Pedrosa, “Neuroprotective effects of seaweeds against 6-hydroxidopamine-induced cell death on an in vitro human neuroblastoma model,” BMC Complementary and Alternative Medicine, vol. 18, no. 1, p. 58, 2018. View at: Publisher Site | Google Scholar
202. J. Silva, C. Alves, R. Freitas et al., “Antioxidant and neuroprotective potential of the Brown seaweed Bifurcaria bifurcata in an in vitro Parkinson’s disease model,” Marine Drugs, vol. 17, p. 2, 2019. View at: Publisher Site | Google Scholar
203. S. J. Heo, S. H. Cha, K. N. Kim et al., “Neuroprotective effect of phlorotannin isolated from Ishige okamurae against H₂O₂ -induced oxidative stress in murine hippocampal neuronal cells, HT22,” Applied Biochemistry and Biotechnology, vol. 166, no. 6, pp. 1520–1532, 2012. View at: Publisher Site | Google Scholar
204. M. Y. Um, D. W. Lim, H. J. Son, S. Cho, and C. Lee, “Phlorotannin-rich fraction from Ishige foliacea brown seaweed prevents the scopolamine-induced memory impairment via regulation of ERK-CREB-BDNF pathway,” Journal of Functional Foods, vol. 40, pp. 110–116, 2018. View at: Publisher Site | Google Scholar
205. L. Cunha and A. Grenha, “Sulfated seaweed polysaccharides as multifunctional materials in drug delivery applications,” Marine Drugs, vol. 14, no. 3, p. 42, 2016. View at: Publisher Site | Google Scholar
206. T. H. Silva, A. Alves, E. G. Popa et al., “Marine algae sulfated polysaccharides for tissue engineering and drug delivery approaches,” Biomatter, vol. 2, no. 4, pp. 278–289, 2012. View at: Publisher Site | Google Scholar
207. J. Venkatesan, S. Anil, S.-K. Kim, and M. S. Shim, “Seaweed polysaccharide-based nanoparticles: preparation and applications for drug delivery,” Polymers, vol. 8, no. 2, p. 30, 2016. View at: Publisher Site | Google Scholar
208. K. Sana, A. Munawar, S. Farhan, B.-U.-A. Huma, and S. Hafiz Ansar Rasul, “Therapeutic potential of seaweed bioactive compounds,” in Seaweed Biomaterials, S. Maiti, Ed., IntechOpen Limited, London, UK, 2018. View at: Google Scholar
209. D. Luo, Q. Zhang, H. Wang et al., “Fucoidan protects against dopaminergic neuron death in vivo and in vitro,” European Journal of Pharmacology, vol. 617, no. 1–3, pp. 33–40, 2009. View at: Publisher Site | Google Scholar
210. F. L. Zhang, Y. He, Y. Zheng et al., “Therapeutic effects of fucoidan in 6-hydroxydopamine-lesioned rat model of Parkinson’s disease: role of NADPH oxidase-1,” CNS Neuroscience and Therapeutics, vol. 20, no. 12, pp. 1036–1044, 2014. View at: Publisher Site | Google Scholar
211. L. Zhang, J. Hao, Y. Zheng et al., “Fucoidan protects dopaminergic neurons by enhancing the mitochondrial function in a rotenone-induced rat model of Parkinson’s disease,” Aging and Disease, vol. 9, no. 4, pp. 590–604, 2018. View at: Publisher Site | Google Scholar
212. H. Wei, Z. Gao, L. Zheng et al., “Protective effects of fucoidan on Aβ 25–35 and d-gal-induced neurotoxicity in PC12 cells and d-gal-induced cognitive dysfunction in mice,” Marine Drugs, vol. 15, no. 3, p. 77, 2017. View at: Publisher Site | Google Scholar
213. M. Alghazwi, S. Smid, S. Karpiniec, and W. Zhang, “Comparative study on neuroprotective activities of fucoidans from Fucus vesiculosus and Undaria pinnatifida,” International Journal of Biological Macromolecules, vol. 122, pp. 255–264, 2019. View at: Publisher Site | Google Scholar
214. M. H. Kim, H. Namgoong, B. D. Jung et al., “Fucoidan Attenuates 6-hydroxydopamine-induced neurotoxicity by exerting anti-oxidative and anti-apoptotic actions in SH-Sy5y cells,” Korean Journal of Veterinary Research, vol. 57, no. 1, pp. 1–7, 2017. View at: Google Scholar
215. S. Vijayakumar and M. Menakha, “Pharmaceutical applications of cyanobacteria-a review,” Journal of Acute Medicine, vol. 5, no. 1, pp. 15–23, 2015. View at: Publisher Site | Google Scholar
216. C. S. Ku, Y. Yang, Y. Park, and J. Lee, “Health benefits of blue-green algae: prevention of cardiovascular disease and nonalcoholic fatty liver disease,” Journal of Medicinal Food, vol. 16, no. 2, pp. 103–111, 2013. View at: Publisher Site | Google Scholar
217. M. Nagarajan, V. Maruthanayagam, and M. Sundararaman, “A review of pharmacological and toxicological potentials of marine cyanobacterial metabolites,” Journal of Applied Toxicology, vol. 32, no. 3, pp. 153–185, 2012. View at: Publisher Site | Google Scholar
218. R. Raja, S. Hemaiswarya, V. Ganesan, and I. S. Carvalho, “Recent developments in therapeutic applications of Cyanobacteria,” Critical Reviews in Microbiology, vol. 42, no. 3, pp. 394–405, 2016. View at: Google Scholar
219. M. A. Borowitzka, “Chapter 3-biology of microalgae,” in Microalgae in Health and Disease Prevention, I. A. Levine and J. Fleurence, Eds., pp. 23–72, Academic Press, Cambridge, MA, USA, 2018. View at: Google Scholar
220. F. Zhang, J. Lu, J. G. Zhang, and J. X. Xie, “Protective effects of a polysaccharide from Spirulina platensis on dopaminergic neurons in an MPTP-induced Parkinson’s disease model in C57BL/6J mice,” Neural Regeneration Research, vol. 10, no. 2, pp. 308–313, 2015. View at: Publisher Site | Google Scholar
221. F. A. V. Lima, I. P. Joventino, F. P. Joventino et al., “Neuroprotective activities of spirulina platensis in the 6-OHDA model of parkinson’s disease are related to its anti-inflammatory effects,” Neurochemical Research, vol. 42, no. 12, pp. 3390–3400, 2017. View at: Publisher Site | Google Scholar
222. P. Bermejo-Bescós, E. Piñero-Estrada, and Á.M. Villar del Fresno, “Neuroprotection by Spirulina platensis protean extract and phycocyanin against iron-induced toxicity in SH-SY5Y neuroblastoma cells,” Toxicology in Vitro, vol. 22, no. 6, pp. 1496–1502, 2008. View at: Publisher Site | Google Scholar
223. P. Bermejo, E. Piñero, and Á. M. Villar, “Iron-chelating ability and antioxidant properties of phycocyanin isolated from a protean extract of Spirulinaplatensis,” Food Chemistry, vol. 110, no. 2, pp. 436–445, 2008. View at: Publisher Site | Google Scholar
224. J.-C. Chen, K. S. Liu, T.-J. Yang, J.-H. Hwang, Y.-C. Chan, and I. T. Lee, “Spirulina and C-phycocyanin reduce cytotoxicity and inflammation-related genes expression of microglial cells,” Nutritional Neuroscience, vol. 15, no. 6, pp. 252–256, 2012. View at: Publisher Site | Google Scholar
225. R. A. Kay and L. L. Barton, “Microalgae as food and supplement,” Critical Reviews in Food Science and Nutrition, vol. 30, no. 6, pp. 555–573, 1991. View at: Publisher Site | Google Scholar
226. J. C. Lee, M. F. Hou, H. W. Huang et al., “Marine algal natural products with anti-oxidative, anti-inflammatory, and anti-cancer properties,” Cancer Cell International, vol. 13, pp. 55–61, 2013. View at: Publisher Site | Google Scholar
227. E.-J. Koh, K.-J. Kim, J.-H. Song et al., “Spirulina maxima extract ameliorates learning and memory impairments via inhibiting GSK-3β phosphorylation induced by intracerebroventricular injection of amyloid-β 1–42 in mice,” International Journal of Molecular Sciences, vol. 18, no. 11, p. 2401, 2017. View at: Publisher Site | Google Scholar
228. E.-J. Koh, K.-J. Kim, J. Choi, D.-H. Kang, and B.-Y. Lee, “Spirulina maxima extract prevents cell death through BDNF activation against amyloid beta 1–42 (Aβ1-42) induced neurotoxicity in PC12 cells,” Neuroscience Letters, vol. 673, pp. 33–38, 2018. View at: Publisher Site | Google Scholar
229. G. Chamorro, M. Pérez-Albiter, N. Serrano-García, J. J. Mares-Sámano, and P. Rojas, “Spirulina maxima pretreatment partially protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity,” Nutritional Neuroscience, vol. 9, no. 5-6, pp. 207–212, 2006. View at: Publisher Site | Google Scholar
230. J. C. Tobon-Velasco, V. Palafox-Sanchez, L. Mendieta et al., “Antioxidant effect of Spirulina (Arthrospira) maxima in a neurotoxic model caused by 6-OHDA in the rat striatum,” Journal of Neural Transmission, vol. 120, no. 8, pp. 1179–1189, 2013. View at: Publisher Site | Google Scholar
231. A. Pérez-Juárez, J. Pacheco-Rosado, N. Paniagua, C. Alva Sánchez, and G. Chamorro, “Neuroprotective effect of spirulina (arthrospira) maxima against kainic acid-induced neurotoxicity,” Journal of Medicinal Plants Research, vol. 6, no. 2, 2012. View at: Publisher Site | Google Scholar
232. W. Y. Choi, H. K. Do, and H. Y. Lee, “Effect of fermented Spirulina maxima extract on cognitive-enhancing activities in mice with scopolamine-induced dementia,” Evidence-Based Complementary and Alternative Medicine, vol. 2018, Article ID 7218504, 9 pages, 2018. View at: Publisher Site | Google Scholar
233. E. J. Koh, Y. J. Seo, J. Choi et al., “Spirulina maxima extract prevents neurotoxicity via promoting activation of BDNF/CREB signaling pathways in neuronal cells and mice,” Molecules, vol. 22, p. 8, 2017. View at: Publisher Site | Google Scholar
234. N. Zhang, D. Dou, X. Ran, and T. Kang, “Neuroprotective effect of arctigenin against neuroinflammation and oxidative stress induced by rotenone,” RSC Advances, vol. 8, no. 5, pp. 2280–2292, 2018. View at: Publisher Site | Google Scholar
235. P. Chonpathompikunlert, P. Boonruamkaew, W. Sukketsiri, P. Hutamekalin, and M. Sroyraya, “The antioxidant and neurochemical activity of Apium graveolens L. and its ameliorative effect on MPTP-induced Parkinson-like symptoms in mice,” BMC Complementary and Alternative Medicine, vol. 18, no. 1, p. 103, 2018. View at: Publisher Site | Google Scholar
236. V. Venkateshgobi, S. Rajasankar, W. Johnson, K. Prabu, and M. Ramkumar, “Neuroprotective effect of agaricus blazei extract against rotenone-induced motor and nonmotor symptoms in experimental model of parkinson’s disease,” International Journal of Nutrition, Pharmacology, Neurological Diseases, vol. 8, no. 2, pp. 59–65, 2018. View at: Google Scholar
237. V. VenkateshGobi, S. Rajasankar, M. Ramkumar et al., “Agaricus blazei extract abrogates rotenone-induced dopamine depletion and motor deficits by its anti-oxidative and anti-inflammatory properties in Parkinsonic mice,” Nutritional Neuroscience, vol. 21, no. 9, pp. 657–666, 2018. View at: Publisher Site | Google Scholar
238. Z.-X. Ren, Y.-F. Zhao, T. Cao, and X.-C. Zhen, “Dihydromyricetin protects neurons in an MPTP-induced model of Parkinson’s disease by suppressing glycogen synthase kinase-3 beta activity,” Acta Pharmacologica Sinica, vol. 37, no. 10, pp. 1315–1324, 2016. View at: Publisher Site | Google Scholar
239. Q. Ye, W. Wang, C. Hao, and X. Mao, “Agaropentaose protects SH-SY5Y cells against 6-hydroxydopamine-induced neurotoxicity through modulating NF-κB and p38MAPK signaling pathways,” Journal of Functional Foods, vol. 57, pp. 222–232, 2019. View at: Publisher Site | Google Scholar
240. A. M. Ameen, A. Y. Elkazaz, H. M. F. Mohammad, and B. M. Barakat, “Anti-inflammatory and neuroprotective activity of boswellic acids in rotenone parkinsonian rats,” Canadian Journal of Physiology and Pharmacology, vol. 95, no. 7, pp. 819–829, 2017. View at: Publisher Site | Google Scholar
241. A.-S. Omar M.E., A. S. Amany, R. Y. Eman, N. Y. Noha, S. Nermeen, and A. E.-T. Sayed, “Capsicum protects against rotenone-induced toxicity in mice brain via reduced oxidative stress and 5-lipoxygenase activation,” Journal of Pharmacy and Pharmacology Research, vol. 2, no. 3, pp. 60–77, 2018.
242. R.-Y. Pan, J. Ma, H.-T. Wu, Q.-S. Liu, X.-Y. Qin, and Y. Cheng, “Neuroprotective effects of a Coeloglossum viride var. Bracteatum extract in vitro and in vivo,” Scientific Reports, vol. 7, no. 1, p. 9209, 2017. View at: Publisher Site | Google Scholar
243. R. P. Ojha, M. Rastogi, B. P. Devi, A. Agrawal, and G. P. Dubey, “Neuroprotective effect of curcuminoids against inflammation-mediated dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease,” Journal of Neuroimmune Pharmacology, vol. 7, no. 3, pp. 609–618, 2012. View at: Publisher Site | Google Scholar
244. S. Ojha, H. Javed, S. Azimullah, and M. E. Haque, “β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease,” Molecular and Cellular Biochemistry, vol. 418, no. 1-2, pp. 59–70, 2016. View at: Publisher Site | Google Scholar
245. M. A. Mori, A. M. Delattre, B. Carabelli et al., “Neuroprotective effect of omega-3 polyunsaturated fatty acids in the 6-OHDA model of Parkinson’s disease is mediated by a reduction of inducible nitric oxide synthase,” Nutritional Neuroscience, vol. 21, no. 5, pp. 341–351, 2018. View at: Publisher Site | Google Scholar
246. S. Chompoopong, S. Jarungjitaree, T. Punbanlaem et al., “Neuroprotective effects of germinated Brown rice in rotenone-induced Parkinson’s-like disease rats,” NeuroMolecular Medicine, vol. 18, no. 3, pp. 334–346, 2016. View at: Publisher Site | Google Scholar
247. K. Aruna, P. D. R. Rajeswari, and S. R. Sankar, “The effect of Oxalis corniculata extract against the behavioral changes induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice,” Journal of Applied Pharmaceutical Science, vol. 7, no. 03, pp. 148–153, 2017. View at: Google Scholar
248. M. Sarbishegi, E. A. Charkhat Gorgich, O. Khajavi, G. Komeili, and S. Salimi, “The neuroprotective effects of hydro-alcoholic extract of olive (Olea europaea L.) leaf on rotenone-induced Parkinson’s disease in rat,” Metabolic Brain Disease, vol. 33, no. 1, pp. 79–88, 2018. View at: Publisher Site | Google Scholar
249. G. Zhu, X. Wang, S. Wu, X. Li, and Q. Li, “Neuroprotective effects of puerarin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson’s disease model in mice,” Phytotherapy Research, vol. 28, no. 2, pp. 179–186, 2014. View at: Publisher Site | Google Scholar
250. J. Wang, H. Xu, H. Jiang, X. Du, P. Sun, and J. Xie, “Neurorescue effect of rosmarinic acid on 6-hydroxydopamine-lesioned nigral dopamine neurons in rat model of Parkinson’s disease,” Journal of Molecular Neuroscience, vol. 47, no. 1, pp. 113–119, 2012. View at: Publisher Site | Google Scholar
251. H.-C. Chang, K.-F. Liu, C.-J. Teng et al., “Sophora tomentosa extract prevents MPTP-induced parkinsonism in C57BL/6 mice via the inhibition of GSK-3β phosphorylation and oxidative stress,” Nutrients, vol. 11, no. 2, p. 252, 2019. View at: Publisher Site | Google Scholar
252. J. Kosaraju, S. Chinni, P. D. Roy, E. Kannan, A. S. Antony, and M. N. Kumar, “Neuroprotective effect of Tinospora cordifolia ethanol extract on 6-hydroxy dopamine induced Parkinsonism,” Indian Journal of Pharmacology, vol. 46, no. 2, pp. 176–180, 2014. View at: Publisher Site | Google Scholar
253. S. Alzahrani, W. Ezzat, R. E. Elshaer et al., “Standarized Tribulus terrestris extract protects against rotenone-induced oxidative damage and nigral dopamine neuronal loss in mice,” Journal of Physiology and Pharmacology, vol. 69, p. 6, 2018. View at: Google Scholar
254. R. Bisht, B. C. Joshi, A. N. Kalia, and A. Prakash, “Antioxidant-rich fraction of urtica dioica mediated rescue of striatal mito-oxidative damage in MPTP-induced behavioral, cellular, and neurochemical alterations in rats,” Molecular Neurobiology, vol. 54, no. 7, pp. 5632–5645, 2017. View at: Publisher Site | Google Scholar
255. F. W. Ibrahim, U. Noraashikin Zainudin, M. Abdul Latif, and A. Hamid, “Neuroprotective effects of ethyl acetate extract of Zingiber zerumbet (L.) smith against oxidative stress on paraquat-induced parkinsonism in rats,” Sains Malaysiana, vol. 47, no. 10, pp. 2337–2347, 2018. View at: Publisher Site | Google Scholar
256. N. Hishikawa, Y. Takahashi, Y. Amakusa et al., “Effects of turmeric on Alzheimer’s disease with behavioral and psychological symptoms of dementia,” Ayu, vol. 33, no. 4, pp. 499–504, 2012. View at: Publisher Site | Google Scholar
257. J. E. de la Rubia Orti, M. P. Garcia-Pardo, E. Drehmer et al., “Improvement of main cognitive functions in patients with alzheimer’s disease after treatment with coconut oil enriched mediterranean diet: a pilot study,” Journal of Alzheimer’s Disease, vol. 65, no. 2, pp. 577–587, 2018. View at: Publisher Site | Google Scholar
258. N. H. Azmi, M. Ismail, N. Ismail, M. U. Imam, N. B. M. Alitheen, and M. A. Abdullah, “Germinated brown rice alters Aβ (1–42) aggregation and modulates Alzheimer’s disease-related genes in differentiated human SH-SY5Y cells,” Evidence-Based Complementary and Alternative Medicine, vol. 2015, Article ID 153684, 12 pages, 2015. View at: Publisher Site | Google Scholar
259. R. Wang and X. C. Tang, “Neuroprotective effects of huperzine A. A natural cholinesterase inhibitor for the treatment of Alzheimer’s disease,” Neurosignals, vol. 14, no. 1-2, pp. 71–82, 2005. View at: Publisher Site | Google Scholar
260. S. S. Xu, Z. X. Gao, Z. Weng et al., “Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer’s disease,” Zhongguo Yao Li Xue Bao, vol. 16, no. 5, pp. 391–395, 1995. View at: Google Scholar
261. P. A. Postu, J. A. K. Noumedem, O. Cioanca et al., “Lactuca capensis reverses memory deficits in Aβ1-42-induced an animal model of Alzheimer’s disease,” Journal of Cellular and Molecular Medicine, vol. 22, no. 1, pp. 111–122, 2018. View at: Publisher Site | Google Scholar
262. T. Ali, G. H. Yoon, S. A. Shah, H. Y. Lee, and M. O. Kim, “Osmotin attenuates amyloid beta-induced memory impairment, tau phosphorylation and neurodegeneration in the mouse hippocampus,” Scientific Reports, vol. 5, Article ID 11708, 2015. View at: Publisher Site | Google Scholar
263. L. Zhang, Z. Zhou, W. Zhai et al., “Safflower yellow attenuates learning and memory deficits in amyloid β-induced Alzheimer’s disease rats by inhibiting neuroglia cell activation and inflammatory signaling pathways,” Metabolic Brain Disease, vol. 34, no. 3, pp. 927–939, 2019. View at: Publisher Site | Google Scholar
264. O. Khongsombat, W. nakdook, and K. ingkaninan, “Inhibitory effects of Tabernaemontana divaricata root extract on oxidative stress and neuronal loss induced by amyloid β25–35 peptide in mice,” Journal of Traditional and Complementary Medicine, vol. 8, no. 1, pp. 184–189, 2018. View at: Publisher Site | Google Scholar
265. P. Martinez-Oliveira, M. F. de Oliveira, N. Alves et al., “Yacon leaf extract supplementation demonstrates neuroprotective effect against memory deficit related to β-amyloid-induced neurotoxicity,” Journal of Functional Foods, vol. 48, pp. 665–675, 2018. View at: Publisher Site | Google Scholar
266. A. N. Winter, E. K. Ross, H. M. Wilkins et al., “An anthocyanin-enriched extract from strawberries delays disease onset and extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis,” Nutritional Neuroscience, vol. 21, no. 6, pp. 414–426, 2018. View at: Publisher Site | Google Scholar
267. K.-K. Huang, M.-N. Lin, Y.-L. Hsu, I.-H. Lu, I.-H. Pan, and J.-L. Yang, “Alpinia oxyphylla fruit extract ameliorates experimental autoimmune encephalomyelitis through the regulation of Th1/Th17 cells,” Evidence-Based Complementary and Alternative Medicine, vol. 2019, Article ID 6797030, 15 pages, 2019. View at: Publisher Site | Google Scholar
268. M. Wang, Y. Xie, Y. Zhong et al., “Amelioration of experimental autoimmune encephalomyelitis by isogarcinol extracted from Garcinia mangostana L. Mangosteen,” Journal of Agricultural and Food Chemistry, vol. 64, no. 47, pp. 9012–9021, 2016. View at: Publisher Site | Google Scholar
269. M. Ahn, J. Kim, W. Yang et al., “Amelioration of experimental autoimmune encephalomyelitis by Ishige okamurae,” Anatomy and Cell Biology, vol. 51, no. 4, pp. 292–298, 2018. View at: Publisher Site | Google Scholar
270. N. A. Noor, H. M. Fahmy, F. F. Mohammed, A. A. Elsayed, and N. M. Radwan, “Nigella sativa amliorates inflammation and demyelination in the experimental autoimmune encephalomyelitis-induced Wistar rats,” International Journal of Clinical and Experimental Pathology, vol. 8, no. 6, pp. 6269–6286, 2015. View at: Google Scholar
271. W. Li, H. Wu, C. Gao, D. Yang, D. Yang, and J. Shen, “Radix rehmanniae extract ameliorates experimental autoimmune encephalomyelitis by suppressing macrophage-derived nitrative damage,” Frontiers in Physiology, vol. 9, p. 864, 2018. View at: Publisher Site | Google Scholar
272. S. Giacoppo, M. Galuppo, G. E. Lombardo et al., “Neuroprotective effects of a polyphenolic white grape juice extract in a mouse model of experimental autoimmune encephalomyelitis,” Fitoterapia, vol. 103, pp. 171–186, 2015. View at: Publisher Site | Google Scholar
273. N. Thangthaeng, S. M. Poulose, D. R. Fisher, and B. Shukitt-Hale, “Walnut extract modulates activation of microglia through alteration in intracellular calcium concentration,” Nutrition Research, vol. 49, pp. 88–95, 2018. View at: Publisher Site | Google Scholar
274. S. Maqbool, I. Younus, R. Sadaf, and A. Fatima, “Neuro-pharmacological evaluation of anticonvulsant and neuroprotective activity of Cocculus laurifolius leaves in wistar rats,” Metabolic Brain Disease, vol. 34, no. 4, pp. 991–999, 2019. View at: Publisher Site | Google Scholar
275. S.-J. Zhong, L. Wang, H.-T. Wu, R. Lan, and X.-Y. Qin, “Coeloglossum viride var. bracteatum extract improves learning and memory of chemically-induced aging mice through upregulating neurotrophins BDNF and FGF2 and sequestering neuroinflammation,” Journal of Functional Foods, vol. 57, pp. 40–47, 2019. View at: Publisher Site | Google Scholar
276. T. Jawaid, M. Kamal, R. Singh, D. Shukla, V. Devanathadesikan, and M. Sinha, “Anticonvulsant and neuroprotective effects of methanolic extract of Cinnamomum camphora leaves in rat brain,” Oriental Pharmacy and Experimental Medicine, vol. 18, no. 3, pp. 237–246, 2018. View at: Publisher Site | Google Scholar
277. H. M. Aldawsari, B. G. Eid, T. Neamatallah, S. A. Zaitone, and J. M. Badr, “Anticonvulsant and neuroprotective activities of phragmanthera austroarabica extract in pentylenetetrazole-kindled mice,” Evidence-Based Complementary and Alternative Medicine, vol. 2017, Article ID 5148219, 12 pages, 2017. View at: Publisher Site | Google Scholar
278. H. A. Fachim, M. R. Mortari, L. Gobbo-Netto, and W. F. Dos Santos, “Neuroprotective activity of parawixin 10, a compound isolated from Parawixia bistriata spider venom (Araneidae: araneae) in rats undergoing intrahippocampal NMDA microinjection,” Pharmacognosy Magazine, vol. 11, no. 43, pp. 579–585, 2015. View at: Google Scholar
279. H. A. Fachim, A. O. Cunha, A. C. Pereira et al., “Neurobiological activity of Parawixin 10, a novel anticonvulsant compound isolated from Parawixia bistriata spider venom (Araneidae: araneae),” Epilepsy and Behavior, vol. 22, no. 2, pp. 158–164, 2011. View at: Publisher Site | Google Scholar
280. J.-M. Yon, Y.-B. Kim, and D. Park, “The ethanol fraction of white rose petal extract abrogates excitotoxicity-induced neuronal damage in vivo and in vitro through inhibition of oxidative stress and proinflammation,” Nutrients, vol. 10, no. 10, p. 1375, 2018. View at: Publisher Site | Google Scholar
281. E. Naderali, F. Nikbakht, S. N. Ofogh, and H. Rasoolijazi, “The role of rosemary extract in degeneration of hippocampal neurons induced by kainic acid in the rat: a behavioral and histochemical approach,” Journal of Integrative Neuroscience, vol. 17, no. 1, pp. 19–25, 2018. View at: Publisher Site | Google Scholar
282. S. Hu, P. Maiti, Q. Ma et al., “Clinical development of curcumin in neurodegenerative disease,” Expert Review of Neurotherapeutics, vol. 15, no. 6, pp. 629–637, 2015. View at: Publisher Site | Google Scholar
283. S. Rigacci and M. Stefani, “Nutraceuticals and amyloid neurodegenerative diseases: a focus on natural phenols,” Expert Review of Neurotherapeutics, vol. 15, no. 1, pp. 41–52, 2015. View at: Publisher Site | Google Scholar
284. M. Singh, M. Arseneault, T. Sanderson, V. Murthy, and C. Ramassamy, “Challenges for research on polyphenols from foods in Alzheimer’s disease: bioavailability, metabolism, and cellular and molecular mechanisms,” Journal of Agricultural and Food Chemistry, vol. 56, no. 13, pp. 4855–4873, 2008. View at: Publisher Site | Google Scholar
285. D. Zhao, J. E. Simon, and Q. Wu, “A critical review on grape polyphenols for neuroprotection: strategies to enhance bioefficacy,” Critical Reviews in Food Science and Nutrition, vol. 60, no. 4, pp. 597–625, 2020. View at: Publisher Site | Google Scholar
286. A. R. Bilia, V. Piazzini, L. Risaliti et al., “Nanocarriers: a successful tool to increase solubility, stability and optimise bioefficacy of natural constituents,” Current Medicinal Chemistry, vol. 26, no. 24, pp. 4631–4656, 2019. View at: Publisher Site | Google Scholar
287. J. Renaud and M. G. Martinoli, “Considerations for the use of polyphenols as therapies in neurodegenerative diseases,” International Journal of Molecular Sciences, vol. 20, no. 8, 2019. View at: Publisher Site | Google Scholar
288. M. Cascella, S. Bimonte, M. R. Muzio, V. Schiavone, and A. Cuomo, “The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: an overview of pre-clinical studies and translational perspectives in clinical practice,” Infectious Agents and Cancer, vol. 12, no. 1, p. 36, 2017. View at: Publisher Site | Google Scholar
289. M. J. Rein, M. Renouf, C. Cruz-Hernandez, L. Actis-Goretta, S. K. Thakkar, and M. da Silva Pinto, “Bioavailability of bioactive food compounds: a challenging journey to bioefficacy,” British Journal of Clinical Pharmacology, vol. 75, no. 3, pp. 588–602, 2013. View at: Publisher Site | Google Scholar
290. A. B. Hodgson, R. K. Randell, and A. E. Jeukendrup, “The effect of green tea extract on fat oxidation at rest and during exercise: evidence of efficacy and proposed mechanisms,” Advances in Nutrition, vol. 4, no. 2, pp. 129–140, 2013. View at: Publisher Site | Google Scholar
291. R. A. Sharma, W. P. Steward, and A. J. Gescher, “Pharmacokinetics and pharmacodynamics of curcumin,” Advances In Experimental Medicine And Biology, vol. 595, pp. 453–470, 2007. View at: Publisher Site | Google Scholar
292. A. N. Begum, M. R. Jones, G. P. Lim et al., “Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer’s disease,” Journal of Pharmacology and Experimental Therapeutics, vol. 326, no. 1, pp. 196–208, 2008. View at: Publisher Site | Google Scholar
293. M. Rakotoarisoa and A. Angelova, “Amphiphilic nanocarrier systems for curcumin delivery in neurodegenerative disorders,” Medicines, vol. 5, no. 4, p. 126, 2018. View at: Publisher Site | Google Scholar
294. Y. Shoji and H. Nakashima, “Nutraceutics and delivery systems,” Journal of Drug Targeting, vol. 12, no. 6, pp. 385–391, 2004. View at: Publisher Site | Google Scholar
295. M. Coimbra, B. Isacchi, L. van Bloois et al., “Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes,” International Journal of Pharmaceutics, vol. 416, no. 2, pp. 433–442, 2011. View at: Publisher Site | Google Scholar
296. M. Ovais, N. Zia, I. Ahmad et al., “Phyto-therapeutic and nanomedicinal approaches to cure alzheimer’s disease: present status and future opportunities,” Frontiers in Aging Neuroscience, vol. 10, p. 284, 2018. View at: Publisher Site | Google Scholar
297. X. Niu, J. Chen, and J. Gao, “Nanocarriers as a powerful vehicle to overcome blood-brain barrier in treating neurodegenerative diseases: focus on recent advances,” Asian Journal of Pharmaceutical Sciences, vol. 14, no. 5, pp. 480–496, 2019. View at: Publisher Site | Google Scholar
298. D. M. Teleanu, I. Negut, V. Grumezescu, A. M. Grumezescu, and R. I. Teleanu, “Nanomaterials for drug delivery to the central nervous system,” Nanomaterials, vol. 9, no. 3, p. 371, 2019. View at: Publisher Site | Google Scholar
299. N. Poovaiah, Z. Davoudi, H. Peng et al., “Treatment of neurodegenerative disorders through the blood-brain barrier using nanocarriers,” Nanoscale, vol. 10, no. 36, pp. 16962–16983, 2018. View at: Publisher Site | Google Scholar
300. S. T. Rahaman, “The role of nanomedicine in the treatment of neurodegenerative disorders,” in Nanobiotechnology in Neurodegenerative Diseases, M. Rai and A. Yadav, Eds., pp. 49–63, Springer International Publishing, Berlin, Germany, 2019. View at: Google Scholar
301. C. Saraiva, C. Praça, R. Ferreira, T. Santos, L. Ferreira, and L. Bernardino, “Nanoparticle-mediated brain drug delivery: overcoming blood–brain barrier to treat neurodegenerative diseases,” Journal of Controlled Release, vol. 235, pp. 34–47, 2016. View at: Publisher Site | Google Scholar
302. A. Smith, B. Giunta, P. C. Bickford, M. Fountain, J. Tan, and R. D. Shytle, “Nanolipidic particles improve the bioavailability and alpha-secretase inducing ability of epigallocatechin-3-gallate (EGCG) for the treatment of Alzheimer’s disease,” International Journal of Pharmaceutics, vol. 389, no. 1-2, pp. 207–212, 2010. View at: Publisher Site | Google Scholar
303. R. Bhatt, D. Singh, A. Prakash, and N. Mishra, “Development, characterization and nasal delivery of rosmarinic acid-loaded solid lipid nanoparticles for the effective management of Huntington’s disease,” Drug Delivery, vol. 22, no. 7, pp. 931–939, 2015. View at: Publisher Site | Google Scholar
304. M. L. Del Prado-Audelo, I. H. Caballero-Florán, J. A. Meza-Toledo et al., “Formulations of curcumin nanoparticles for brain diseases,” Biomolecules, vol. 9, p. 56, 2019. View at: Publisher Site | Google Scholar

Copyright

Copyright © 2020 Nur Shafika Mohd Sairazi and K. N. S. Sirajudeen. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.