Oxidative Medicine and Cellular Longevity

Oxidative Medicine and Cellular Longevity / 2020 / Article
Special Issue

Interplay of Inflammatory Cytokines and Oxidative Stress in Neurodegenerative Diseases

View this Special Issue

Review Article | Open Access

Volume 2020 |Article ID 3153082 | https://doi.org/10.1155/2020/3153082

Bangrong Cai, Ying Zhang, Zengtao Wang, Dujuan Xu, Yongyan Jia, Yanbin Guan, Aimei Liao, Gaizhi Liu, ChangJu Chun, Jiansheng Li, "Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances", Oxidative Medicine and Cellular Longevity, vol. 2020, Article ID 3153082, 16 pages, 2020. https://doi.org/10.1155/2020/3153082

Therapeutic Potential of Diosgenin and Its Major Derivatives against Neurological Diseases: Recent Advances

Academic Editor: Roman Fischer
Received20 Aug 2019
Revised16 Dec 2019
Accepted30 Dec 2019
Published06 Mar 2020

Abstract

Diosgenin (DG), a well-known steroidal sapogenin, is present abundantly in medicinal herbs such as Dioscorea rhizome, Dioscorea villosa, Trigonella foenum-graecum, Smilax China, and Rhizoma polgonati. DG is utilized as a major starting material for the production of steroidal drugs in the pharmaceutical industry. Due to its wide range of pharmacological activities and medicinal properties, it has been used in the treatment of cancers, hyperlipidemia, inflammation, and infections. Numerous studies have reported that DG is useful in the prevention and treatment of neurological diseases. Its therapeutic mechanisms are based on the mediation of different signaling pathways, and targeting these pathways might lead to the development of effective therapeutic agents for neurological diseases. The present review mainly summarizes recent progress using DG and its derivatives as therapeutic agents for multiple neurological disorders along with their various mechanisms in the central nervous system. In particular, those related to therapeutic efficacy for Parkinson’s disease, Alzheimer’s disease, brain injury, neuroinflammation, and ischemia are discussed. This review article also critically evaluates existing limitations associated with the solubility and bioavailability of DG and discusses imperatives for translational clinical research. It briefly recapitulates recent advances in structural modification and novel formulations to increase the therapeutic efficacy and brain levels of DG. In the present review, databases of PubMed, Web of Science, and Scopus were used for studies of DG and its derivatives in the treatment of central nervous system diseases published in English until December 10, 2019. Three independent researchers examined articles for eligibility. A total of 150 articles were screened from the above scientific literature databases. Finally, a total of 46 articles were extracted and included in this review. Keywords related to glioma, ischemia, memory, aging, cognitive impairment, Alzheimer, Parkinson, and neurodegenerative disorders were searched in the databases based on DG and its derivatives.

1. Introduction

With an increasingly aging population, human neurological disorders have become a great burden in terms of impact on quality of life and living costs [1]. In developed countries, a dramatic improvement in average life expectancy has led to substantial increases in the prevalence of diseases that mainly afflict the elderly [2, 3]. Human neurological disorders, including stroke, Alzheimer’s disease, Parkinson’s disease, depression, ischemic brain injury, and spinal cord injury, resulting from gradual and progressive loss of neural cells in CNS can lead to nervous system dysfunction [4]. Currently, no clinically effective treatments are available for these diseases. The only options to treat CNS disorders are by using drugs and performing surgery [5, 6]. However, most patients with neurological diseases need lifelong medication and long-term use of drugs is associated with serious side effects. Surgical treatment often increases the chance of infection and leads to other dysfunctions. In recent years, natural medicine has shown a great potential to treat nervous system disorders in many western countries [7, 8].

Natural products (NPs) derived from medicinal herbs, plants, vegetables, and fruits play an important role in the prevention and treatment of various human diseases, including cancer, cardiovascular disorders, diabetes, obesity, metabolic syndromes, and neurological disorders. NPs isolated from Chinese herbs have been widely used in traditional medicine over centuries. Many natural products derived from herbs exhibit a wide range of pharmacological properties, including the antimalarial drug artemisinin from Artemisia apiacea [9], the anticancer drug paclitaxel from Taxus brevifolia [10], and quercetin found in various vegetables and fruits [11]. Diosgenin (DG) is a naturally occurring steroidal sapogenin isolated from Agavaceae, Dioscoreaceae, Liliaceae, Solanaceae, Scrophulariaceae, Amaryllidaceae, Leguminosae, and Rhamnaceae [1217]. It has been extensively studied for the management and treatment of different types of cancer [18], osteoporosis [19], cardiovascular diseases [20], atherosclerosis [21], diabetes mellitus [22], and skin diseases [23]. DG is being increasingly investigated in the treatment of neurological diseases [24]. Numerous studies have demonstrated that DG and its derivatives have preventive and therapeutic effects against various neurological disorders. Animal experiments have shown that DG is active in the treatment of nervous system diseases such as Parkinson’s disease and Alzheimer’s disease [2527].

Despite its pharmacological activities in the treatment of various diseases, the clinical application of DG is severely hindered by its low aqueous solubility, poor bioavailability and pharmacokinetics, and rapid biotransformation under physiological conditions [28]. Several recent reviews have provided a comprehensive account of its pharmacological effects in cancer [18], diabetes mellitus, metabolic syndrome [29], and others [24, 30]. In this review, we will discuss recent progress of DG as a therapeutic agent against various neurological diseases along with its mechanisms of action in CNS. This review also critically evaluates existing limitations of DG solubility and bioavailability. It briefly recapitulates recent advances involving structural modification and formulations to increase its therapeutic efficacy.

2. Chemistry of Diosgenin

Diosgenin (Figure 1, DG, 25R-spirost-en-3β-ol) is a C27 spiroketal steroid sapogenin belonging to a family of spirostanol steroidal compounds. Its molecular formula is C27H42O3 with a relative molecular mass of 414.62. DG is a white needle crystal or light amorphous powder with a proven thermal and chemical stability under various physical conditions [31]. DG is relatively stable against temperature and light exposure. However, DG is destabilized when it is exposed to hydrochloric acid [31]. DG is strongly hydrophobic (with Log ), and it is insoluble in water [32, 33]. The solubility of DG is around 0.7 ng/mL in aqueous medium [34]. However, it is highly soluble in most nonpolar organic solvents (such as chloroform, dichloroethane, propanol, ethyl acetate, and propylacetate) and in partially polar solvents (such as acetone, methanol, and anhydrous ethanol).

3. Sources of Diosgenin

Primary sources of diosgenin (DG) include the Dioscorea species, Heterosmilax species, and Trigonella foenum-graecum, although DG and related steroidal sapogenins can be commercially obtained from tubers of various Dioscorea species [17]. DG is present in high levels in tubers of various wild yams (D. villosa Linn). A total of 137 types of Dioscorea species contain DG. Of them, 41 contain DG at more than 1%. The seeds of fenugreek (T. foenum graecum Linn) [35] and the rhizomes of D. zingiberensis are also important sources of DG. In addition, Trillium govanianum and Costus speciosus contain around 2.5% and more than 2.12% of DG, respectively [3638]. DG is mainly generated by the hydrolysis of steroidal saponins in the presence of a strong acid, base, or enzyme catalyst [39]. Currently, microbial transformation is a promising method for the production of DG because of its environmentally friendly, highly specific, and mild reaction conditions at a low cost [36, 40].

4. Biosynthesis of Diosgenin

DG is biosynthesized from cholesterol via the isoprenoid pathway in several plant species [41, 42]. The biosynthesis of DG starts with acetyl CoA. It involves several steps to generate squalene that cyclizes to yield lanosterol. Lanosterol is further catalyzed to cholesterol by various enzymes. Cholesterol is sequentially converted to glucoside furostanols and spirostanols. These glycosides are eventually converted to spirostanols after the elimination of the glucose molecules at C26, resulting in ring closure during the catalysis of glucosidases. DG aglycone may convert to glycoside forms with mono-, di-, or trisaccharides known as saponins (Figure 1, Compounds 2 and 3; Compound 3 is also called dioscin). The attachment of a carbohydrate moiety improves both the solubility and potency of DG.

5. Toxicity and Safety of Diosgenin

Diosgenin (DG) shows high biocompatibility and low toxicity. For instance, in an acute study, the oral administration of a single dose of 112.5–9000 mg/kg ethanol extracts of Dioscorea sp. containing 28.34% DG (31.7-2550.6 mg/kg) did not result in any signs of acute toxicity in rats. In a subchronic toxicity study, Sprague-Dawley rats orally administrated with DG at doses of 127.5, 255, and 510 mg/kg/day for 30 days did not show any significant changes in biochemical or hematological parameters. DG was the main metabolite in the serum [43, 44]. Additionally, a toxicological assay using D. villosa (DV) root extract showed that both acute (5 g/kg, single dose) and subchronic (1 g/kg/day, 30 days) treatments of rats resulted in only unremarkable changes in hematological, biochemical, and histopathological parameters [45]. Wojcikowski et al. reported that no acute renal or hepatic toxicity was observed with a crude extract of DG obtained from D. villosa at a dose of 0.79 g/kg/day administered orally. However, an increase in kidney fibrosis and liver inflammation was found when mice received a continuous treatment for 28 days in the same study. In a 90-day subchronic study, no toxic sign was found in mice fed fenugreek seeds at doses of DG ranging from 1% to 10% [46]. However, an in vitro study showed deleterious effects of DG mediated via genetic instability. At concentrations greater than 30 μM, DG reduced cell viability and increased micronucleus frequency. It also has a significant cytostatic effect with DNA damage in HepG2 cells [47].

6. Bioavailability and Pharmacokinetic Studies of Diosgenin

Using a rat model, Okawara et al. have elucidated the pharmacological effect of cyclodextrin-bound diosgenin (DG). The peak level of DG in the skin was observed at 6 h after oral administration. The plasma concentration of an orally administered DG reached () at with an AUC of and an absolute oral bioavailability of [32, 33]. Similarly, Liu et al. have demonstrated that treatment with DG resulted in a of at along with an AUC0–60 h of and of [48]. It was suggested that a single dosage of DG administered to rats, monkeys, and dogs was mostly excreted into feces, while the amount absorbed was rapidly eliminated via bile. Tissue distribution of DG in rats most notably occurred in the liver, adrenals, and gastrointestinal walls. Unchanged DG at concentrations up to 15 μg/mL was found when multiple doses (100 mg/kg/day for 4 weeks) were administered to dogs. Several metabolites of DG were found in the bile of rats and dogs with a pattern of metabolites different in the two tested species. One of its major biliary metabolites was monohydroxylated diosgenin in the F ring. In humans, oral administration of DG at 3 g/day for 4 weeks did not alter the levels of DG in human serum (less than 1 mg/mL) [43].

7. Semisynthetic Derivatives of Diosgenin against Neurological Diseases

Although DG possesses numerous pharmacological activities against various diseases, it has weak biological activity, low aqueous solubility, poor pharmacokinetic profile, and instability under physiological conditions which greatly hinder its clinical application. Covalent modification of therapeutic agents is a clinically proven strategy that can enhance treatment efficacies. Semisynthetic modification of DG at C3 can address these issues by altering its physicochemical characteristics, thus improving its metabolic profile in terms of adsorption, distribution, metabolism, elimination, and biological activities.

To date, a variety of DG derivatives have been designed and synthesized, and most of them have shown improved physicochemical properties and enhanced pharmacological activities compared to parent drug DG. Semisynthetic DG derivatives can be roughly divided into four major categories on the basis of covalent linkage and attached functional entities. First, an amino acid prodrug strategy has been successfully used in the oral delivery of drugs that have low solubility and permeability [49, 50]. The introduction of an amino acid, either natural or its analog, to a parent drug generally can increase the aqueous solubility by orders of magnitude through an ionized carboxylate anion or the formation of amine salts. Moreover, various amino acid transporters are expressed in brush-border membranes of intestinal epithelial cells known to play a significant role in the absorption of several amino acid prodrugs [51]. In the past decade, a series of DG amino acid derivatives have been synthesized for the treatment of cancer, inflammation, diabetes, thrombosis, and neurodegenerative disorders [52]. Representative structures of diosgenin-arginine derivatives (Compound 4, Arg-DG) are presented in Figure 2 [50]. Second, the carbohydrate moiety plays a critical role in biological functions of steroidal saponins [53, 54]. An increasing number of synthetic steroidal saponins (DG-carbohydrates) have been created and tested for their biological activities mainly against inflammation and cancer (Compound 5) [55]. Third, DG-fatty acid derivatives with a hydrophobic moiety have been designed and prepared based on DG 3-caproate, also known as caprospinol, a naturally occurring compound in Gynura japonica that can protect neuronal cells from Aβ1–42 neurotoxicity [56]. Additionally, a series of DG derivatives with hydrophilic moieties such as PEG oligomers [28] and polyamines [57] have been synthesized to improve its solubility and biological activity (Compound 7). Fourth, DG-drug conjugates including DG moieties have been covalently linked to other therapeutic agents directly or via a linkage, forming codrugs with enhanced physicochemical, biopharmaceutical, and drug delivery properties (Compounds 8 and 9) [58, 59]. Several representatives of DG-drug conjugates reported in previous studies are presented in Figure 2.

8. Novel Formulations and Increased Bioavailability of Diosgenin

In addition to structural modification, drug delivery system, particularly nanotechnology, can be used to develop novel formulations with improved solubility, enhanced pharmacokinetics, and/or target delivery. Okawara et al. have prepared DG-cyclodextrin (CD) complexes to improve the skin concentration of DG and its pharmacokinetic profile, resulting in about 4- to 11-fold higher oral bioavailability of DG in the inclusion complex of DG/β-CD compared to a DG suspension [32, 33]. In addition, the bioavailability of DG has been further improved by combining β-CD and liquid crystal DG to enhance the bioavailability of poorly water-soluble drugs [34]. Recently, DG nanocrystals have been prepared via a media-milling method using a combination of pluronic F127 and sodium dodecyl sulfate as surface stabilizers, resulting in a significant improvement in the dissolution rate and pharmacokinetic profile compared to DG alone as well as increased bioavailability of DG [60]. An eight-arm-PEG-DG conjugate has been prepared for hydrophobic drug delivery via self-assembly to nanoparticles [61]. It has been reported that hyaluronate-DG conjugation via esterification can promote self-assembly into stable, negatively charged nanoparticles measuring 159-441 nm in water, which significantly enhances its solubility [62]. The DG-PEG conjugate can self-assemble into micelles in water, thus significantly enhancing the therapeutic efficacy for the prevention of arterial thrombus and venous thrombus [63].

9. Pharmacological Activity and Mechanism of Diosgenin and Its Derivatives in Central Nervous System (CNS) Diseases

The experimental design, pharmacological evidence, and underlying mechanism for diosgenin, dioscin, and diosgenin derivatives against various diseases in the central nervous system are summarized in Table 1.


EntryActive ingredientExperimental modelPharmacological effectMechanisms of actionRef

1Diosgenin5XFAD transgenic mouse model of AD;
Rat cortical neurons and mouse cortical neuron primary culture
Increased memory and decreased axonal degeneration;
Reduced amyloid plaques and neurofibrillary tangles in the cerebral cortex and hippocampus
1,25D₃-membrane-associated, rapid response steroid-binding protein (1,25D3-MARRS)[65]
2DiosgeninNormal mouseImproved memory and axonal density;
Increased c-Fos expression in the medial prefrontal and perirhinal cortices
1,25D3-MARRS-triggered axonal growth[66]
3DiosgeninTrimethyltin- (TMT-) injected transgenic 2576 (TG) miceDecreased the number of Aβ-stained plaques and dead cells in the granule cell layer of the dentate gyrus;
Reduced acetylcholinesterase (AChE) activity and Bax/Bcl-2 expression; increased expression of nerve growth factor (NGF) and superoxide dismutase (SOD) activity
Increased phosphorylation of downstream members in TrkA signaling;
Evaluated p75(NTR) expression and JNK phosphorylation in the NGF signaling pathway
[67]
4Compound 6Memory-impaired Long-Evans rats induced by infusion of Fe2+, Aβ42, and buthionine-sulfoximine (FAB) into the left cerebral ventricle for 4 weeksEnhanced cognitive function;
Decreased amyloid deposits, astrogliosis, and Tau protein phosphorylation in hippocampus
[68]
5Compound 6Aβ-induced neurotoxicity in rat PC12 and human NT2N neuronal cellsProtected against 0.1 μM Aβ in PC12 cells;
Reversed 0.1-10 μM Aβ-induced decrease in ATP levels
Physicochemical interaction with Aβ inhibited the formation of neurotoxic amyloid-derived diffusible ligands[70, 71]
6Compound 6Aβ1-42-induced SK-N-AS cellsProtected MPT and inhibited accumulation of the Aβ1-42 in the mitochondrial matrixDirectly targeting complexes IV and the mitochondrial respiratory chain[72]
7Compound 8A cellular AD model using MC65 neuroblastoma cells from TC withdrawal-induced cytotoxicityAntioxidative ability and inhibitory effects on amyloid-β oligomer (AβO) formationBind directly to Aβ[56]
8Compound 9A cellular AD model using MC65 neuroblastoma cells from TC withdrawal-induced cytotoxicity;
Neuronal N2a cells and rat primary cortical neurons
Significant stimulating activity on neurotic outgrowth and the state 3 oxidative rate of glutamate while preserving the coupling capacity of the mitochondriaInterfere with glutamate uptake or its redox reaction[27]
9Diosgenin-rich yam extractsSenescent mice induced by D-galactoseImprove their learning and memory abilities;
Increase the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) and decrease malondialdehyde (MDA) level
Enhancing endogenous antioxidant enzymatic activities[56, 58]
10DiosgeninPD model using Sprague-Dawley rats using intrastriatal injection of lipopolysaccharide (LPS)Attenuate the inflammatory and oxidative stress response;
Restore LPS-induced motor deficits;
Decrease the expression levels of TLR2, TLR4, and NF-κB
Inhibiting the TLR/NF-κB pathway[26]
11DiosgeninIn vitro model of HIV-induced dementia using human neuronal cultures with E4 allele of ApoEProtected against the neurotoxicity of Tat+morphine;
Tat-induced oxidative stress impaired morphine metabolism
[76]
12DiosgeninA rat model with brain aging through subcutaneous injection of D-galactoseImprove learning and memory;
Upregulating Rheb and downregulating mTOR
Rescuing dysfunctional autophagy mediated by Rheb-mTOR signal pathway
13Compound 3Neuroinflammation induced by intraperitoneal injection of LPSEnhanced the serotonergic system and produced the antidepressant effectProtects the hippocampus from LPS-induced neuroinflammation by the neurotransmitter 5-HT and the HMGB-1/TLR4 signaling pathway[80]
14Compound 2Neuroinflammation model using rat microglia and BV2 cells induced by LPSSuppressed the expression levels of proinflammatory M1 markers, such as NO, IL-6, and TNF-α;
Repressed IκB-α, ERK, MAPK, and p38 MAPK phosphorylation
Inhibiting NF-κB, ERK/MAP, and p38/MAPK signaling[81]
15Compound 7Neuroinflammation model using BV2 cells induced by LPSInhibition of the inflammatory mediators such as NO, iNOS, COX-2, IL-6/1b, and TNF-α in protein and mRNA levels;
Suppressed the NF-κB activity and phosphorylation level of JNK
Inactivation of NF-κB and JNK MAPK signaling[82]
16Compound 4Neuroinflammation model using BV2 cells or mice by I.C.V. injection of LPSImproved the cognitive function impaired by LPS and attenuated LPS-impaired neurogenesis;
Suppressed the production of proinflammatory cytokines in hippocampal DG
Blocking microglial activation;
Underlying NF-κB and JNK MAPK;
Signaling in LPS-induced adult mice
[57]
17DiosgeninC57BL/6J mice model of experimental autoimmune encephalomyelitisInhibit the activation of microglia and macrophages, suppress CD4+ T cell proliferation, and hinder Th1/Th17 cell differentiation[84]
18DiosgeninRat primary oligodendrocyte progenitor cell (OPC) culture model, a cuprizone-induced demyelination C57BL/6J mice modelSignificantly and specifically promotes OPC differentiation;
Enhances remyelination;
Increases the number of mature oligodendrocytes in the corpus callosum
Differentiation of OPC into mature oligodendrocytes through an ER-mediated ERK1/2 activation pathway to accelerate remyelination[85]
19Compound 2Sprague-Dawley rats with traumatic spinal cord injurySignificantly less tissue injury and edema;
Functional recovery
Significantly attenuated p62 expression and upregulated the Rheb/mTOR signaling pathway due to the downregulation of miR-155-3p[87]
20Compound 3Ischemic stroke rat modelImproved infarct volume and neurological scores;
Reduced inflammatory responses, and suppressed the expression of TLR4, MyD88, NF-κB, TGF-β1, HMGB-1, IRAK1, and TRAF6
Inhibition of TLR4/MyD88/NF-κB induced inflammation[89]
21Compound 5Thrombosis model using male balb/C miceProlonging the bleeding time;
Inhibited platelet aggregation, prolonged partial thromboplastin time (APTT), and inhibited factor VIII activities
[90]
22DiosgeninTransient focal cerebral ischemia-reperfusion (I/R) injury model by middle cerebral artery occlusion (MCAO) using the intraluminal thread for 90 minInhibited the death rate and improved the impaired neurological functions, neurological deficit scores, and cerebral infarct size;
Reduced cell apoptosis in the hippocampus CA1 and cortex;
Suppressed the production of proinflammatory cytokines TNF-α, IL-1β, and IL-6 in blood serum
Antiapoptosis, anti-inflammation, and intervening NF-κB signaling pathway[92]
23Compound 3In vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model and an in vivo middle cerebral artery occlusion (MCAO) modelPrevented OGD/R insult and cerebral I/R injury;
Inhibition in the expression and the nuclear-to-cytosolic translocation of HMGB-1;
Blockade of the TLR4/MyD88/TRAF6 signaling pathway;
Inhibited NF-κB and AP-1 transcriptional activities, inhibited MAPK and STAT3 phosphorylation, inhibited proinflammatory cytokine responses, and upregulated the levels of anti-inflammatory factors
HMGB-1/TLR4 signaling[93]
24Compound 3Cerebral ischemia-reperfusion model by middle cerebral artery occlusion (MCAO) ischemic miceEnhanced spatial learning memory in ischemic mice;
An improvement in deficient ability and reduction in infarct volume
[94]
25DiosgeninOvariectomized (OVX) female Wistar ratsDose-dependently influences IL-2 levels in the brain of OVX rats and affects depressive behavior in OVX with high-anxiety rats[95]
26DiosgeninNeuropathic pain model induced by chronic constriction injury (CCI) in ratsReversed the mechanical withdrawal threshold and thermal withdrawal latency;
Inhibited the expression levels of proinflammatory cytokines TNF-α, IL-1β, and IL-2;
Suppressed oxidative stress
Inhibiting activation of p38 MAPK and NF-κB signaling pathways[96]
27DiosgeninDiabetic neuropathy mice modelIncreased NGF levels in the sciatic nerve, enhanced neurite outgrowth in PC12 cells, and improved nerve conduction velocities;
Reduced disarrangement of the myelin sheath, increased area of myelinated axons, and an improvement in the damaged axons
Increased the nerve conduction velocity by induction of NGF[97]
28DiosgeninPeripheral nerve injury model using male Sprague-Dawley rat to crush the right sciatic nerve for 30 secIncreased sciatic function index (SFI) value;
Suppressed nerve injury-induced c-Fos expression in the ventrolateral periaqueductal gray (vlPAG) and paraventricular nucleus (PVN);
Increased expression levels of BDNF, TrkB, COX-2, and iNOS
[99]
29DiosgeninC6 rat glioma cellsReduced the dosage regimen of TMZ and overcome temozolomide resistance in TMZ-resistant GBM cells;
Underwent apoptosis and early cell cycle arrest with significant reduction in MMP-2 levels
Upregulation of MMP-2 level and apoptosis signaling pathway[103]
30Compound 3In vitro study using GBM, U87MG, A172, LN18, NBRC, T98G, and LN229 cell linesInhibited proliferation of C6 glioma cells, ROS generation caused mitochondrial damage and cell apoptosis;
Inhibited tumor size and extended the life cycle of rats
Increase in ROS accumulation, DNA damage, and mitochondrial-mediated apoptosis signaling[104]

9.1. Alzheimer’s Disease and Parkinson’s Diseases

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders characterized by learning disabilities and declining cognitive function. It is a multifactorial disease caused by multiple etiological and pathogenic mechanisms. However, the exact mechanism underlying AD remains unclear. Several hypotheses such as amyloid-β (Aβ) accumulation, hyperphosphorylation of Tau, altered energy metabolism, oxidative stress, and neuroinflammation have been proposed [64].

Extracellular aggregation of Aβ leading to the formation of plaques via stepwise formation of oligomers and fibrils is a neuropathological hallmark of AD brains. Reduction in Aβ has been considered as a major therapeutic strategy against AD [65]. Tohda et al. have reported that DG can significantly improve memory loss and spike firing in the medial prefrontal cortex and hippocampal CA1 in 5XFAD mice. The accumulation of Aβ plaques and neurofibrillary tangles in the cerebral cortex and hippocampus was significantly decreased after DG treatment. Additionally, DG treatment decreased the number of degenerated axons and presynaptic terminals in regions surrounding amyloid plaques. These events were mediated by 1,25D3-membrane-associated, rapid response steroid-binding protein (1,25D3-MARRS) [66, 67], or heat shock cognate 70 by normalization of α-tubulin expression, which is a potentially critical event in axonal formation [25]. Koh et al. have reported that DG can ameliorate multiple types of brain injury in transgenic 2576 (TG) mouse models, in which the accumulation of Aβ plaques is induced by Aβ-42 peptides and neurotoxicant trimethyltin (TMT). Their results demonstrated that the numbers of Aβ plaques and dead cells in the granule cell layer of the dentate gyrus were significantly decreased by pretreatment with DG for 21 days. Additionally, a significant increase in the expression of nerve growth factor (NGF) and variation in corresponding components of NGF signaling pathways were found, suggesting that DG could stimulate NGF biosynthesis in multiple types of brain damage [68].

Although extracellular accumulation of neurotoxic Aβ species in the brain has been proposed as one of the main events in early stages of AD, continued failure of clinical trials involving Aβ-targeting drugs have prompted scientists to explore alternative mechanisms and therapeutic strategies [69]. Neurofibrillary tangles (NFTs) mainly composed of hyperphosphorylated Tau are another histopathological hallmark of AD and associated tauopathies. Hyperphosphorylation of Tau protein can lead to neurodegenerative disorders. Tohda et al. found that DG treatment can also decrease the hyperphosphorylation of Tau protein in the cortex and hippocampus in an AD mouse model [66, 67].

Teper et al. have identified the diosgenin analog (22R,25R)-20α-spirost-5-en-3β-yl hexanoate (Figure 2, diosgenin 3-caproate; caprospinol, Compound 6) using the 22R-hydroxycholesterol chemical structure as a probe. Compound 6 is a naturally occurring compound in Gynura japonica, a plant belonging to the Asteraceae family. It can protect neuronal PC12 cells against Aβ1-42-induced neurotoxicity [70]. In later studies, Lecanu et al. and Tillement et al. have screened potential candidates among the prepared DG derivatives in human NT2N neuronal cells and PC12 cells against β-amyloid (1-42)- (Aβ-) induced neurotoxicity. Their results showed that DG and its derivatives exert their neuroprotective effect via inhibiting the formation of neurotoxic amyloid-derived diffusible ligands and preferentially binding to two binding sites of Aβ identified by computational docking simulations in contrast to 22R-hydroxycholesterol that could only bind a single site. A subsequent study has revealed that Compound 6 has a direct effect on mitochondrial function. It blocked Aβ uptake by mitochondria in neuronal cells and protected SK-N-AS cells from Aβ-induced mitochondrial impairment by targeting Complexes 4 and 5 of the respiratory chain, indicating that DG derivatives might have potential in AD therapy [71, 72]. Compound 6 can prevent the formation of amyloid-derived diffusible ligands (ADDLs) by binding to Aβ42, decreasing amyloid accumulation in mitochondria, and directly targeting the mitochondrial respiratory chain [73]. Lecanu et al. have found that the neuroprotective effect of Compound 6 against AD is mediated by decreasing the level of tau phosphorylation [74]. Compound 6 can significantly reduce neurodegeneration and attenuate memory loss and cognitive disorders in a rat model of AD. The recovery from cognitive impairment is accompanied by a reduction in amyloid accumulation in the hippocampus [74]. A series of DG derivatives with different lengths of lateral carbon chains at C3 have been investigated. The structure-activity relationship has revealed that a six-carbon Compound 6 is the most effective one among all tested derivatives at different concentrations. The closest analogs with chain lengths of 4 to 5 carbons failed to exhibit any neuroprotective activity at the lowest concentration of 10 μM, while the analogs with chains longer than C6 were less effective than Compound 6 [73]. Papadopoulos and Lecanu have reviewed the pharmacological activity of Compound 6 [56, 73].

Apart from the naturally occurring diosgenin derivatives such as Compound 6, a series of multifunctional, bivalent diosgenin-curcumin conjugates have been developed as neuroprotectants to combat AD [27, 58]. The results showed a clear structural preference for the introduction of the methylene carbon between diosgenin and curcumin. The conjugate with a spacer length of 17 atoms showed the highest protective activity in MC65 neuroblastoma cells and a decrease in neuroprotective activity was observed when the spacer length was extended to 28 atoms. The most potent Compounds 8 and 9 are presented in Figure 2. Their mechanism of action involves antioxidant activity and inhibitory effects on amyloid-β oligomer formation by directly binding to Aβ [58]. Additionally, DG can act as a membrane-anchoring moiety to improve the access to the cell membrane for the conjugates, suggesting that DG is a novel anchor that can facilitate the multifunctional role of bivalent conjugates for further development as potential therapeutic agents for AD treatment [27]. Recently, Yang et al. synthesized a series of multifunctional DG derivatives and evaluated their effect from Aβ-induced damage in PC12 cells and improved learning and memory impairments in Aβ-injected mice. Among them, Compound 10 (AA36) significantly prevented Aβ-induced PC12 cell damage and restored the cognitive impairment in Aβ-injected mice, suggesting that DG is a promising skeleton structure for anti-AD drug development [59].

Parkinson’s disease (PD) is another neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. The protective effect of DG against LPS-induced PD has been evaluated using a rat model. DG can attenuate LPS-induced motor deficits in rats by suppressing the TLR4/NF-κB signaling pathway [26]. Recently, Cai et al. has synthesized and evaluated the neuroprotective potential of the diosgenin-amino acid derivative and the diosgenin derivative conjugated with L-isoleucine (Compound 11) displayed a neuroprotective role on damaged SH-SY5Ycells by reducing apoptosis as well as promoting angiogenesis at 4 mg/mL on the chorioallantoic membrane model [75].

9.2. Cognitive Effects

Oxidative stress is intimately associated with cognitive function in neurodegenerative disorders such as Alzheimer’s disease. Chiu et al. have acknowledged the neuroprotective effects of DG-rich yam in senescent mice induced by D-galactose (D-gal). Compared with D-gal treatment alone, DG treatment for 4 weeks significantly restored learning and memory impairment in mice starting from week six. The mechanism is partly mediated through an increase in endogenous antioxidant enzyme activities [76]. They found similar results after treatment with DG at the concentration range of 5 to 125 mg/kg [77]. Turchan-Cholewo et al. have reported that DG may improve the cognitive impairment associated with human immunodeficiency virus (HIV) infection. Increased levels of oxidative stress and the E4 allele of apolipoprotein E (ApoE) have been found in the CNS of an HIV-infected population or in individuals with a history of intravenous drug abuse, and were considered as the risk factors contributing to the development of dementia. The results revealed that HIV proteins such as gp120, Tat, and Tat+morphine treatment increased the neurotoxicity in cultured human neuronal cells with ApoE4. DG can protect against neurotoxicity induced by Tat+morphine treatment, and the Tat-induced oxidative stress-impaired morphine metabolism can be prevented by DG treatment [78]. Moreover, the learning and memory capacity of Compound 2 derived from Trillium tschonoskii Maxim has been investigated in aging rats induced by D-gal with impaired cognitive function using the Morris water maze test. Treatment with Compound 2 improved the learning and memory capacity in aging rats induced by D-gal and the mechanism might be associated with rescuing dysfunctional autophagy via the upregulation of Rheb and the downregulation of mTOR signaling, suggesting that Compound 2 has potential in health promotion and aging-related disease therapy [79].

9.3. Neuroinflammation

Overactivated microglia are present in large numbers in several neurodegenerative disorders. Overproduction of various proinflammatory cytokines may result in neurotoxicity in neurodegenerative disorders. Cumulative evidence has suggested that microglial activation is an early and ongoing stage in neurodegenerative disorders. Anti-inflammatory drugs might be beneficial during the early stages of diseases in several animal models. They can inhibit microglial activation and result in the suppression of proinflammatory cytokines in the hippocampus, finally reversing the decline in memory and learning. It is a practical strategy to develop therapies by preventing the progression of neurodegenerative disorders via the modulation of the neuroinflammation markers in the hippocampus [80].

Binesh et al. have investigated the efficacy of DG in the amelioration of atherosclerotic progression in the heart and inhibition of inflammatory mediators in the liver and brain of Wistar rats treated with an atherogenic diet. DG can inhibit the inflammatory mediators triggered by atherogenic diet in the heart, liver, and brain of rats via the downregulation of COX-2, TNF-α, and NF-κBp65, thereby preventing atherosclerotic disease progression [81]. Yang et al. have reported that Compound 3 can rescue endotoxemia-induced neuroinflammation and has a neuroprotective effect on hippocampal neurogenesis impaired by neuroinflammation, which is consistent with the results obtained in the behavior test showing that Compound 3 reversed cognitive impairment. The endotoxemia-triggered neuroinflammation cascade involves the neurotransmitter 5-HT and the HMGB-1/TLR4 signaling pathway [82]. Wang et al. has reported that Compound 2 extracted from Tritulus terrestris L. can selectively inhibit inflammatory M1 markers (NO, IL-6, and TNF-α) in activated rat microglia and BV2 cells induced by LPS, without affecting the production of inflammatory M2 markers (IL-10, IL-1Rα, and CD206) in LPS- and IL-4-treated microglia. Its mechanism involves the inactivation of NF-κB, ERK1/2/MAPK, and p38/MAPK signaling pathways indicating that DG glycoside might be a potential candidate for the treatment of various neurodegenerative disorders mediated by neuroinflammation [83].

Recently, we reported that DG derivatives carrying primary amine (Compound 7, DGP) or the amino acid L-arginine (Compound 4, Arg-DG) at the C3 show a significant increase in aqueous solubility and anti-inflammatory activity in LPS-induced BV2 cells compared to DG. The possible mechanisms of both derivatives involve the inhibition of NF-κB activation and JNK/MAPK signaling [57, 84]. Arg-DG can also rescue hippocampal neurogenesis and cognitive function impaired by LPS via the inhibition of microglial overactivation, the expression of the TLR4 receptor and downstream signaling of NF-κB and JNK/MAPK, and the ultimate suppression of proinflammatory cytokines. Our results suggested that the chemical modification of DG might be an effective approach to improve its physicochemical properties and pharmacological activities in neurodegenerative disorders resulting from microglia-mediated neuroinflammation [84]. Interestingly, although the DG glycoside and DG derivatives including DGP and Arg-DG exhibited strong anti-inflammatory activity in LPS-induced microglial BV2 cells, they differed in inhibitory activity against MAPK signaling. Structural differences involving the substituted groups of DG at C3 might have led to the selective inhibition of MAPK subfamily members (ERK1/2, JNK, and p38).

9.4. Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease involving the central nervous system. Currently, curative drugs are unavailable for MS in clinics. Phagocytosis by microglia or macrophages is considered a hallmark of MS lesions. Activated microglia with different phenotypes exhibit either neuroprotective or neurotoxic effects in MS depending on the disease stage and severity of disease. They might lead to a relapsing-remitting MS [80, 85].

Recently, Liu et al. have reported the therapeutic potential of DG in an experimental autoimmune encephalomyelitis (EAE) model of mice using myelin oligodendrocyte glycoprotein. Their results showed that DG significantly alleviated the progression of EAE in mice and obviously reduced the inflammation and demyelination in the CNS. A mechanistic study has shown that DG can inhibit the microglial/macrophage activation, reduce CD4+ T cell proliferation, and suppress Th1/Th17 cell differentiation [86]. Additionally, in their earlier study involving a purified rat OPC culture model, DG significantly and specifically promoted the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes, which is considered as a prerequisite for remyelination after demyelination. Moreover, DG administration can enhance remyelination in a demyelination model induced by cuprizone. DG can also significantly increase the number of mature oligodendrocytes in the corpus callosum without affecting the number of OPCs. The underlying mechanism for the accelerated remyelination is attributed to the ER-mediated ERK1/2 activation. DG not only attenuates the progression of EAE, and reduces demyelination and inflammation of CNS as an immunomodulator, but also promotes the differentiation of OPCs, and enhance remyelination and the number of OPCs in demyelinating lesions of the CNS, suggesting that DG is a promising therapeutic candidate in the treatment of MS [87].

9.5. Spinal Cord Injury

Spinal cord injury (SCI) is a severe neurological disorder of CNS that usually causes permanent disability or motor deficit and sensory loss in patients, and it also leads to numerous complications associated with complex pathological mechanisms. Very few restorative therapeutic options are available clinically to improve the neurologic deficits in the SCI. Chen et al. has reported that the DG-rich extract of Trillium tschonoskii Max has a neuroprotective role against the spinal cord in rats by upregulating the expression of ciliary neurotrophic factor (CNTF) and its receptor (CNTFRα) at mRNA and protein levels [88]. Chen et al. has further evaluated the neuroprotective effect of the bioactive component of Compound 2 in T. tschonoskii Max on motor function recovery and the underlying mechanism after SCI in rats. Compound 2 could significantly reduce tissue injury and edema. The underlying mechanism might be associated with autophagy via the suppression of p62 expression and upregulation of Rheb/mTOR signaling due to the downregulation of miR-155-3p, leading to the prevention of neuronal cell damage and apoptosis [89].

9.6. Stroke and Thrombosis

Stroke is a major public health concern with high morbidity and mortality. The main stroke pathological types include ischemic stroke, primary intracerebral hemorrhage, and subarachnoid hemorrhage. Stroke is the third leading cause of death worldwide with a progressively increasing incidence and involving younger individuals. Thus, developing therapies to treat stroke is highly desirable [90]. Zhu et al. have reported that Compound 3 has therapeutic potential against ischemic stroke in rats. Compound 3 can significantly reduce the infarct volume and neurological scores in rat models of ischemic stroke. Compound 3 can inhibit the expression levels of TLR4, myeloid differentiation factor 88 (MyD88), and activation of NF-κB, leading to the inhibition of inflammatory responses in a rat model of ischemic stroke, suggesting that Compound 3 acts as an anti-inflammatory agent against ischemic stroke via the inhibition of the TLR4/MyD88/NF-κB signaling pathway [91].

Thrombosis of cerebral arteries is the major cause of morbidity and mortality worldwide. Zhang et al. have designed several monomers of diosgenyl saponin using a simple and convenient method. The antithrombotic effects of a synthetic disaccharide saponin of DG attached to two glucose units (Compound 5) along with the naturally occurring DG saponin have been examined. Their results showed that Compound 5 exhibited a strong efficiency in prolonging bleeding time and altering platelet aggregation both in vitro and in vivo. Moreover, their results demonstrated that Compound 5 could inhibit platelet aggregation, prolong the activated partial thromboplastin time, reduce factor VIII activities in rats, and significantly enhance the protection in mice. However, its mechanism of action was not determined in their study [55]. It needs to be examined in further studies.

9.7. Cerebral Brain Ischemia-Reperfusion Injury

Cerebral I/R injury refers to cerebral ischemia-induced brain damage that occurs if blood supply is restored [92]. It often causes a series of consequences including neurotoxicity induced by excitatory amino acids (EAA), mitochondrial dysfunction, overproduction of reactive oxygen species (ROS), inflammatory reaction, and neuronal cell death, which ultimately leads to irreversible brain injury. Great strides have been made in treatment modalities for ischemic stroke. However, an effective therapeutic strategy is currently unavailable for ischemic stroke clinically. Ischemic stroke is still a major cause of deaths in developed countries [93]. A recent study has uncovered that DG is effective in treating transient cerebral I/R injury via different mechanisms. Intragastric administration of DG once daily for 7 days prior to surgery can significantly inhibit the death rate in rats, restore motor impairment, and reduce neurological deficit scores along with cerebral infarct size. DG decreased the cellular apoptosis in the hippocampus CA1 and cortex via suppression of caspase-3 activity and Bax/Bcl-2 ratio. Moreover, DG can suppress the overproduction of proinflammatory cytokines including TNF-α, IL-1β, and IL-6 in the blood serum of I/R insulted rats. Its action is mediated by blocking the NF-κB signaling pathway via the downregulation of IκBα, suggesting that DG has a great potential to combat similar diseases in the clinic [94].

Compound 3 (Figure 1), a saponin of diosgenin, also possesses neuroprotective activities against ischemia-reperfusion injury. It can protect PC12 cells and primary cortical neurons in oxygen-glucose deprivation and reoxygenation (OGD/R) insults in vitro. It can also significantly attenuate cerebral I/R injury in the middle cerebral artery occlusion (MCAO) model. Further studies have indicated that the neuroprotective mechanism of Compound 3 is related to a blockade of the HMGB-1/TLR4/MyD88/TRAF6 signaling pathway via the inhibition of transcriptional activities of NF-κB and AP-1, the phosphorylation of MAPK and STAT3, and the proinflammatory cytokine responses and augmentation of anti-inflammatory mediator levels. These findings indicate that Compound 3 is a potential therapeutic agent for the prevention of cerebral I/R injury [95]. Furthermore, a combination treatment of Compound 3 and baicalein has resulted in a significant improvement in spatial memory and reduction in the infarct volume in a mice model of cerebral I/R injury. Hippocampal gene expression profiles of MCAO ischemic mice using cDNA microarray analysis of 1176 known genes have shown that numerous genes including those involved in cell cycle regulation, DNA binding, signal transduction pathways, and neuronal transcription factors are associated with neuroprotective effects [96].

9.8. Antidepressant Effects

Depression is becoming a common neuropsychiatric disorder. However, there is no effective antidepression therapy available clinically. Ho et al. reported that chronic diosgenin administration at a dosage of 10 mg/kg/day can improve avoidance behavior in a learned helplessness test involving ovariectomized rats with high anxiety levels but not in low-anxiety rats. Chronic administration of DG can reduce the expression of IL-2, an indicator of neuroimmune function, in the brains of ovariectomized rats, suggesting that DG might relieve depressive behavior via the modulation of the neuroimmune system [97]. Moreover, Yang et al. have reported that Compound 3 exhibits the antidepressant effect by enhancing 5-HT levels in endotoxemia-induced acute neuroinflammation in mice [82].

9.9. Neuropathic Pain

Neuropathic pain is a prevalent and complicated condition arising from diseases such as diabetes mellitus (DM), postherpetic neuralgia, and brain injury affecting the peripheral or central nervous system. It is often resistant to treatment. It is associated with poor treatment satisfaction in patients [98]. Zhao et al. has shown the effect of DG on allodynia and the underlying mechanism in a neuropathic pain model of rats induced by chronic constriction injury (CCI). Their results showed that DG could significantly reverse mechanical allodynia and thermal hyperalgesia induced by CCI. DG can alleviate CCI-induced neuropathic pain in rats by inhibiting the activation of the p38MAPK and NF-κB pathways, ultimately leading to the suppression of CCI-induced overexpression of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1β, and IL-2, and reduction of oxidative stress induced by CCI [99]. In addition, Zhao et al. has shown the efficacy of DG in the alleviation of neuropathic pain in streptozotocin- (STZ-) induced diabetic rats. Their study revealed that daily administration of DG at a dose of 40 mg/kg over 5 weeks obviously increased the mechanical and thermal nociceptive thresholds and lowered the pain score at delayed stages of the formalin test, but not in the early stage. An antinociceptive mechanism of DG is that it can lower oxidative stress and inflammation in diabetic rats via the restoration of the malondialdehyde (MDA) level, the activity of superoxide dismutase (SOD) and catalase, and the expression of TNF-α and IL-1β via NF-κB signaling [100]. Moreover, Kang et al. has reported that DG from Dioscorea nipponica can ameliorate diabetic neuropathy in diabetic rats. DG can increase levels of the nerve growth factor (NGF) that are reduced in diabetic rats and enhanced nerve conduction velocities in a mouse model of diabetic neuropathy. Additionally, DG can increase neurite outgrowth in PC12 cells, improve damaged axons, reduce disorganization of the myelin sheath and increase the area of myelinated axons. Beneficial effects of DG in a diabetic neuropathy model in restoring ultrastructural changes and neural regeneration might be associated with increased expression of NGF [101].

Lee et al. have examined the effect of DG on chronic pain and functional deficit resulting from sciatic crushed nerve injury in rats. DG treatment increased the sciatic function index and suppressed the nerve injury-induced overexpression of BDNF, TrkB, COX-2, iNOS, and c-Fos in the ventrolateral periaqueductal gray and paraventricular nucleus, suggesting that DG treatment could prolong pain control and extended functional recovery after peripheral nerve injury [102].

9.10. Glioblastoma

Glioblastoma is the most aggressive and malignant primary central nervous system cancer, characterized by rapid proliferation and high invasion. Surgical resection is still the mainstay of treatment for glioblastoma. Currently, no effective treatments are available to cure patients with glioblastoma due to its exceptionally heterogeneous nature and unique microenvironment. Temozolomide (TMZ) and bevacizumab are the only FDA-approved therapeutic agents for the treatment of primary and recurrent glioblastoma, respectively [105]. Acquired TMZ resistance seriously restricts the therapeutic index and fails to prolong the overall survival. DG can significantly reduce the dosage regimen of TMZ in the combinatorial therapy of DG and TMZ. It can also overcome TMZ resistance in glioblastoma cells as well. The underlying mechanism involves the downregulation of matrix metalloproteinase-2 (MMP-2) and the promotion of apoptosis [103]. The antitumor activity and the underlying mechanism of dioscin has been examined both in vitro and in vivo. Dioscin exhibited a growth inhibitory effect on C6 glioma cancer cells. It significantly inhibited tumor size and prolonged the life cycle of rats. The mechanism of action of dioscin involves the promotion of ROS accumulation, DNA damage, and mitochondrial-mediated apoptosis signaling [104].

9.11. Clinical Studies

Tohda et al. have investigated the effects of a DG-rich yam extract on cognitive enhancement in 28 healthy volunteers aged between 20 and 81 years recruited from the Toyama Prefecture, Japan. The administration of DG-rich yam extract for 12 weeks significantly improved the semantic fluency without any adverse effects, indicating that DG could enhance the cognitive function in healthy adults [106].

10. Conclusion and Future Perspectives

Diosgenin and its derivatives have attracted considerable attention from researchers worldwide. Several studies have described the pharmacological effects of DG and its derivatives against a variety of diseases such as cancer, diabetes, osteoporosis, AD, and stroke. Several reviews have emphasized the pharmacological advances of DG in the treatment of cancer and described the analytical methodology. In recent years, increasing experimental evidence has shown that DG and its derivatives exhibit promising therapeutic potential in several neurodegenerative and neurological disorders. Therefore, the present review mainly addressed recent progresses of DG and its potent derivatives against multiple diseases of CNS including AD, PD, stroke, neuroinflammation, multiple sclerosis, spinal cord injury, ischemia-induced brain damage, depressive disorders, neuropathic pain, glioblastoma, and cognitive impairment, along with their underlying mechanisms of action at the molecular and cellular levels. This review will facilitate the exploration of new horizons for further research of DG or its derivatives at the preclinical and clinical levels for potential treatment of neurodegenerative disorders.

Although DG is abundant in nature, with high biocompatibility and with thousands of reports elaborating the remarkable pharmacological properties of DG and its derivatives documented in the literature, most of the current results are derived from in vitro or animal studies which prevents definitive conclusions about its clinical efficacy. Clinical testing and validation of preclinical data are still insufficient, especially in the treatment of specific neurological disorders. Additional data from clinical trials are highly desired, including test period, dosage, formulation, ethical approvals, adverse effects, drug interactions, and food interactions. Additionally, most patients suffering from neurodegenerative disorders require lifelong medication due to the slow progression of such diseases. Therefore, a systematic experimental design to assess the long-term outcomes of DG and/or its derivatives for the treatment of neurodegenerative disorders and the management of related symptoms is highly recommended in future studies. Furthermore, the risk assessment and safety evaluation of the pharmacological use of DG or its derivatives in the treatment of neurodegenerative disorders need to be investigated in depth.

The successful development of a therapeutic candidate against neurological disorders is a challenge. First, DG suffers from several drawbacks including low solubility and poor pharmacokinetic profiles which severely restrict its clinical application. Structural modifications or drug delivery systems are reliable techniques to solve these limitations. For structural modification, a balanced analysis of biological activity, solubility, cytotoxicity, and the permeability of blood-brain barrier after modification should be conducted to screen for potential lead compounds for further study. Second, the pathogenesis of neurodegenerative diseases such as AD and PD is complex and multifactorial. The prevention and treatment of those diseases using DG or its derivatives alone might be unsatisfactory. Combination therapies of DG with compounds possessing multiple mechanisms of action are expected to be more effective than individual drugs to treat varied pathological aspects of these diseases. Further, a multitarget drug strategy against multiple risk factors in the development of therapies for neurodegenerative disorders is an essential paradigm and an innovative approach to treat neurological diseases with complex pathogenesis. Numerous studies have indicated that the multifunctional compounds can enhance therapeutic effectiveness and minimize side effects, subsequently leading to better patient compliance via simultaneous modulation of multiple targets in a selective manner.

Conflicts of Interest

The authors declare no conflict of interest.

Acknowledgments

This research was financially supported by the Doctoral Scientific Research Start-up Foundation from Henan University of Chinese Medicine (No. 00104311-2019-33) and the 2020 Key Technologies R&D Program of Henan Province.

References

  1. C. L. Gooch, E. Pracht, and A. R. Borenstein, “The burden of neurological disease in the United States: a summary report and call to action,” Annals of Neurology, vol. 81, no. 4, pp. 479–484, 2017. View at: Publisher Site | Google Scholar
  2. C. Rock and P. J. Moos, “Selenoprotein P protects cells from lipid hydroperoxides generated by 15-LOX-1,” Prostaglandins, Leukotrienes, and Essential Fatty Acids, vol. 83, no. 4-6, pp. 203–210, 2010. View at: Publisher Site | Google Scholar
  3. J. R. Berger, D. Choi, H. J. Kaminski et al., “Importance and hurdles to drug discovery for neurological disease,” Annals of Neurology, vol. 74, no. 3, pp. 441–446, 2013. View at: Publisher Site | Google Scholar
  4. Z. Wang, H. Wan, J. Li, H. Zhang, and M. Tian, “Molecular imaging in traditional Chinese medicine therapy for neurological diseases,” BioMed Research International, vol. 2013, Article ID 608430, 11 pages, 2013. View at: Publisher Site | Google Scholar
  5. H. Liu-Seifert, J. Schumi, X. Miao et al., “Disease modification in Alzheimer’s disease: current thinking,” Therapeutic Innovation & Regulatory Science, vol. 14, 2019. View at: Publisher Site | Google Scholar
  6. V. K. Gribkoff and L. K. Kaczmarek, “The need for new approaches in CNS drug discovery: why drugs have failed, and what can be done to improve outcomes,” Neuropharmacology, vol. 120, pp. 11–19, 2017. View at: Publisher Site | Google Scholar
  7. F. J. B. Mendonça-Junior, M. T. Scotti, A. Nayarisseri, E. N. T. Zondegoumba, and L. Scotti, “Natural bioactive products with antioxidant properties useful in neurodegenerative diseases,” Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 7151780, 2 pages, 2019. View at: Publisher Site | Google Scholar
  8. M. K. Parvez, “Natural or plant products for the treatment of neurological disorders: current knowledge,” Current Drug Metabolism, vol. 19, no. 5, pp. 424–428, 2018. View at: Publisher Site | Google Scholar
  9. Y. Tu, “Artemisinin—a gift from traditional Chinese medicine to the world (Nobel lecture),” Angewandte Chemie (International Ed. in English), vol. 55, no. 35, pp. 10210–10226, 2016. View at: Publisher Site | Google Scholar
  10. R. C. Alves, R. P. Fernandes, J. O. Eloy, H. R. N. Salgado, and M. Chorilli, “Characteristics, properties and analytical methods of paclitaxel: a review,” Critical Reviews in Analytical Chemistry, vol. 48, no. 2, pp. 110–118, 2018. View at: Publisher Site | Google Scholar
  11. F. Babaei, M. Mirzababaei, and M. Nassiri-Asl, “Quercetin in food: possible mechanisms of its effect on memory,” Journal of Food Science, vol. 83, no. 9, pp. 2280–2287, 2018. View at: Publisher Site | Google Scholar
  12. B. Yuan, D. R. Byrnes, F. F. Dinssa, J. E. Simon, and Q. Wu, “Identification of polyphenols, glycoalkaloids, and saponins in Solanum scabrum berries using HPLC-UV/Vis-MS,” Journal of Food Science, vol. 84, no. 2, pp. 235–243, 2019. View at: Publisher Site | Google Scholar
  13. A. Narula, S. Kumar, and P. S. Srivastava, “Genetic fidelity of in vitro regenerants, encapsulation of shoot tips and high diosgenin content in Dioscorea bulbifera L., a potential alternative source of diosgenin,” Biotechnology Letters, vol. 29, no. 4, pp. 623–629, 2007. View at: Publisher Site | Google Scholar
  14. H. A. Deshpande and S. R. Bhalsing, “Isolation and characterization of diosgenin from in vitro cultured tissues of Helicteres isora L,” Physiology and Molecular Biology of Plants, vol. 20, no. 1, pp. 89–94, 2014. View at: Publisher Site | Google Scholar
  15. B. Avula, Y. H. Wang, Z. Ali, T. J. Smillie, and I. A. Khan, “Chemical fingerprint analysis and quantitative determination of steroidal compounds from Dioscorea villosa, Dioscorea species and dietary supplements using UHPLC-ELSD,” Biomedical Chromatography, vol. 28, no. 2, pp. 281–294, 2014. View at: Publisher Site | Google Scholar
  16. F. Yang, Y. Liang, L. Xu et al., “Exploration in the cascade working mechanisms of liver injury induced by total saponins extracted from Rhizoma Dioscorea bulbifera,” Biomedicine & Pharmacotherapy, vol. 83, pp. 1048–1056, 2016. View at: Publisher Site | Google Scholar
  17. T. Yi, L. L. Fan, H. L. Chen et al., “Comparative analysis of diosgenin in Dioscorea species and related medicinal plants by UPLC-DAD-MS,” BMC Biochemistry, vol. 15, no. 1, p. 19, 2014. View at: Publisher Site | Google Scholar
  18. G. Sethi, M. Shanmugam, S. Warrier et al., “Pro-apoptotic and anti-cancer properties of diosgenin: a comprehensive and critical review,” Nutrients, vol. 10, no. 5, p. 645, 2018. View at: Publisher Site | Google Scholar
  19. S. S. Chiang, S. P. Chang, and T. M. Pan, “Osteoprotective effect of Monascus-fermented Dioscorea in ovariectomized rat model of postmenopausal osteoporosis,” Journal of Agricultural and Food Chemistry, vol. 59, no. 17, pp. 9150–9157, 2011. View at: Publisher Site | Google Scholar
  20. P. Kalailingam, B. Kannaian, E. Tamilmani, and R. Kaliaperumal, “Efficacy of natural diosgenin on cardiovascular risk, insulin secretion, and beta cells in streptozotocin (STZ)-induced diabetic rats,” Phytomedicine, vol. 21, no. 10, pp. 1154–1161, 2014. View at: Publisher Site | Google Scholar
  21. Y. C. Lv, J. Yang, F. Yao et al., “Diosgenin inhibits atherosclerosis via suppressing the MiR-19b-induced downregulation of ATP-binding cassette transporter A1,” Atherosclerosis, vol. 240, no. 1, pp. 80–89, 2015. View at: Publisher Site | Google Scholar
  22. S. Hua, Y. Li, L. Su, and X. Liu, “Diosgenin ameliorates gestational diabetes through inhibition of sterol regulatory element-binding protein-1,” Biomedicine & Pharmacotherapy, vol. 84, pp. 1460–1465, 2016. View at: Publisher Site | Google Scholar
  23. J. E. Kim, J. Go, E. K. Koh et al., “Diosgenin effectively suppresses skin inflammation induced by phthalic anhydride in IL-4/Luc/CNS-1 transgenic mice,” Bioscience, Biotechnology, and Biochemistry, vol. 80, no. 5, pp. 891–901, 2016. View at: Publisher Site | Google Scholar
  24. Y. Chen, Y. M. Tang, S. L. Yu et al., “Advances in the pharmacological activities and mechanisms of diosgenin,” Chinese Journal of Natural Medicines, vol. 13, no. 8, pp. 578–587, 2015. View at: Publisher Site | Google Scholar
  25. X. Yang and C. Tohda, “Diosgenin restores Aβ-induced axonal degeneration by reducing the expression of heat shock cognate 70 (HSC70),” Scientific Reports, vol. 8, no. 1, p. 11707, 2018. View at: Publisher Site | Google Scholar
  26. B. Li, P. Xu, S. Wu et al., “Diosgenin attenuates lipopolysaccharide-induced Parkinson’s disease by inhibiting the TLR/NF-κB pathway,” Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 943–955, 2018. View at: Publisher Site | Google Scholar
  27. L. He, Y. Jiang, K. Liu et al., “Insights into the impact of a membrane-anchoring moiety on the biological activities of bivalent compounds as potential neuroprotectants for Alzheimer’s disease,” Journal of Medicinal Chemistry, vol. 61, no. 3, pp. 777–790, 2018. View at: Publisher Site | Google Scholar
  28. D. H. Kim, B. N. Hong, H. T. le et al., “Small molecular weight PEGylation of diosgenin in an in vivo animal study for diabetic auditory impairment treatment,” Bioorganic & Medicinal Chemistry Letters, vol. 22, no. 14, pp. 4609–4612, 2012. View at: Publisher Site | Google Scholar
  29. S. Fuller and J. M. Stephens, “Diosgenin, 4-hydroxyisoleucine, and fiber from fenugreek: mechanisms of actions and potential effects on metabolic syndrome,” Advances in Nutrition, vol. 6, no. 2, pp. 189–197, 2015. View at: Publisher Site | Google Scholar
  30. M. Jesus, A. P. J. Martins, E. Gallardo, and S. Silvestre, “Diosgenin: recent highlights on pharmacology and analytical methodology,” Journal of Analytical Methods in Chemistry, vol. 2016, Article ID 4156293, 16 pages, 2016. View at: Publisher Site | Google Scholar
  31. G. Blunden and C. T. Rhodes, “Stability of diosgenin,” Journal of Pharmaceutical Sciences, vol. 57, no. 4, pp. 602–604, 1968. View at: Publisher Site | Google Scholar
  32. M. Okawara, Y. Tokudome, H. Todo, K. Sugibayashi, and F. Hashimoto, “Effect of β-cyclodextrin derivatives on the diosgenin absorption in Caco-2 cell monolayer and rats,” Biological & Pharmaceutical Bulletin, vol. 37, no. 1, pp. 54–59, 2014. View at: Publisher Site | Google Scholar
  33. M. Okawara, Y. Tokudome, H. Todo, K. Sugibayashi, and F. Hashimoto, “Enhancement of diosgenin distribution in the skin by cyclodextrin complexation following oral administration,” Biological & Pharmaceutical Bulletin, vol. 36, no. 1, pp. 36–40, 2013. View at: Publisher Site | Google Scholar
  34. M. Okawara, F. Hashimoto, H. Todo, K. Sugibayashi, and Y. Tokudome, “Effect of liquid crystals with cyclodextrin on the bioavailability of a poorly water-soluble compound, diosgenin, after its oral administration to rats,” International Journal of Pharmaceutics, vol. 472, no. 1-2, pp. 257–261, 2014. View at: Publisher Site | Google Scholar
  35. M. Al-Habori, A. Raman, M. J. Lawrence, and P. Skett, “In vitro effect of fenugreek extracts on intestinal sodium-dependent glucose uptake and hepatic glycogen phosphorylase A,” International Journal of Experimental Diabetes Research, vol. 2, no. 2, pp. 91–99, 2001. View at: Publisher Site | Google Scholar
  36. S. Ur Rahman, A. Adhikari, M. Ismail et al., “Beneficial effects of Trillium govanianum rhizomes in pain and inflammation,” Molecules, vol. 21, no. 8, p. 1095, 2016. View at: Publisher Site | Google Scholar
  37. P. Singh, G. Singh, A. Bhandawat et al., “Spatial transcriptome analysis provides insights of key gene (s) involved in steroidal saponin biosynthesis in medicinally important herb Trillium govanianum,” Scientific Reports, vol. 7, no. 1, pp. 1–12, 2017. View at: Google Scholar
  38. T. Zheng, L. Yu, Y. Zhu, and B. Zhao, “Evaluation of different pretreatments on microbial transformation of saponins inDioscorea zingiberensisfor diosgenin production,” Biotechnology & Biotechnological Equipment, vol. 28, no. 4, pp. 740–746, 2014. View at: Publisher Site | Google Scholar
  39. W. G. Taylor, J. L. Elder, P. R. Chang, and K. W. Richards, “Microdetermination of diosgenin from fenugreek (Trigonella foenum-graecum) seeds,” Journal of Agricultural and Food Chemistry, vol. 48, no. 11, pp. 5206–5210, 2000. View at: Publisher Site | Google Scholar
  40. Y. Zhu, H. Zhu, M. Qiu, T. Zhu, and J. Ni, “Investigation on the mechanisms for biotransformation of saponins to diosgenin,” World Journal of Microbiology and Biotechnology, vol. 30, no. 1, pp. 143–152, 2014. View at: Publisher Site | Google Scholar
  41. S. Chaudhary, S. K. Chikara, M. C. Sharma et al., “Elicitation of diosgenin production in Trigonella foenum-graecum (fenugreek) seedlings by methyl jasmonate,” International Journal of Molecular Sciences, vol. 16, no. 12, pp. 29889–29899, 2015. View at: Publisher Site | Google Scholar
  42. W. de Souza and J. C. F. Rodrigues, “Sterol biosynthesis pathway as target for anti-trypanosomatid drugs,” Interdisciplinary Perspectives on Infectious Diseases, vol. 2009, Article ID 642502, 19 pages, 2009. View at: Publisher Site | Google Scholar
  43. M. N. Cayen, E. S. Ferdinandi, E. Greselin, and D. Dvornik, “Studies on the disposition of diosgenin in rats, dogs, monkeys and man,” Atherosclerosis, vol. 33, no. 1, pp. 71–87, 1979. View at: Publisher Site | Google Scholar
  44. Y. Qin, X. Wu, W. Huang et al., “Acute toxicity and sub-chronic toxicity of steroidal saponins from Dioscorea zingiberensis C.H.Wright in rodents,” Journal of Ethnopharmacology, vol. 126, no. 3, pp. 543–550, 2009. View at: Publisher Site | Google Scholar
  45. C. M. Lima, A. K. Lima, M. G. D. Melo et al., “Bioassay-guided evaluation of Dioscorea villosa—an acute and subchronic toxicity, antinociceptive and anti-inflammatory approach,” BMC Complementary and Alternative Medicine, vol. 13, no. 1, 2013. View at: Publisher Site | Google Scholar
  46. K. Wojcikowski, H. Wohlmuth, D. W. Johnson, and G. Gobe, “Dioscorea villosa (wild yam) induces chronic kidney injury via pro-fibrotic pathways,” Food and Chemical Toxicology, vol. 46, no. 9, pp. 3122–3131, 2008. View at: Publisher Site | Google Scholar
  47. M. S. Cruz, J. A. Navoni, L. A. da Costa Xavier et al., “Diosgenin induces genotoxic and mutagenic effects on HepG2 cells,” Food and Chemical Toxicology, vol. 120, pp. 98–103, 2018. View at: Publisher Site | Google Scholar
  48. Y. C. Liu, H. Zhu, S. Shakya, and J. W. Wu, “Metabolic profile and pharmacokinetics of polyphyllin I, an anticancer candidate, in rats by UPLC-QTOF-MS/MS and LC-TQ-MS/MS,” Biomedical Chromatography, vol. 31, no. 3, 2017. View at: Publisher Site | Google Scholar
  49. H. Zheng, Z. Wei, G. Xin et al., “Preventive effect of a novel diosgenin derivative on arterial and venous thrombosis in vivo,” Bioorganic & Medicinal Chemistry Letters, vol. 26, no. 14, pp. 3364–3369, 2016. View at: Publisher Site | Google Scholar
  50. A. M. Liao, H. Jung, J. W. Yu et al., “Synthesis and biological evaluation of arginyl-diosgenin conjugate as a potential bone tissue engineering agent,” Chemical Biology & Drug Design, vol. 91, no. 1, pp. 17–28, 2018. View at: Publisher Site | Google Scholar
  51. B. S. Vig, K. M. Huttunen, K. Laine, and J. Rautio, “Amino acids as promoieties in prodrug design and development,” Advanced Drug Delivery Reviews, vol. 65, no. 10, pp. 1370–1385, 2013. View at: Publisher Site | Google Scholar
  52. B. Z. Huang, G. Xin, L. M. Ma et al., “Synthesis, characterization, and biological studies of diosgenyl analogs,” Journal of Asian Natural Products Research, vol. 19, no. 3, pp. 272–298, 2017. View at: Publisher Site | Google Scholar
  53. P. S. Chae, S. G. F. Rasmussen, R. R. Rana et al., “A new class of amphiphiles bearing rigid hydrophobic groups for solubilization and stabilization of membrane proteins,” Chemistry, vol. 18, no. 31, pp. 9485–9490, 2012. View at: Publisher Site | Google Scholar
  54. B. Wang, J. Chun, Y. Liu et al., “Synthesis of novel diosgenyl saponin analogues and apoptosis-inducing activity on A549 human lung adenocarcinoma,” Organic & Biomolecular Chemistry, vol. 10, no. 44, pp. 8822–8834, 2012. View at: Publisher Site | Google Scholar
  55. R. Zhang, B. Huang, D. du et al., “Anti-thrombosis effect of diosgenyl saponins in vitro and in vivo,” Steroids, vol. 78, no. 11, pp. 1064–1070, 2013. View at: Publisher Site | Google Scholar
  56. L. Lecanu, L. Tillement, G. Rammouz, J. P. Tillement, J. Greeson, and V. Papadopoulos, “Caprospinol: moving from a neuroactive steroid to a neurotropic drug,” Expert Opinion on Investigational Drugs, vol. 18, no. 3, pp. 265–276, 2009. View at: Publisher Site | Google Scholar
  57. B. Cai, K. J. Seong, S. W. Bae, C. Chun, W. J. Kim, and J. Y. Jung, “A synthetic diosgenin primary amine derivative attenuates LPS-stimulated inflammation via inhibition of NF-κB and JNK MAPK signaling in microglial BV2 cells,” International Immunopharmacology, vol. 61, pp. 204–214, 2018. View at: Publisher Site | Google Scholar
  58. J. E. Chojnacki, K. Liu, J. M. Saathoff, and S. Zhang, “Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer’s disease,” Bioorganic & Medicinal Chemistry, vol. 23, no. 22, pp. 7324–7331, 2015. View at: Publisher Site | Google Scholar
  59. G. X. Yang, S. L. Ge, Y. Wu et al., “Design, synthesis and biological evaluation of 3-piperazinecarboxylate sarsasapogenin derivatives as potential multifunctional anti-Alzheimer agents,” European Journal of Medicinal Chemistry, vol. 156, pp. 206–215, 2018. View at: Publisher Site | Google Scholar
  60. C. Z. Liu, J. H. Chang, L. Zhang et al., “Preparation and evaluation of diosgenin nanocrystals to improve oral bioavailability,” AAPS PharmSciTech, vol. 18, no. 6, pp. 2067–2076, 2017. View at: Publisher Site | Google Scholar
  61. C. Li, J. Dai, D. Zheng et al., “An efficient prodrug-based nanoscale delivery platform constructed by water soluble eight-arm-polyethylene glycol-diosgenin conjugate,” Materials Science & Engineering C, Materials for biological applications, vol. 98, pp. 153–160, 2019. View at: Publisher Site | Google Scholar
  62. J. P. Quinones, O. Bruggemann, C. P. Covas, and D. A. Ossipov, “Self-assembled hyaluronic acid nanoparticles for controlled release of agrochemicals and diosgenin,” Carbohydrate Polymers, vol. 173, pp. 157–169, 2017. View at: Publisher Site | Google Scholar
  63. Z. Wei, G. Xin, H. Wang et al., “The diosgenin prodrug nanoparticles with pH-responsive as a drug delivery system uniquely prevents thrombosis without increased bleeding risk,” Nanomedicine : Nanotechnology, Biology, and Medicine, vol. 14, no. 3, pp. 673–684, 2018. View at: Publisher Site | Google Scholar
  64. J. Cao, J. Hou, J. Ping, and D. Cai, “Advances in developing novel therapeutic strategies for Alzheimer’s disease,” Molecular Neurodegeneration, vol. 13, no. 1, p. 64, 2018. View at: Publisher Site | Google Scholar
  65. G. K. Gouras, T. T. Olsson, and O. Hansson, “β-Amyloid peptides and amyloid plaques in Alzheimer’s disease,” Neurotherapeutics, vol. 12, no. 1, pp. 3–11, 2015. View at: Publisher Site | Google Scholar
  66. C. Tohda, T. Urano, M. Umezaki, I. Nemere, and T. Kuboyama, “Diosgenin is an exogenous activator of 1,25D3-MARRS/Pdia3/ERp57 and improves Alzheimer's disease pathologies in 5XFAD mice,” Scientific Reports, vol. 2, no. 1, 2012. View at: Publisher Site | Google Scholar
  67. C. Tohda, Y. A. Lee, Y. Goto, and I. Nemere, “Diosgenin-induced cognitive enhancement in normal mice is mediated by 1,25D3-MARRS,” Scientific Reports, vol. 3, no. 1, 2013. View at: Publisher Site | Google Scholar
  68. E. K. Koh, W. B. Yun, J. E. Kim et al., “Beneficial effect of diosgenin as a stimulator of NGF on the brain with neuronal damage induced by Aβ-42 accumulation and neurotoxicant injection,” Laboratory Animal Research, vol. 32, no. 2, pp. 105–115, 2016. View at: Publisher Site | Google Scholar
  69. J. T. Pedersen and E. M. Sigurdsson, “Tau immunotherapy for Alzheimer’s disease,” Trends in Molecular Medicine, vol. 21, no. 6, pp. 394–402, 2015. View at: Publisher Site | Google Scholar
  70. G. L. Teper, L. Lecanu, J. Greeson, and V. Papadopoulos, “Methodology for Multi‐Site Ligand–Protein Docking Identification Developed for the Optimization of Spirostenol Inhibition of β‐Amyloid‐Induced Neurotoxicity,” Chemistry & Biodiversity, vol. 2, no. 11, pp. 1571–1579, 2005. View at: Publisher Site | Google Scholar
  71. L. Lecanu, W. Yao, G. L. Teper, Z. X. Yao, J. Greeson, and V. Papadopoulos, “Identification of naturally occurring spirostenols preventing beta-amyloid-induced neurotoxicity,” Steroids, vol. 69, no. 1, pp. 1–16, 2004. View at: Publisher Site | Google Scholar
  72. L. Tillement, L. Lecanu, W. Yao, J. Greeson, and V. Papadopoulos, “The spirostenol (22R, 25R)-20alpha-spirost-5-en-3beta-yl hexanoate blocks mitochondrial uptake of Abeta in neuronal cells and prevents Abeta-induced impairment of mitochondrial function,” Steroids, vol. 71, no. 8, pp. 725–735, 2006. View at: Publisher Site | Google Scholar
  73. V. Papadopoulos and L. Lecanu, “Caprospinol: discovery of a steroid drug candidate to treat Alzheimer’s disease based on 22R-hydroxycholesterol structure and properties,” Journal of Neuroendocrinology, vol. 24, no. 1, pp. 93–101, 2012. View at: Publisher Site | Google Scholar
  74. L. Lecanu, G. Rammouz, A. McCourty, E. K. Sidahmed, J. Greeson, and V. Papadopoulos, “Caprospinol reduces amyloid deposits and improves cognitive function in a rat model of Alzheimer’s disease,” Neuroscience, vol. 165, no. 2, pp. 427–435, 2010. View at: Publisher Site | Google Scholar
  75. D. Cai, J. Qi, Y. Yang et al., “Design, synthesis and biological evaluation of diosgenin-amino acid derivatives with dual functions of neuroprotection and angiogenesis,” Molecules, vol. 24, no. 22, p. 4025, 2019. View at: Publisher Site | Google Scholar
  76. C. S. Chiu, J. S. Deng, M. T. Hsieh et al., “Yam (Dioscorea pseudojaponica Yamamoto) ameliorates cognition deficit and attenuates oxidative damage in senescent mice induced by D-galactose,” The American Journal of Chinese Medicine, vol. 37, no. 5, pp. 889–902, 2009. View at: Publisher Site | Google Scholar
  77. C. S. Chiu, Y. J. Chiu, L. Y. Wu et al., “Diosgenin ameliorates cognition deficit and attenuates oxidative damage in senescent mice induced by D-galactose,” The American Journal of Chinese Medicine, vol. 39, no. 3, pp. 551–563, 2011. View at: Publisher Site | Google Scholar
  78. J. Turchan-Cholewo, Y. Liu, S. Gartner et al., “Increased vulnerability of ApoE4 neurons to HIV proteins and opiates: protection by diosgenin and L-deprenyl,” Neurobiology of Disease, vol. 23, no. 1, pp. 109–119, 2006. View at: Publisher Site | Google Scholar
  79. L. Wang, J. Du, F. Zhao et al., “Trillium tschonoskii maxim saponin mitigates D-galactose-induced brain aging of rats through rescuing dysfunctional autophagy mediated by Rheb-mTOR signal pathway,” Biomedicine & Pharmacotherapy, vol. 98, pp. 516–522, 2018. View at: Publisher Site | Google Scholar
  80. L. Du, Y. Zhang, Y. Chen, J. Zhu, Y. Yang, and H. L. Zhang, “Role of microglia in neurological disorders and their potentials as a therapeutic target,” Molecular Neurobiology, vol. 54, no. 10, pp. 7567–7584, 2017. View at: Publisher Site | Google Scholar
  81. A. Binesh, S. N. Devaraj, and D. Halagowder, “Atherogenic diet induced lipid accumulation induced NFκB level in heart, liver and brain of Wistar rat and diosgenin as an anti-inflammatory agent,” Life Sciences, vol. 196, pp. 28–37, 2018. View at: Publisher Site | Google Scholar
  82. R. Yang, W. Chen, Y. Lu et al., “Dioscin relieves endotoxemia induced acute neuro-inflammation and protect neurogenesis via improving 5-HT metabolism,” Scientific Reports, vol. 7, no. 1, pp. 1–13, 2017. View at: Google Scholar
  83. S. Wang, F. Wang, H. Yang, R. Li, H. Guo, and L. Hu, “Diosgenin glucoside provides neuroprotection by regulating microglial M1 polarization,” International Immunopharmacology, vol. 50, pp. 22–29, 2017. View at: Publisher Site | Google Scholar
  84. B. Cai, K. J. Seong, S. W. Bae et al., “Water-soluble arginyl-diosgenin analog attenuates hippocampal neurogenesis impairment through blocking microglial activation underlying NF-κB and JNK MAPK signaling in adult mice challenged by LPS,” Molecular Neurobiology, vol. 56, no. 9, pp. 6218–6238, 2019. View at: Publisher Site | Google Scholar
  85. D. Ontaneda, A. J. Thompson, R. J. Fox, and J. A. Cohen, “Progressive multiple sclerosis: prospects for disease therapy, repair, and restoration of function,” Lancet, vol. 389, no. 10076, pp. 1357–1366, 2017. View at: Publisher Site | Google Scholar
  86. W. Liu, M. Zhu, Z. Yu et al., “Therapeutic effects of diosgenin in experimental autoimmune encephalomyelitis,” Journal of Neuroimmunology, vol. 313, pp. 152–160, 2017. View at: Publisher Site | Google Scholar
  87. L. Xiao, D. Guo, C. Hu et al., “Diosgenin promotes oligodendrocyte progenitor cell differentiation through estrogen receptor-mediated ERK1/2 activation to accelerate remyelination,” Glia, vol. 60, no. 7, pp. 1037–1052, 2012. View at: Publisher Site | Google Scholar
  88. X. B. Chen, M. Y. Zhu, F. R. Qin et al., “Effect of extract of Trillium tschonoskii Maxim on ciliary neurotropic factor and its receptor α in rats suffering from spinal cord injury,” Medical Journal of Chinese People's Liberation Army, vol. 40, pp. 622–626, 2015. View at: Publisher Site | Google Scholar
  89. X. B. Chen, Z. L. Wang, Q. Y. Yang et al., “Diosgenin glucoside protects against spinal cord injury by regulating autophagy and alleviating apoptosis,” International Journal of Molecular Sciences, vol. 19, no. 8, p. 2274, 2018. View at: Publisher Site | Google Scholar
  90. V. L. Feigin, G. A. Mensah, B. Norrving, C. J. L. Murray, G. A. Roth, and GBD 2013 Stroke Panel Experts Group, “Atlas of the Global Burden of Stroke (1990–2013): the GBD 2013 study,” Neuroepidemiology, vol. 45, no. 3, pp. 230–236, 2015. View at: Publisher Site | Google Scholar
  91. S. Zhu, S. Tang, and F. Su, “Dioscin inhibits ischemic stroke-induced inflammation through inhibition of the TLR4/MyD88/NF‑κB signaling pathway in a rat model,” Molecular Medicine Reports, vol. 17, no. 1, pp. 660–666, 2018. View at: Publisher Site | Google Scholar
  92. R. J. Winquist and S. Kerr, “Cerebral ischemia-reperfusion injury and adhesion,” Neurology, vol. 49, 5 Suppl 4, pp. S23–S26, 1997. View at: Publisher Site | Google Scholar
  93. S. L. Livesay, “Clinical review and implications of the guideline for the early management of patients with acute ischemic stroke,” AACN Advanced Critical Care, vol. 25, no. 2, pp. 130–141, 2014. View at: Publisher Site | Google Scholar
  94. X. Zhang, X. Xue, J. Zhao et al., “Diosgenin attenuates the brain injury induced by transient focal cerebral ischemia-reperfusion in rats,” Steroids, vol. 113, pp. 103–112, 2016. View at: Publisher Site | Google Scholar
  95. X. Tao, X. Sun, L. Yin et al., “Dioscin ameliorates cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via HMGB-1 inhibition,” Free Radical Biology & Medicine, vol. 84, pp. 103–115, 2015. View at: Publisher Site | Google Scholar
  96. Z. Wang, Q. Du, F. Wang et al., “Microarray analysis of gene expression on herbal glycoside recipes improving deficient ability of spatial learning memory in ischemic mice,” Journal of Neurochemistry, vol. 88, no. 6, pp. 1406–1415, 2004. View at: Publisher Site | Google Scholar
  97. Y. J. Ho, S. Y. Tai, C. R. Pawlak, A. L. Wang, C. W. Cheng, and M. H. Hsieh, “Behavioral and IL-2 responses to diosgenin in ovariectomized rats,” The Chinese Journal of Physiology, vol. 55, no. 2, pp. 91–100, 2012. View at: Publisher Site | Google Scholar
  98. R. K. Khangura, J. Sharma, A. Bali, N. Singh, and A. S. Jaggi, “An integrated review on new targets in the treatment of neuropathic pain,” The Korean journal of physiology & pharmacology, vol. 23, no. 1, pp. 1–20, 2019. View at: Publisher Site | Google Scholar
  99. W. X. Zhao, P. F. Wang, H. G. Song, and N. Sun, “Diosgenin attenuates neuropathic pain in a rat model of chronic constriction injury,” Molecular Medicine Reports, vol. 16, no. 2, pp. 1559–1564, 2017. View at: Publisher Site | Google Scholar
  100. Z. Kiasalari, T. Rahmani, N. Mahmoudi, T. Baluchnejadmojarad, and M. Roghani, “Diosgenin ameliorates development of neuropathic pain in diabetic rats: involvement of oxidative stress and inflammation,” Biomedicine & Pharmacotherapy, vol. 86, pp. 654–661, 2017. View at: Publisher Site | Google Scholar
  101. T. H. Kang, E. Moon, B. N. Hong et al., “Diosgenin from Dioscorea nipponica ameliorates diabetic neuropathy by inducing nerve growth factor,” Biological & Pharmaceutical Bulletin, vol. 34, no. 9, pp. 1493–1498, 2011. View at: Publisher Site | Google Scholar
  102. B. K. Lee, C. J. Kim, M. S. Shin, and Y. S. Cho, “Diosgenin improves functional recovery from sciatic crushed nerve injury in rats,” Journal of Exercise Rehabilitation, vol. 14, no. 4, pp. 566–572, 2018. View at: Publisher Site | Google Scholar
  103. Y. Rajesh, A. Biswas, U. Kumar et al., “Targeting NFE2L2, a transcription factor upstream of MMP-2: a potential therapeutic strategy for temozolomide resistant glioblastoma,” Biochemical Pharmacology, vol. 164, pp. 1–16, 2019. View at: Publisher Site | Google Scholar
  104. L. Lv, L. Zheng, D. Dong et al., “Dioscin, a natural steroid saponin, induces apoptosis and DNA damage through reactive oxygen species: a potential new drug for treatment of glioblastoma multiforme,” Food and Chemical Toxicology, vol. 59, pp. 657–669, 2013. View at: Publisher Site | Google Scholar
  105. J. Mooney, J. D. Bernstock, A. Ilyas et al., “Current approaches and challenges in the molecular therapeutic targeting of glioblastoma,” World Neurosurgery, vol. 129, pp. 90–100, 2019. View at: Publisher Site | Google Scholar
  106. C. Tohda, X. Yang, M. Matsui et al., “Diosgenin-rich yam extract enhances cognitive function: a placebo-controlled, randomized, double-blind, crossover study of healthy adults,” Nutrients, vol. 9, no. 10, p. 1160, 2017. View at: Publisher Site | Google Scholar

Copyright © 2020 Bangrong Cai et al. 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.


More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder
Views2015
Downloads478
Citations

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.