Gastrodin and Vascular Dementia: Advances and Current Perspectives

Deng, Chujun; Chen, Huize; Meng, Zeyu; Meng, Shengxi

doi:https://doi.org/10.1155/2022/2563934

Evidence-Based Complementary and Alternative Medicine

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Abstract Introduction Materials and Methods Results Conclusions Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

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Applications of Complementary and Alternative Therapies in Neurodegenerative Diseases

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Review Article | Open Access

Volume 2022 | Article ID 2563934 | https://doi.org/10.1155/2022/2563934

Gastrodin and Vascular Dementia: Advances and Current Perspectives

Chujun Deng,¹Huize Chen,¹Zeyu Meng,²and Shengxi Meng¹

Academic Editor: Weidong Pan

Received10 Nov 2021

Revised08 Feb 2022

Accepted16 Mar 2022

Published12 Apr 2022

Abstract

Gastrodia elata, a traditional Chinese medicine, has been widely used since ancient times to treat diseases such as dizziness, epilepsy, stroke, and memory loss. Gastrodin, one of the active components of Gastrodia elata, has been used in the treatment of migraine, epilepsy, Parkinson’s disease, dementia, and depression in recent years. It can improve cognitive function and related neuropsychiatric symptoms through various effects and is considered as a promising treatment for dementia. Vascular dementia is a kind of severe cognitive impairment syndrome caused by vascular factors, and it is the dementia syndrome with the largest number of patients besides Alzheimer’s disease. Although there is still a lack of evidence-based explorations, the paper reviewed the mechanism and methods of gastrodin in the treatment of vascular dementia, providing a reference for clinical therapy.

1. Introduction

1.1. Vascular Dementia

Vascular dementia (VaD) refers to the severe cognitive impairment caused by vascular pathology, that is, the classification of vascular cognitive impairment (VCI) described as severe, which is also the second leading cause of dementia [1]. The pathophysiological mechanism of VaD is mainly that vascular dysfunction causes oxidative stress and inflammation in brain tissue. On the one hand, it leads to a series of subsequent apoptosis and autophagy, resulting in reduced number of neurons and synaptic dysfunction. On the other hand, it causes blood brain barrier damage (BBB), resulting in toxic materials (such as amyloid beta) accumulation, and accelerates the pathological process above. In this process, various factors like damaged blood vessels, impaired functions of microglia and astrocytes, inflammation of the nervous system, and accumulation of toxic substances lead to neuron loss by mutual superposition or cascade reaction and ultimately lead to cognitive deficits [2–4]. The pathology of VaD usually has vascular damage caused by cortical and subcortical microinfarction and neuronal atrophy at the corresponding position besides AD-like pathology. The pathology of patients often has strong heterogeneity, accompanied by pathological changes of other types of dementia. Dementia caused by separate vascular pathology is not common [5–7].

In many cases, the risk markers of VaD are likely to be similar to those of stroke, cerebrovascular disease, and Alzheimer’s disease [8–11]. Currently, VaD is mainly treated by targeting vascular diseases and other VaD risk factors, including improving cerebral blood circulation, protecting neurological function, and improving neuropsychiatric symptoms [12]. Although commonly used dementia drugs can show cognitive benefits in some VaD patients, their function and population-wide benefits have remained uncertain [13].

1.2. Gastrodin

Gastrodia elata has been a traditional medicine for epilepsy, vertigo, headache, numbness, and movement disorders since ancient times (Figure 1(b)). Gastrodia elata is composed of many small molecule compounds, such as gastrodin, parishin, phenolic compounds, 4-hydroxybenzyl alcohol, G. elata polysaccharides, and β-sitosterol. Rhizoma gastrodiae polysaccharides are also one of the main active substances in rhizoma gastrodiae, have a sound neuroprotective effect antiviral, antitumor angiogenesis, and biological activities of osteoporosis, and receive also increased attention from the research community in recent years; however, since the separation of polysaccharide in Gastrodia elata in only a few clear the specific structure and function after modification, it is shown that rhizoma gastrodiae polysaccharides research still has a great gap [14].

(a)

(b)

Here, we focus on gastrodin, another major component of Gastrodia that has received much attention in vascular dementia treatment. Gastrodin (GAS), as a phenolic glycoside, and its aglycone (p-hydroxybenzyl alcohol) are major components of the G. elata tuber, which are also markers for the quality control and the main active components of this herbal medicine [15] (Figure 1(a)). Gastrodin is naturally found in Gastrodia elata, and other Gastrodia elata extracts can also be metabolized in the body to produce gastrodin [16].

GAS is separated from Gastrodia elata by ethanol extraction. Modern pharmacological studies have found that GAS can be rapidly absorbed through glucose transport channels in the intestinal tract, and the binding rate of GAS and plasma protein is not high [17]. After 15 minutes of intravenous injection, GAS can penetrate the blood-brain barrier (BBB) and can be detected in the frontal lobe, hippocampus, thalamus, and cerebellum of rats, in which the concentration of cerebellum is the highest and excreted through hepatobiliary tract, which has a good effect on improving neurodegenerative diseases. In the central system, it has sedative, neuronal protection, anti-inflammatory, antioxidant, and other therapeutic effects [17–21]. Compared with western medicine in the treatment of VaD, gastrodin has the advantages of fewer side effects, more action sites, and safe efficacy; therefore, it is a promising TCM treatment [22, 23]. In recent years, gastrodin has been developed into a mature and sustainable industrial production mode, which has advantages over traditional Chinese medicine treatment. Gastrodin can play a better role in the treatment of VaD by improving the method of administration, increasing the BBB permeability with the compatibility of other Traditional Chinese medicines, combined with western medicine treatment and risk factor control methods [24–27].

2. Materials and Methods

This review covers fifteen years of published literature and focuses on the clinical and experimental studies most relevant to gastrodin therapy for vascular dementia. These include in vitro and in vivo trials of gastrodin in the treatment of VaD and associated risk factors. The mentioned and relevant role and mechanism in these studies have been shown in the figures. All studies were retrieved from the following databases: Web of Science, PubMed, Elsevier, and CNKI. The following keywords were used: “Gastrodin,” “Gastrodia elata,” “vascular dementia,” and “Cognitive impairment.” The chemical structures in this article were created by PowerPoint. The figures in this article were created by Adobe Illustrator.

3. Results

3.1. Role of Gastrodin in the Treatment of Vascular Dementia

Gastrodia elata has been used to treat vertebral-basilar artery insufficiency vertigo, neurodegenerative diseases in motility, and cognitive impairment diseases. It was found that gastrodin not only can play a role of neural protection in the early stages of stroke, but also has a good effect on improving vascular cognitive impairment [28].

Gastrodin’s neuroprotective role in nervous system is multidimensional. It is well known that microglia play a phagocytic role in the nervous system, and astrocytes can interact with microglia. Both of them jointly regulate inflammatory responses in the nervous system and play a key role in neuroinflammation and degenerative diseases [29]. Any nervous system disorder can lead to inflammation and activation of glial cells, which can lead to neuronal damage and ultimately cognitive deficits after ischemic hypoxia injury. Gastrodin can reduce the inflammatory response and oxidative stress of neuronal cells, regulate the activation of microglia, and reduce the damage of astrocytes, thus reducing neuronal apoptosis [30–32]. The resistance of gastrodin to neurotoxic substances is also a hotspot in recent years. GAS reduces the generation and deposition of Aβ and Tau in cognition-related brain domains and reduces neuroautophagy induced by toxic substances. GAS has been proved to have neural function preservation effect [33, 34]. In addition to reducing the loss of neuron cells, gastrodin’s neuroprotective effect is also shown in promoting the secretion of neurotrophic factors, which have been found playing a facilitating role in the survival of neurons and the differentiation of neural stem cells. Therefore, it can be said that its protective effect on nervous system function is bidirectional, and its specific mechanism of neural protection is discussed in the next section of this paper.

Because nerve damage is difficult to reverse, currently accepted treatment strategies for vascular dementia emphasize controlling vascular risk factors for prevention and early control in addition to cognitive improvement. Gastrodin can not only reverse cognitive impairment, it can also ameliorate a number of related risk factors. Many effects of gastrodin have been confirmed, which shows that gastrodin has a promising prospect as an important monomer.

Studies have shown that GAS can effectively intervene in the renin-angiotensin-aldosterone system (RAAS) and its resulting myocardial remodeling, thus playing a role in the treatment of hypertension [35, 36]. In addition to hypertension, atherosclerosis is also a risk factor for cardiovascular and cerebrovascular diseases and for VaD. Gastrodin can restore lysosome function and autophagy activity, thereby reducing lipid accumulation and preventing foam cell formation [37]. In addition to reducing the accumulation of foam cells, GAS can also inhibit the proliferation of vascular smooth muscle cells (VSMC), regulate the effect of vascular smooth muscle, and promote angiogenesis [38–40]. Gastrodin can also improve the intestinal microenvironment in terms of bacterial diversity and abundance, thus reducing inflammation damage to blood vessels and protecting cognitive function through the brain-gut axis [41].

Although the relationship between depression-like manifestations and vascular dementia is still unclear, various emotional and mental disorders often occur in patients with cerebrovascular disease. Gastrodin has been proved to be effective in the treatment of various mood disorders, especially in the regulation of depression and anxiety related to diabetes and dementia [42–44]. Gastrodin can regulate NLRP3 pathway, inhibit vascular endothelial growth factor, and improve striatum neuron degeneration [45–47]. It has been proved that gastrodin can reduce depression-like behavior by inhibiting ER stress and regulating the neurovascular remodeling associated with Slit Robo A pathway [48–51]. Furthermore, gastrodin also has the regulatory effect of similar to fluoxetine as brain neurotransmitter and improves the anxiety and depression state in the early stage of cognitive impairment by improving the function of monoamine system in the neurotransmission process [52]. Other studies have shown that gastrodin reversed the decrease of γ aminobutyric acid (GABA) level and the increase of extracellular glutamate level in the prefrontal cortex and hippocampus of rats with cognitive impairment [53, 54]. The main roles of gastrodin treating vascular dementia have been listed in Figure 2.

Figure 2 pink text shows gastrodin’s protective effect on the central nervous system, and purple text shows its effect on metabolic disorders, intestinal flora, and other recently identified risk factors for VaD.

3.2. Mechanisms of Gastrodin in the Treatment of Vascular Dementia

Vascular ischemia, toxic substance deposition, and other factors can induce neuroinflammation. When inflammation persists for a long time, the level of oxidative stress in the nervous system will increase, leading to neuronal apoptosis. As the mechanisms of vascular dementia are very diverse, ranging from stroke, cerebral hemorrhage, and vascular disease to vascular dysfunction caused by toxic substances, the research models are also very diverse [55, 56]. Most studies have observed the phenomenon of early onset of inflammatory response and the increase of oxidative stress-related markers. So, reducing mitigating the above threats is a possible treatment for VaD (Table 1).

3.2.1. Gastrodin Reduces the Expression of Inflammatory Factors

Gastrodin can reduce the levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 and increase the anti-inflammatory factor IL-10 (Figure 3). Gastrodin can also regulate Mir-21-5p and Mir-331-5p to prevent the inflammatory activation caused by ischemia, thus playing a neuroprotective role [57, 58].

Inhibition of extracellular inflammatory peroxidase (Prx) signaling after stroke appears to be a potential therapeutic strategy [59]. Studies have shown that in vivo metabolites of GAS significantly inhibit macrophages, and Prx1, Prx2, and Prx4 induced inflammation in H₂O₂-mediated SH-SY5Y oxidative damage, which can reduce related signal activation of TLR4. It is suggested that TLR4/NF-κB signaling pathway ameliorates neural defects, cerebral infarction, and neuropathological changes in cerebral ischemia-reperfusion rats [60, 61]. What is more, by regulating lncRNA NEAT1/Mir-22-3p axis, gastrodin significantly alleviates the inflammatory response of the nervous system of ischemic rats and alleviates the brain injury in the subacute stage, indicating that gastrodin can play a good therapeutic effect in both early and late pathological changes [62, 63].

Inflammatory factors such as TNF-α and IL-1 can bind to the TRAF6 complex and activate its downstream TGF- beta-activated kinase 1 (TAK1). TAK1 is a key regulator of the induction of transcription factor NF-κB and plays a role by mediating IκBkinase (IKK) activation. Activation of IKK complex results in phosphorylation of IκB-α, which is subsequently degraded by the ubiquitin-proteasome pathway. After NF-κB depolymerizes from IκB-α, it will be transported into the nucleus to promote NF-κB dependent gene transcription. SSeCKS can promote downstream P38 and Akt signal transduction by promoting TAK1 phosphorylation. Gastrodin inhibits NF-κB signal activation induced by toxic substances and blocks PC12 neuronal apoptosis induced by inflammatory factors by reducing sSECKS-TRAF6 interactions [64] (Figure 3).

3.2.2. Gastrodin Reduces Oxidative Stress Level

Previous studies have found that VaD patients often have elevated levels of oxidative stress in the nervous system, which can lead to inflammation, increase of protease secretion, production of reactive oxygen species, and eventually inducing of neuronal apoptosis. Common antioxidants include superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX). Gastrodin has great antioxidant capacity, which can restore the levels of GSH-Px and total mercaptan and reduce the generation of malondialdehyde (MDA) and reactive oxygen species (SOD), thus reversing mitochondrial damage [30, 65]. Gastrodin also activates the p38 mitochondrial protein kinase (P38 MAPK) pathway and reduces the expression levels of P38 and IL-1β [66].

At the molecular level, gastrodin upregulates NFE2L2 gene, activates P38 MAPK/Nrf2, and promotes Nrf2 release from the cytoplasmic Kelch-like epichlorohydrin-associated protein 1 (Keap1) and Nrf2 complex. Then, Nrf2 enters the nucleus and binds with antioxidant response elements (ARE), thereby increasing the expression of downstream antioxidant stress factors. One of them is heme oxygenase-1 (HO-1), whose expression has a protective effect on vascular and nerve damage caused by atherosclerosis and ischemia-reperfusion injury [67]. Through this way, GAS can significantly reduce nerve edema after ischemia and improve neuronal apoptosis [68–70]. Gastrodin can also activate Wnt/β-catenin signaling pathway through NRF2-mediated antioxidant signals and reduce cycx-2 (COX-2) activation, showing neuroprotective properties [71] (Figure 3).

Through the above pathways, gastrodin significantly increased the expression of Bcl-2 and decreased Bax, thus reducing the levels of active Caspase 3 and active Caspase 9, and played a cognitive protective role, which also proved the role of gastrodin in reducing neuron loss through anti-inflammatory and antioxidant ones [61, 70, 72].

3.2.3. Gastrodin Inhibits Excessive Autophagy Caused by Toxic Substances

Amyloid plaque deposition and Tau phosphorylation are often found in patients with vascular dementia’s pathology. Although the mechanism of their role in vascular dementia is still unclear, recent studies have shown that serum Aβ42 is independently associated with cognitive impairment in patients with small vascular disease (CSVD) and can be used to predict cognitive impairment [73]. An overload of neurotoxic substances can cause excessive autophagy, resulting in loss of nerve cells. Common toxic substances, such as Aβ, glutamate, and NO, increase, and neurotrophic substances decrease in VaD patients [74]. Gastrodin can reverse the above pathological changes and play a role in increasing neuronal survival, improving synaptic function and promoting neural differentiation [71]. Studies have shown that GAS can reduce the expression of Aβ1-40/42, APP, and β-site APP Exceller enzyme 1. Long-term gastrodin management inhibits the polymerization and decomposition of oligarchic Aβ, prevents its induced cellular neurotoxicity, reduces the level of Aβ plaques and high pTau, and alleviates oxidative stress in APP/PS1 transgenic mice [75] (Figure 3). Excessive autophagy can be inhibited by lowering the levels of Beclin-1, LC3-II, and P62 in both neuronal cells and astrocytes [76, 77]. In addition, the P38 MAPK signaling pathway is also involved in this process [34].

The GAS and its metabolites in the body can effectively reverse Aβ (1–42), causing spontaneous discharge by concentration dependence. This can inhibit the l-type calcium channel current, inhibition of hippocampal neurons M type potassium channel density, and slow down the process of the activation time, alleviate nerve excitability, improve the chain reaction caused by frequent discharge, and reduce cognitive impairment [78, 79].

Gastrodin also has similar effects as an autophagy inhibitor, which can significantly improve the autophagy flux dysfunction of VaD rats by preventing glutamate-induced influx of calcium ions, inhibiting CaMKII activation, inhibiting CaMKII/ASK-1/P38 MAPK/p53 signaling pathway, and increasing lysosomal acidification and autophagosome lysosomal fusion. Eventually, the cognitive defects of vascular dementia rats were reversed [80, 81].

3.2.4. Gastrodin Promotes Neural Survival and Neural Stem Cell Differentiation

Brain-derived neurotrophic factor (BDNF) is mainly expressed in the central nervous system, with the highest content in the hippocampus and cortex. BDNF binds to TrkB to activate the RAS-MAPK pathway and finally activates CAMP response element binding protein (CREB). CREB promotes nerve cell survival, synaptic plasticity, and neurogenesis by increasing the expression of BDNF gene and antiapoptotic protein gene Bcl-2. Gastrodin has been proved to have the ability to repair axons in the peripheral nervous system [82]. In order to illustrate its role in the central system, relevant studies have shown that GAS can promote the reconstruction of peripheral nerve’s microvascular network by reducing the expression of TNF-α and iNOS. By regulating the cAMP/PKA/CREB signaling pathway, oxidative damage is reduced, and the expression of neurotrophic factor is increased to induce the differentiation of neural stem cells, which has a certain recovery effect on cerebral ischemia focal points [83–85]. Protein kinase G (PKG) is a key downstream effector of cGMP. This pathway promotes the transcription of brain-derived neurotrophic factor (BDNF). PDE9 is specific hydrolase for cGMP, and the hippocampus and cortex are very abundant. Recent studies have found that PDE9 inhibition can promote the proliferation of NSC after oxygen and glucose deprivation injury through the CGMP-PKG pathway [87]. In addition to increasing neuronal survival, gastrodin was observed in animal models to increase the number of neuronal stem cells in the dentate gyrus region, improve cGMP level and upregulate PKG expression by inhibiting PDE9, promote hippocampal neurogenesis after cerebral ischemia, and improve the cognitive function of mice [88–90]. The latest study also showed that it could promote the replication of mouse embryonic neural progenitor cells, further confirming the possible effect of gastrodin on promoting stem cell proliferation and differentiation. GAS targeting SIRT1/BDNF pathway may be a potential therapeutic target for vascular dementia [86].

3.2.5. The Role of Gastrodin in Regulating Glial Cells and Blood-Brain Barrier

Gastrodin regulates microglia-related inflammation in a bidirectional manner. On the one hand, gastrodin promotes microglia to secrete damaging proinflammatory factors that aggravate inflammation. On the other hand, it increases the secretion of protective cytokines by microglia to reduce inflammatory response [91–94].

Gastrodin has been found to inhibit NOTCH-1 signaling pathway in both in vivo and in vitro experiments, and Notch signaling pathway may be involved in the regulation of microglial migration [95]. It reduces the expressions of NICD, RBP-JK, and HES 1, members of the NOTCH-1 signaling pathway, thus enhancing the expression of downstream genes Sirt3 and AT2. And GAS can inhibit the migration of activated BV-2 microglia and inhibit the activation of renin system [70, 96, 97].

Extracellular regulated protein kinases 1 and 2 (ERKl/2) signaling molecules located in the cytoplasm of Ras can be activated by growth factors and enter the nucleus to act as activating transcription factors. Studies have shown that gastrodin not only regulates NRF2-related pathways in neurons, but also inhibits the phosphorylation of ERK1/2, P38 MAPK, Akt, and GSK-3β induced by toxic substances by regulating PI3 K/GSK-3β signaling pathway in glial cells. Through these pathways, GAS inhibits vascular smooth muscle hyperplasia and alleviates intimal hyperplasia induced by vascular injury [45, 52, 98, 99].

In addition to the above pathways, gastrodin treatment significantly preserves the Wnt/β -catenin signaling pathway in neurons, reduces the activation of cox-2 downstream, promotes neurogenesis, and provides neuroprotection against brain injury [100]. However, gastrodin inhibited the phosphorylation of glycogen synthase kinase-3 β (GSK-3β) and β-catenin induced by lipopolysaccharide in microglia and modulated anti-inflammatory and antiproliferation effects in active microglia [57, 101] (Figure 4(a)).

(a)

(b)

Transcriptional regulator STAT3 plays an important role in inflammation and natural immune responses, activating NLRP inflammasome and thereby activating the NF-κB pathway. Application of gastrodin in astrocyte models of oxygen and sugar deprivation effectively suppressed inflammation levels in astrocytes and reduced astrocyte loss by inhibiting STAT3 and reducing NF-κB signaling activation [102] (Figure 4(b)).

Many evidences indicate that the cognitive impairment caused by cerebrovascular injury is closely related to the disorder of the blood-brain barrier (BBB). Peripheral toxic Aβ enters the cognition-related brain domains through the impaired BBB and is deposited. Imaging evidence has been observed, suggesting that BBB therapy may be a new therapeutic target for VaD [103–105]. In BV-2 microglia, GAS pretreatment reduced the number of positive cells for matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9), two repair agents after nerve injury. Current results suggest that GAS pretreatment significantly compensates for neurobehavioral defects in I/R induced injury rats, reduces the size of cerebral infarction, reverses BBB injury, and alleviates inflammation, which is beneficial during recovery from cerebral ischemia/reperfusion (I/R) injury [90]. Studies have shown that single neurovascular damage caused by HIV infection may be the cause of later cognitive impairment [106]. In the nerve injury model induced by METH and HIV-1 protein, it was found that gastrodin pretreatment significantly increased the expressions of ZO1, JAMA, GLUT1, and GLUT and reversed the blood-brain barrier injury [107] (Figure 4(b)).

3.3. Clinical Application of Gastrodin in the Treatment of Vascular Dementia

Gastrodia elata’s clinical application and its treatment in cognition-related diseases have been established for a long time. Although the ancients did not have modern diversified ways of drug analysis, through long-term practice, we have found that Gastrodia elata combined with other drugs can increase the utilization rate in the nervous system of the active components of Gastrodia elata, resulting in better efficacy [108]. In modern times, the ancient prescription is packaged by modern ways, such as Antongshutong capsule. Its protective function of nerve function after stroke has been proved. Prescriptions composed of Gastrodia elata, such as Shenma Yizhi Decoction, have been proved to have brain mitochondrial structure improvement effect in VCI rats, thus improving cognitive impairment [109–111]. Of course, better delivery processing of Gastrodia elata, such as nasal administration or preparation of Gastrodia elata with finer particles, can increase its drug utilization rate. In addition, Gastrodia elata can be used with higher efficacy and fewer side effects by modern extraction of gastrodin, the active ingredient in Gastrodia elata [112]. Interestingly, gastrodin is hydrophilic, and its combination with porous thin film material polyurethane can promote synaptic generation and provide a good growth matrix, showing its possibility in modern surgical materials exploration [113]. Gastrodin and oxido-uncarine have a synergistic effect to reduce the oxidative stress level of neurons. Oxiracetam combined with gastrodin in the treatment of acute intracerebral hemorrhage can effectively reduce the volume of cerebral hematoma and edema [114]. Gastrodin injection combined with deproteinization of calf serum can effectively improve neurological function score and BDNF level in patients with cerebral infarction [115]. Gastrodin injection combined with hyperbaric oxygen in the treatment of vascular dementia patients can optimize cerebral hemodynamics and improve the level of serum brain-derived neurotrophic factor, which is a very effective combination therapy [116]. Electroacupuncture combined with gastrodin can downregulate the expression of NOGO-A and NgR in the frontal cortex of the ischemic focal area and improve neurological function, which is more effective than electroacupuncture alone or gastrodin [117]. Gastrodin combined with donepezil can improve the quality of life and brain function of patients with vascular dementia, and the effect is better than that of single drug [118]. These methods have shown that gastrodin can improve cerebrovascular and cognition with fewer side effects. And gastrodin can reduce drug dosage when combined with other drugs, showing superior therapeutic effect.

Recent study shows that single pulse of low-energy focused shockwave treatment can get gastrodin through the blood-cerebrospinal fluid barrier [119]. The combination of focused ultrasound (FUS) and microbubbles (MBs) to deliver gastrodin can improve the permeability of its blood-brain barrier (BBB) and improve the drug effect. The combination of gastrodin injection and FUS has also been confirmed to improve cognition in mice with dementia [120, 121]. This indicates that gastrodin does have sufficient cognitive repair function, and its treatment of vascular dementia has realistic scientific basis. Its application method still has great development prospect [122]. Therefore, gastrodin treatment of vascular dementia is a realistic scientific basis, and its application methods still have a great prospect of development.

4. Conclusions

Gastrodin has been proved to have anti-inflammatory effects, reduce oxidative stress, reduce nerve apoptosis, regulate nerve autophagy, and have a good neuroprotective effect. Interestingly, many studies have shown that gastrodin can improve anxiety and depression symptoms associated with vascular damage in diabetes and atherosclerosis and dementia. More importantly, gastrodin, a natural extract of the plant Gastrodia elata, has better coverage of the complex symptoms of cognitive impairment syndrome than existing dementia drugs and is safer. Therefore, gastrodin can be a promising treatment for vascular dementia due to its wide range of effects. Although gastrodin has a promising future, the BBB penetration rate of gastrodin metabolites is low, and pharmacokinetics suggest that its action time is short. This indicates that gastrodin, as a clinical therapeutic drug, needs to develop more effective drug delivery methods. Other studies have shown that gastrodin in combination with other Chinese or Western medicines can increase the time taken to metabolize the drug and improve cognition. Therefore, the development of diversified drug application methods will be another difficulty in the application of gastrodin. So far, the application of gastrodin lacks sufficient evidence-based evidence, and more clinical studies are needed.

Data Availability

The data used in the current study are included within this article.

Conflicts of Interest

The authors disclose no conflicts of interest.

Authors’ Contributions

Chujun Deng (e-mail:chujun_deng28@163 com), Huize Chen (e-mail:huize0512@163 com), and Zeyu Meng (e-mail:mengzeyu2020@163 com) contributed equally to this work.

Acknowledgments

This work was supported by the Project of Shanghai Science and Technology Commission (19401970600) and the Project of Shanghai Science and Technology Commission (19401932500), and Shanghai will further accelerate the 3-year action plan for the development of TCM (2018–2020) for Major Clinical Research on TCM (ZY (2018–2020)-CCCX-4010), the Innovation Fund of Integrated Traditional Chinese and Western Medicine, School of Medicine, Shanghai Jiao Tong University (18zxy002), the 2019 Teacher Training and Development Project of Medical School of Shanghai Jiao Tong University (JFXM201909), and the Experimental Project of Scientific and Technological Innovation for College Students of Heilongjiang University of Traditional Chinese Medicine.

References

O. A. Skrobot, S. E. Black, C. Chen et al., “Progress toward standardized diagnosis of vascular cognitive impairment: guidelines from the vascular impairment of cognition classification consensus study,” Alzheimer’s and Dementia, vol. 14, no. 3, pp. 280–292, 2018.
View at: Google Scholar
J. M. Livingston, M. W. McDonald, T. Gagnon et al., “Influence of metabolic syndrome on cerebral perfusion and cognition,” Neurobiology of Disease, vol. 137, Article ID 104756, 2020.
View at: Publisher Site | Google Scholar
D. H. Nguyen, J. T. Cunningham, and N. Sumien, “Estrogen receptor involvement in vascular cognitive impairment and vascular dementia pathogenesis and treatment,” GeroScience, vol. 43, no. 1, pp. 159–166, 2021.
View at: Publisher Site | Google Scholar
J. He, X. Li, S. Yang et al., “Gastrodin extends the lifespan and protects against neurodegeneration in the drosophila PINK1 model of Parkinson’s disease,” Food & Function, vol. 12, no. 17, pp. 7816–7824, 2021.
View at: Publisher Site | Google Scholar
W. M. van der Flier, I. Skoog, J. A. Schneider et al., “Vascular cognitive impairment,” Nature Reviews Disease Primers, vol. 4, no. 1, pp. 1–16, 2018.
View at: Publisher Site | Google Scholar
R. N. Kalaria, “Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease,” Acta Neuropathologica, vol. 131, no. 5, pp. 659–685, 2016.
View at: Publisher Site | Google Scholar
N. K. Lee, H. Kim, J. Yang et al., “Heterogeneous disease progression in a mouse model of vascular cognitive impairment,” International Journal of Molecular Sciences, vol. 21, no. 8, p. 2820, 2020.
View at: Publisher Site | Google Scholar
P. B. Gorelick, A. Scuteri, S. E. Black et al., “Vascular contributions to cognitive impairment and dementia,” Stroke, vol. 42, no. 9, pp. 2672–2713, 2011.
View at: Publisher Site | Google Scholar
O. A. Skrobot, J. O'Brien, S. Black et al., “The vascular impairment of cognition classification consensus study,” Alzheimer’s and Dementia : The Journal of the Alzheimer’s Association, vol. 13, no. 6, pp. 624–633, 2017.
View at: Publisher Site | Google Scholar
L. G. Exalto, J. M. F. Boomsma, R. Babapour Mofrad et al., “Sex differences in memory clinic patients with possible vascular cognitive impairment,” Alzheimer’s and Dementia, vol. 12, no. 1, Article ID e12090, 2020.
View at: Publisher Site | Google Scholar
X. Chen, L. Duan, Y. Han et al., “Predictors for vascular cognitive impairment in stroke patients,” BMC Neurology, vol. 16, no. 1, p. 115, 2016.
View at: Publisher Site | Google Scholar
A. Frances, O. Sandra, and U. Lucy, “Vascular cognitive impairment, a cardiovascular complication,” World Journal of Psychiatry, vol. 6, no. 2, p. 199, 2016.
View at: Publisher Site | Google Scholar
M. U. Farooq, J. Min, C. Goshgarian, and P. B. Gorelick, “Pharmacotherapy for vascular cognitive impairment,” CNS Drugs, vol. 31, no. 9, pp. 759–776, 2017.
View at: Publisher Site | Google Scholar
H. Zhu, C. Liu, J. Hou et al., “Gastrodia elata blume polysaccharides: a review of their acquisition, analysis, modification, and pharmacological activities,” Molecules, vol. 24, no. 13, p. 2436, 2019.
View at: Publisher Site | Google Scholar
Y. Li, Y. Zhang, Z. Zhang, Y. Hu, X. Cui, and Y. Xiong, “Quality evaluation of gastrodia elata tubers based on HPLC fingerprint analyses and quantitative analysis of multi-components by single marker,” Molecules, vol. 24, no. 8, p. 1521, 2019.
View at: Publisher Site | Google Scholar
C. Tang, L. Wang, X. Liu, M. Cheng, Y. Qu, and H. Xiao, “Comparative pharmacokinetics of gastrodin in rats after intragastric administration of free gastrodin, parishin and gastrodia elata extract,” Journal of Ethnopharmacology, vol. 176, no. 24, pp. 49–54, 2015.
View at: Publisher Site | Google Scholar
L.-C. Lin, Y.-F. Chen, T.-R. Tsai, and T.-H. Tsai, “Analysis of brain distribution and biliary excretion of a nutrient supplement, gastrodin, in rat,” Analytica Chimica Acta, vol. 590, no. 2, pp. 173–179, 2007.
View at: Publisher Site | Google Scholar
K. Guo, X. Wang, B. Huang et al., “Comparative study on the intestinal absorption of three gastrodin analogues via the glucose transport pathway,” European Journal of Pharmaceutical Sciences, vol. 163, Article ID 105839, 2021.
View at: Publisher Site | Google Scholar
Q. Wang, G. Chen, and S. Zeng, “Distribution and metabolism of gastrodin in rat brain,” Journal of Pharmacy Biomedicine Analytical, vol. 46, no. 2, pp. 399–404, 2008.
View at: Google Scholar
L. Li, X. Yang, Y. Liu, L. Chen, and X. Jin, “Studies on pharmacokinetics and tissue distribution of curcumol liposome,” Latin American Journal of Pharmacy, vol. 33, no. 5, pp. 709–716, 2014.
View at: Google Scholar
X. Li, Y.-W. Jia, J.-S. Wang, M.-H. Yang, K. D. G. Wang, and L.-Y. Kong, “H nuclear magnetic resonance-based metabolomics reveals sex-specific metabolic changes of gastrodin intervention in rats,” Asian Pacific Journal of Tropical Medicine, vol. 7, no. 10, pp. 811–818, 2014.
View at: Publisher Site | Google Scholar
Y. Li, X. Q. Liu, S. S. Liu, D. H. Liu, X. Wang, and Z. M. Wang, “Transformation mechanisms of chemical ingredients in steaming process of gastrodia elata blume,” Molecules, vol. 24, no. 17, 2019.
View at: Publisher Site | Google Scholar
Y. Yang, F. M. Han, P. Du, and Y. Chen, “Pharmacokinetics of gastrodin from compound tianma granule in rats,” Yaoxue Xuebao, vol. 45, no. 4, pp. 484–488, 2010.
View at: Google Scholar
Y. Long, Q. Yang, Y. Xiang et al., “Nose to brain drug delivery - a promising strategy for active components from herbal medicine for treating cerebral ischemia reperfusion,” Pharmacological Research, vol. 159, Article ID 104795, 2020.
View at: Google Scholar
Y. Mi, M. Wang, M. Liu, H. Cheng, and S. Li, “Pharmacokinetic comparative study of GAS with different concentration of tetramethylpyrazine and ferulic acid on liver-yang hyperactivity migraine model by blood-brain microdialysis method,” Journal of Pharmacy Biomedicine Analytical, vol. 191, Article ID 113643, 2020.
View at: Google Scholar
H. B. Li, F. Wu, K. R. Xiong, H. C. Miao, and X. L. Zhu, “Effects of electroacupuncture intervention combined with gastrodin on expression of proteins related to proliferation-differentiation of neural stem cells in hippocampal CA 1 and CA 3 regions in focal cerebral ischemia rats,” Zhen Ci Yan Jiu = Acupuncture Research, vol. 40, no. 6, pp. 455–460, 2015.
View at: Google Scholar
Y. Bu, P. Y. Zhang, D. Q. Geng, J. X. Cao, and J. Z. Li, “Effects of electroacupuncture plus oxygenmedicine on the expression of Bcl-2 and Bax proteins in the hippocampal CA 1 area in rats with global cerebral ischemia/reperfusion injury,” Zhen Ci Yan Jiu = Acupuncture Research, vol. 35, no. 3, pp. 208–212, 2010.
View at: Google Scholar
X. Jie, “Clinical study on gastrodin injection combined with alprostadil for posterior circulation ischemic vertigo,” Journal of New Chinese Medicine, vol. 53, no. 14, pp. 75–77, 2021.
View at: Google Scholar
J. Kriska, Z. Hermanova, T. Knotek, J. Tureckova, and M. Anderova, “On the common journey of neural cells through ischemic brain injury and Alzheimer’s disease,” International Journal of Molecular Sciences, vol. 22, no. 18, p. 9689, 2021.
View at: Publisher Site | Google Scholar
Y. Li and Z. Zhang, “Gastrodin improves cognitive dysfunction and decreases oxidative stress in vascular dementia rats induced by chronic ischemia,” International Journal of Clinical and Experimental Pathology, vol. 8, no. 11, Article ID 14099, 2015.
View at: Google Scholar
J.-S. Zhang, S.-F. Zhou, Q. Wang et al., “Gastrodin suppresses BACE1 expression under oxidative stress condition via inhibition of the PKR/eIF2α pathway in Alzheimer’s disease,” Neuroscience, vol. 325, pp. 1–9, 2016.
View at: Publisher Site | Google Scholar
H. Tayler, J. S. Miners, Ö. Güzel, R. MacLachlan, and S. Love, “Mediators of cerebral hypoperfusion and blood-brain barrier leakiness in Alzheimer’s disease, vascular dementia and mixed dementia,” Brain Pathology, vol. 31, no. 4, Article ID e12935, 2021.
View at: Google Scholar
R. Shi, C. B. Zheng, H. Wang et al., “Gastrodin alleviates vascular dementia in a 2-VO-vascular dementia rat model by altering amyloid and Tau levels,” Pharmacology, vol. 105, no. 7-8, pp. 386–396, 2020.
View at: Google Scholar
B. Liu, J.-M. Gao, F. Li, Q. H. Gong, and J. S. Shi, “Gastrodin attenuates bilateral common carotid artery occlusion-induced cognitive deficits via regulating aβ-related proteins and reducing autophagy and apoptosis in rats,” Frontiers in Pharmacology, vol. 9, p. 405, 2018.
View at: Google Scholar
T. Ye, X. Meng, R. Wang et al., “Gastrodin alleviates cognitive dysfunction and depressive-like behaviors by inhibiting ER stress and NLRP3 inflammasome activation in db/db mice,” International Journal of Molecular Sciences, vol. 19, no. 12, 2018.
View at: Publisher Site | Google Scholar
X.-E. Zhao, Y. He, S. Zhu et al., “Stable isotope labeling derivatization and magnetic dispersive solid phase extraction coupled with UHPLC-MS/MS for the measurement of brain neurotransmitters in post-stroke depression rats administrated with gastrodin,” Analytica Chimica Acta, vol. 1051, pp. 73–81, 2019.
View at: Publisher Site | Google Scholar
F. Zhang, C.-K. Deng, Y.-J. Huang et al., “Early intervention of gastrodin improved motor learning in diabetic rats through ameliorating vascular dysfunction,” Neurochemical Research, vol. 45, no. 8, pp. 1769–1780, 2020.
View at: Publisher Site | Google Scholar
Y. H. Qi, R. Zhu, Q. Wang et al., “Early intervention with gastrodin reduces striatal neurotoxicity in adult rats with experimentally-induced diabetes mellitus,” Molecular Medicine Reports, vol. 19, no. 4, pp. 3114–3122, 2019.
View at: Google Scholar
C. K. Deng, Z. H. Mu, Y. H. Miao et al., “Gastrodin ameliorates motor learning deficits through preserving cerebellar long-term depression pathways in diabetic rats,” Frontiers in Neuroscience, vol. 13, p. 1239, 2019.
View at: Google Scholar
Z. Dong, L. Bian, Y. L. Wang, and L. M. Sun, “Gastrodin protects against high glucose-induced cardiomyocyte toxicity via GSK-3β-mediated nuclear translocation of Nrf2,” Human & Experimental Toxicology, vol. 40, no. 9, pp. 1584–1597, 2021.
View at: Google Scholar
R. Zhang, Z. Peng, H. Wang et al., “Gastrodin ameliorates depressive-like behaviors and up-regulates the expression of BDNF in the hippocampus and hippocampal-derived astrocyte of rats,” Neurochemical Research, vol. 39, no. 1, pp. 172–179, 2013.
View at: Publisher Site | Google Scholar
H. Wang, R. Zhang, Y. Qiao et al., “Gastrodin ameliorates depression-like behaviors and up-regulates proliferation of hippocampal-derived neural stem cells in rats: involvement of its anti-inflammatory action,” Behavioural Brain Research, vol. 266, pp. 153–160, 2014.
View at: Publisher Site | Google Scholar
W.-C. Chen, Y.-S. Lai, S.-H. Lin et al., “Anti-depressant effects of gastrodia elata blume and its compounds gastrodin and 4-hydroxybenzyl alcohol, via the monoaminergic system and neuronal cytoskeletal remodeling,” Journal of Ethnopharmacology, vol. 182, pp. 190–199, 2016.
View at: Publisher Site | Google Scholar
T. Ye, X. Meng, Y. Zhai et al., “Gastrodin ameliorates cognitive dysfunction in diabetes rat model via the suppression of endoplasmic reticulum stress and NLRP3 inflammasome activation,” Frontiers in Pharmacology, vol. 9, p. 1346, 2018.
View at: Google Scholar
G. Li, Y. Ma, J. Ji, X. Si, and Q. Fan, “Effects of gastrodin on 5-HT and neurotrophic factor in the treatment of patients with post-stroke depression,” Experimental and Therapeutic Medicine, vol. 16, no. 6, pp. 4493–4498, 2018.
View at: Publisher Site | Google Scholar
X. Wang, P. Li, J. Liu et al., “Gastrodin attenuates cognitive deficits induced by 3,3′-iminodipropionitrile,” Neurochemical Research, vol. 41, no. 6, pp. 1401–1409, 2016.
View at: Publisher Site | Google Scholar
X. Xu, Y. Lu, and X. Bie, “Protective effects of gastrodin on hypoxia-induced toxicity in primary cultures of rat cortical neurons,” Planta Medica, vol. 73, no. 7, pp. 650–654, 2007.
View at: Google Scholar
W. Liu, L. Wang, J. Yu, P. F. Asare, and Y. Q. Zhao, “Gastrodin reduces blood pressure by intervening with RAAS and PPARγ in SHRs,” Evidence-Based Complementary and Alternative Medicine, vol. 2015, Article ID 828427, 8 pages, 2015.
View at: Publisher Site | Google Scholar
C. Zheng, C. Y. Lo, Z. Meng et al., “Gastrodin inhibits store-operated Ca²⁺ entry and alleviates cardiac hypertrophy,” Frontiers in Pharmacology, vol. 8, p. 222, 2017.
View at: Google Scholar
F.-Y. Liu, J. Wen, J. Hou et al., “Gastrodia remodels intestinal microflora to suppress inflammation in mice with early atherosclerosis,” International Immunopharmacology, vol. 96, Article ID 107758, 2021.
View at: Publisher Site | Google Scholar
J. Tao, P. Yang, L. Xie et al., “Gastrodin induces lysosomal biogenesis and autophagy to prevent the formation of foam cells via AMPK‐FoxO1‐TFEB signalling axis,” Journal of Cellular and Molecular Medicine, vol. 25, no. 12, pp. 5769–5781, 2021.
View at: Publisher Site | Google Scholar
L. Zhu, H. Guan, C. Cui et al., “Gastrodin inhibits cell Proliferation in vascular smooth muscle cells and attenuates neointima formation in vivo,” International Journal of Molecular Medicine, vol. 30, no. 5, pp. 1034–1040, 2012.
View at: Google Scholar
S. Chen, X. Hao, L. Yu et al., “Gastrodin causes vasodilation by activating K ATP channels in vascular smooth muscles via PKA-dependent signaling pathway,” Journal of Receptors and Signal Transduction Research, vol. 37, no. 6, pp. 543–549, 2017.
View at: Google Scholar
M. Zheng, J. Guo, Q. Li et al., “Syntheses and characterization of anti-thrombotic and anti-oxidative Gastrodin-modified polyurethane for vascular tissue engineering,” Bioactive Materials, vol. 6, no. 2, pp. 404–419, 2020.
View at: Google Scholar
J. Hort, M. Vališ, K. Kuča, and F. Angelucci, “Vascular cognitive impairment: information from animal models on the pathogenic mechanisms of cognitive deficits,” International Journal of Molecular Sciences, vol. 20, no. 10, 2019.
View at: Publisher Site | Google Scholar
Q.-Z. Tuo, J.-J. Zou, and P. Lei, “Rodent models of vascular cognitive impairment,” Journal of Molecular Neuroscience, vol. 71, no. 5, pp. 1–12, 2020.
View at: Publisher Site | Google Scholar
X. Wang, L. Chen, Y. Xu et al., “Gastrodin alleviates perioperative neurocognitive dysfunction of aged mice by suppressing neuroinflammation,” European Journal of Pharmacology, vol. 892, Article ID 173734, 2021.
View at: Publisher Site | Google Scholar
H.-S. Zhang, M.-F. Liu, X.-Y. Ji, C.-R. Jiang, Z.-L. Li, and B. OuYang, “Gastrodin combined with rhynchophylline inhibits cerebral ischaemia-induced inflammasome activation via upregulating miR-21-5p and miR-331-5p,” Life Sciences, vol. 239, Article ID 116935, 2019.
View at: Publisher Site | Google Scholar
C. J. Zhang, M. Jiang, H. Zhou et al., “TLR-stimulated IRAKM activates caspase-8 inflammasome in microglia and promotes neuroinflammation,” Journal of Clinical Investigation, vol. 128, no. 12, pp. 5399–5412, 2018.
View at: Google Scholar
X. N. Mao, H. J. Zhou, X. J. Yang et al., “Neuroprotective effect of a novel gastrodin derivative against ischemic brain injury: involvement of peroxiredoxin and TLR4 signaling inhibition supplementary materials,” Oncotarget, vol. 8, no. 53, pp. 90979–90995, 2017.
View at: Google Scholar
L. Y. Q. Shengna, “Study on the effect of gastrodin on TLR4/NF-κB signaling pathway in rats with epilepsy induced by pilocarpine,” Journal of new Chinese medicine, vol. 52, no. 4, pp. 1–6, 2020.
View at: Google Scholar
H.-S. Zhang, B. Ouyang, X.-Y. Ji, and M.-F. Liu, “Gastrodin alleviates cerebral ischaemia/reperfusion injury by inhibiting pyroptosis by regulating the lncRNA NEAT1/miR-22-3p Axis,” Neurochemical Research, vol. 46, no. 7, pp. 1747–1758, 2021.
View at: Publisher Site | Google Scholar
B. Liu, F. Li, J. Shi, D. Yang, Y. Deng, and Q. Gong, “Gastrodin ameliorates subacute phase cerebral ischemia-reperfusion injury by inhibiting inflammation and apoptosis in rats,” Molecular Medicine Reports, vol. 14, no. 5, p. 4144, 2016.
View at: Google Scholar
M. Jiao, K. Yin, T. Zhang et al., “Effect of the SSeCKS-TRAF6 interaction on gastrodin-mediated protection against 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced astrocyte activation and neuronal death,” Chemosphere, vol. 226, pp. 678–686, 2019.
View at: Publisher Site | Google Scholar
M. R. de Oliveira, F. de Bittencourt Brasil, and C. R. Fürstenau, “Inhibition of the Nrf2/HO-1 Axis suppresses the mitochondria-related protection promoted by gastrodin in human neuroblastoma cells exposed to paraquat,” Molecular Neurobiology, vol. 563, no. 3, pp. 2174–2184, 2018.
View at: Publisher Site | Google Scholar
L. Wang, H. Wang, Z. Duan, J. Zhang, and W. Zhang, “Mechanism of gastrodin in cell apoptosis in rat hippocampus tissue induced by desflurane,” Experimental and Therapeutic Medicine, vol. 15, no. 3, p. 2767, 2018.
View at: Google Scholar
T. Jiang, H. Cheng, J. Su et al., “Gastrodin protects against glutamate-induced ferroptosis in HT-22 cells through Nrf2/HO-1 signaling pathway,” Toxicology in Vitro, vol. 62, Article ID 104715, 2020.
View at: Publisher Site | Google Scholar
G. Jiang, Y. Hu, L. Liu, J. Cai, C. Peng, and Q. Li, “Gastrodin protects against MPP⁺-induced oxidative stress by up regulates heme oxygenase-1 expression through p38 MAPK/Nrf2 pathway in human dopaminergic cells,” Neurochemistry International, vol. 75, pp. 79–88, 2014.
View at: Publisher Site | Google Scholar
Z. Peng, S. Wang, G. Chen et al., “Gastrodin alleviates cerebral ischemic damage in mice by improving anti-oxidant and anti-inflammation activities and inhibiting apoptosis pathway,” Neurochemical Research, vol. 40, no. 4, pp. 661–673, 2015.
View at: Publisher Site | Google Scholar
X. C. Liu, C. Z. Wu, X. F. Hu et al., “Gastrodin attenuates neuronal apoptosis and neurological deficits after experimental intracerebral hemorrhage,” Journal of Stroke and Cerebrovascular Diseases: The Official Journal of National Stroke Association, vol. 29, no. 1, Article ID 104483, 2020.
View at: Publisher Site | Google Scholar
C. M. Liu, Z. K Tian, Y. J. Zhang, Q. L. Ming, J. Q. Ma, and L. P. Ji, “Effects of gastrodin against lead-induced brain injury in mice associated with the Wnt/Nrf2 pathway,” Nutrients, vol. 12, no. 6, pp. 1–13, 2020.
View at: Publisher Site | Google Scholar
M. R. de Oliveira, F. B. Brasil, and C. R. Fürstenau, “Nrf2 mediates the anti-apoptotic and anti-inflammatory effects induced by gastrodin in hydrogen peroxide-treated SH-SY5Y cells,” Journal of Molecular Neuroscience, vol. 69, no. 1, pp. 115–122, 2019.
View at: Publisher Site | Google Scholar
Y. Huan, Z. Kui, S. Ran, and C. Xu, “Correlation between serum β-amyloid 42 level and cognitive impairment in patients with cerebral small vessel disease,” International Journal of Cerebrovascular Diseases, vol. 28, no. 7, pp. 492–497, 2020.
View at: Google Scholar
X. Wang, Z. Tian, N. Zhang et al., “Protective effects of gastrodin against autophagy-mediated astrocyte death,” Phytotherapy Research : PTR, vol. 30, no. 3, pp. 386–396, 2016.
View at: Google Scholar
G. Yang, X. Zeng, J. Li et al., “Protective effect of gastrodin against methamphetamine-induced autophagy in human dopaminergic neuroblastoma SH-SY5Y cells via the AKT/mTOR signaling pathway,” Neuroscience Letters, vol. 707, Article ID 134287, 2019.
View at: Publisher Site | Google Scholar
Y. Q. Zeng, J. H. Gu, L. Chen, T.-T. Zhang, and X.-F. Zhou, “Gastrodin as a multi-target protective compound reverses learning memory deficits and AD-like pathology in APP/PS1 transgenic mice,” Journal of Functional Foods, vol. 77, 2021.
View at: Publisher Site | Google Scholar
P. Z. Chen, H. H. Jiang, B. Wen et al., “Gastrodin suppresses the amyloid β-induced increase of spontaneous discharge in the entorhinal cortex of rats,” Neural Plasticity, vol. 2014, Article ID 320937, 10 pages, 2014.
View at: Publisher Site | Google Scholar
C. S. Yang, M. C. Lai, P. Y. Liu, Y. C. Lo, C. W. Huang, and S. N. Wu, “Characterization of the inhibitory effect of gastrodigenin and gastrodin on M-type K⁺ currents in pituitary cells and hippocampal neurons,” International Journal of Molecular Sciences, vol. 21, no. 1, 2020.
View at: Google Scholar
T.-T. Chen, X. Zhou, Y.-N. Xu et al., “Gastrodin ameliorates learning and memory impairment in rats with vascular dementia by promoting autophagy flux via inhibition of the Ca²⁺/CaMKII signal pathway,” Aging, vol. 13, no. 7, pp. 9542–9565, 2021.
View at: Publisher Site | Google Scholar
G. Jiang, H. Wu, Y. Hu, J. Li, and Q. Li, “Gastrodin inhibits glutamate-induced apoptosis of PC12 cells via inhibition of CaMKII/ASK-1/p38 MAPK/p53 signaling cascade,” Cellular and Molecular Neurobiology, vol. 34, no. 4, pp. 591–602, 2014.
View at: Publisher Site | Google Scholar
Y. Niu, C. Wan, J. Zhang et al., “Aerobic exercise improves VCI through circRIMS2/miR-186/BDNF-mediated neuronal apoptosis,” Molecular Medicine, vol. 27, no. 1, p. 4, 2021.
View at: Publisher Site | Google Scholar
H. Yang, Q. Li, L. Li et al., “Gastrodin modified polyurethane conduit promotes nerve repair via optimizing Schwann cells function,” Bioactive Materials, vol. 8, pp. 355–367, 2021.
View at: Google Scholar
C.-L. Ma, L. Li, G.-M. Yang et al., “Neuroprotective effect of gastrodin in methamphetamine-induced apoptosis through regulating cAMP/PKA/CREB pathway in cortical neuron,” Human & Experimental Toxicology, vol. 39, no. 8, pp. 1118–1129, 2020.
View at: Publisher Site | Google Scholar
G. Sun, Z. Yuan, B. Zhang et al., “Gastrodin blocks neural stem cell differentiation into glial cells mediated by kainic acid,” Neural Regeneration Research, vol. 7, no. 12, pp. 891–5, 2012.
View at: Publisher Site | Google Scholar
B. Liu, L. Ding, F. Li, and Q. Gong, “Effect of Gastrodin on related genes mRNA expression in cerebral ischemia-reperfusion rats,” Journal of Zunyi Mecial University, vol. 39, no. 02, pp. 139–142, 2016.
View at: Google Scholar
A. Tian, W. Li, Q. Zai, H. Li, and R.-W. Zhang, “3-N-Butyphthalide improves learning and memory in rats with vascular cognitive impairment by activating the SIRT1/BDNF pathway,” Molecular Medicine Reports, vol. 22, no. 1, p. 525, 2020.
View at: Google Scholar
H. Xiao, Q. Jiang, H. Qiu et al., “Gastrodin promotes hippocampal neurogenesis via PDE9-cGMP-PKG pathway in mice following cerebral ischemia,” Neurochemistry International, vol. 150, Article ID 105171, 2021.
View at: Google Scholar
M. Li and S. Qian, “Gastrodin protects neural progenitor cells against amyloid β (1-42)-induced neurotoxicity and improves hippocampal neurogenesis in amyloid β (1–42)-injected mice,” Journal of Molecular Neuroscience, vol. 601, no. 1, pp. 21–32, 2016.
View at: Publisher Site | Google Scholar
H. Xiao, M. Xj, C. Om, Q. Hm, and J. Qs, “Gastrodin improves hippocampal neurogenesis by NO-cGMP-PKG signaling pathway in cerebral ischemic mice,” Zhongguo Zhongyao Zazhi, vol. 44, no. 24, pp. 5451–5456, 2019.
View at: Google Scholar
S. Li, L. Bian, X. Fu et al., “Gastrodin pretreatment alleviates rat brain injury caused by cerebral ischemic-reperfusion,” Brain Research, vol. 1712, pp. 207–216, 2019.
View at: Publisher Site | Google Scholar
L. Ying, The Effects of Gastrodin on Microglia and Cognitive Function in Mice with the Model of Ischemic Cerebrovascular Disease, Guizhou Medical University, Guiyang, China, 2018.
J.-N. Dai, Y. Zong, L.-M. Zhong et al., “Gastrodin inhibits expression of inducible NO synthase, cyclooxygenase-2 and proinflammatory cytokines in cultured LPS-stimulated microglia via MAPK pathways,” PLoS One, vol. 6, no. 7, Article ID e21891, 2011.
View at: Publisher Site | Google Scholar
L. Xia and Y. Chen, “Effect of gastrodine on expression of IL-1β,IL-6 induced by different concentrations of glucose in gitter cells,” Pharmaceutical Biotechnology, vol. 21, no. 02, pp. 136–138, 2014.
View at: Google Scholar
Y. Lv, H. Cao, L. Chu, H. Peng, X. Shen, and H. Yang, “Effects of Gastrodin on BV2 cells under oxygen-glucose deprivation and its mechanism,” Gene, vol. 766, Article ID 145152, 2021.
View at: Publisher Site | Google Scholar
J. Guo, X. L. Zhang, Z. R. Bao et al., “Gastrodin regulates the notch signaling pathway and Sirt3 in activated microglia in cerebral hypoxic-ischemia Neonatal rats and in activated BV-2 microglia,” NeuroMolecular Medicine, vol. 23, no. 3, pp. 348–362, 2021.
View at: Google Scholar
Y. Yao, R. Li, Y. Guo et al., “Gastrodin attenuates lipopolysaccharide-induced inflammatory response and migration via the Notch-1 signaling pathway in activated microglia,” NeuroMolecular Medicine, vol. 1, pp. 1–16, 2021.
View at: Publisher Site | Google Scholar
S.-J. Liu, X.-Y. Liu, J.-H. Li et al., “Gastrodin attenuates microglia activation through renin-angiotensin system and Sirtuin3 pathway,” Neurochemistry International, vol. 120, pp. 49–63, 2018.
View at: Publisher Site | Google Scholar
X. Li, X. Tj, L. Lk, and D. Mx, “Antioxidant mechanism of gastrodin combined with isorhynchophylline in inhibiting MPP⁺-induced apoptosis of PC12 cells,” Zhongguo Zhongyao Zazhi, vol. 46, no. 2, pp. 420–425, 2021.
View at: Google Scholar
X. Zhao, Y. Zou, H. Xu et al., “Gastrodin protect primary cultured rat hippocampal neurons against amyloid-beta peptide-induced neurotoxicity via ERK1/2-Nrf2 pathway,” Brain Research, vol. 1482, pp. 13–21, 2012.
View at: Publisher Site | Google Scholar
C.-W. Qiu, Z.-Y. Liu, F.-L. Zhang et al., “Post-stroke gastrodin treatment ameliorates ischemic injury and increases neurogenesis and restores the Wnt/β-Catenin signaling in focal cerebral ischemia in mice,” Brain Research, vol. 1712, pp. 7–15, 2019.
View at: Publisher Site | Google Scholar
Y.-Y. Yao, L.-G. Bian, P. Yang et al., “Gastrodin attenuates proliferation and inflammatory responses in activated microglia through Wnt/β-catenin signaling pathway,” Brain Research, vol. 1717, pp. 190–203, 2019.
View at: Publisher Site | Google Scholar
Y. Sui, L. Bian, Q. Ai et al., “Gastrodin inhibits inflammasome through the STAT3 signal pathways in TNA2 astrocytes and reactive astrocytes in experimentally induced cerebral ischemia in rats,” NeuroMolecular Medicine, vol. 21, no. 3, pp. 275–286, 2019.
View at: Publisher Site | Google Scholar
V. Lam, R. Takechi, M. J. Hackett et al., “Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype,” PLoS Biology, vol. 19, no. 9, Article ID e3001358, 2021.
View at: Publisher Site | Google Scholar
K. Toyama, J. M. Spin, and P. S. Tsao, “Role of microRNAs on blood brain barrier dysfunction in vascular cognitive impairment,” Current Drug Delivery, vol. 14, no. 6, 2016.
View at: Google Scholar
K. Toyama, J. M. Spin, M. Mogi, and P. S. Tsao, “Therapeutic perspective on vascular cognitive impairment,” Pharmacological Research, vol. 146, 2019.
View at: Google Scholar
L. A. Cysique and B. J. Brew, “Vascular cognitive impairment and HIV-associated neurocognitive disorder: a new paradigm,” Journal of NeuroVirology, vol. 25, no. 5, pp. 710–721, 2019.
View at: Publisher Site | Google Scholar
J. Li, J. Huang, Y. He et al., “The protective effect of gastrodin against the synergistic effect of HIV-Tat protein and METH on the blood-brain barrier via glucose transporter 1 and glucose transporter 3,” Toxicology Research, vol. 10, no. 1, pp. 91–101, 2021.
View at: Publisher Site | Google Scholar
Y. Mi, M. Wang, M. Liu, H. Cheng, and S. Li, “Pharmacokinetic comparative study of GAS with different concentration of tetramethylpyrazine and ferulic acid on liver–yang hyperactivity migraine model by blood–brain microdialysis method,” Journal of Pharmacy Biomedicine Analytical, vol. 191, 2020.
View at: Publisher Site | Google Scholar
C. Sun, M. Liu, J. Liu et al., “ShenmaYizhi decoction improves the mitochondrial structure in the brain and ameliorates cognitive impairment in VCI rats via the AMPK/UCP2 signaling pathway,” Neuropsychiatric Disease and Treatment, vol. 17, pp. 1937–1951, 2021.
View at: Google Scholar
L. Luo, S. Wu, R. Chen, H. Rao, W. Peng, and W. Su, “The study of neuroprotective effects and underlying mechanism of Naoshuantong capsule on ischemia stroke mice,” Chinese Medicine, vol. 15, no. 1, p. 119, 2020.
View at: Publisher Site | Google Scholar
Y. Mi, S. Guo, H. Cheng et al., “Pharmacokinetic comparative study of tetramethylpyrazine and ferulic acid and their compatibility with different concentration of gastrodin and gastrodigenin on blood-stasis migraine model by blood-brain microdialysis method,” Journal of Pharmacy Biomedicine Analytical, vol. 177, 2020.
View at: Google Scholar
Z. Cai, S. Hou, Y. Li et al., “Effect of borneol on the distribution of gastrodin to the brain in mice via oral administration,” Journal of Drug Targeting, vol. 16, no. 2, pp. 178–184, 2008.
View at: Google Scholar
Q. Li, L. Li, M. Yu et al., “Elastomeric polyurethane porous film functionalized with gastrodin for peripheral nerve regeneration,” Journal of Biomedical Materials Research Part A, vol. 108, no. 8, pp. 1713–1725, 2020.
View at: Publisher Site | Google Scholar
Y. Chunlei, L. Qiang, N. Yingcai, and D. Miaoxian, “The combination of gastrodin and isorhynchophylline exhibits a synergistic ROS-scav-enging action in MPP⁺- challenged PC12 cells,” Lishizhen Medicine and Materia Medica Research, vol. 32, no. 5, pp. 1046–1050, 2021.
View at: Google Scholar
T. Yuanxu, L. Yan, L. Chen, W. Yali, and W. Xinghe, “Effect of oxiracetam combined with gastrodin on acute cerebral hemorrhage and its influence on by-metabolites levels,” Chinese Medicine, vol. 16, no. 3, pp. 373–376, 2021.
View at: Google Scholar
L. Lixia, C. Qingxian, L. Yingyuan, and X. Qiong, “Effect of Gastrodin Injections combined with calf serum deproteinization in the treatment of cerebral infarction patients and the effect on serum pentraxins 3 and brain-derived neurotrophic factor levels,” Northwest Pharmaceutical Journal, vol. 35, no. 5, pp. 747–761, 2020.
View at: Google Scholar
L. Hongwei, “Influence of Gastrodin injection combined with hyperbaric oxygen on cognitive impairment,cerebral hemodynamics in patients with vascular dementia,” Journal of Clinical Psychosomatic Diseases, vol. 23, no. 6, pp. 105–109, 2017.
View at: Google Scholar
F. Wu, H. Li, J. Zhao et al., “Effect of electroacupuncture intervention combined with gastrodin administration on neurological function, Nogo-A and NgR expression in the frontal lobe cortex of focal cerebral ischemia rats,” Acupuncture Research, vol. 41, no. 1, pp. 65–69, 2016.
View at: Google Scholar
X. He and X. Wang, “Clinical efficacy of gastrodin and donepezil on vascular dementia,” Practical Geriatrics, vol. 28, no. 07, pp. 580–582, 2014.
View at: Google Scholar
Y. Kung, M. Y. Hsiao, S. M. Yang et al., “A single low-energy shockwave pulse opens blood-cerebrospinal fluid barriers and facilitates gastrodin delivery to alleviate epilepsy,” Ultrasonics Sonochemistry, vol. 78, 2021.
View at: Publisher Site | Google Scholar
K. Luo, Y. Wang, W.-S. Chen et al., “Treatment combining focused ultrasound with gastrodin alleviates memory deficit and neuropathology in an Alzheimer’s disease-like experimental mouse model,” Neural Plasticity, vol. 2022, Article ID 5241449, 13 pages, 2022.
View at: Publisher Site | Google Scholar
J. Wang, L. Xie, Y. Shi, L. Ao, F. Cai, and F. Yan, “Early detection and reversal of cell apoptosis induced by focused ultrasound-mediated blood-brain barrier opening,” ACS Nano, vol. 15, 2021.
View at: Google Scholar

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