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Objective　 To investigate the effects of different dosages of gastrodin onTLR4/ MyD88 / NFκB signal pathway in the hippocampus of methamphetamine (meth)dependence rats. Methods　The conditioned place preference (CPP) model of meth was established, meth (10mg/kg) was administered (i.p, 14 d), and then, different dosages (10, 30, 100 mg/kg) of gastrodin were used to intervene in 14 days. Western blotting and RTqPCR were used to explore the expression level of protein and mRNA of key factors in TLR4/ MyD88 / NF-κB signal pathway in hippocampus. Results　Gastrodin decreased the protein and mRNA expression of TLR4, MyD88, TRAF6, NF-κBp65 in a dose-dependent manner (P < 0.001, P < 0.01 or P < 0.05), and the protein expression of p-NF-κB p65 was reduced with showing a significant dose-response relationship ( P < 0.01 or P < 0.05) . Gastrodin increased the protein and mRNA expression of IκB-α with showing a significant dose-response relationship ( P < 0.01 or P < 0.05) . Gastrodin reduced the protein expression of p-IκB-α ( P < 0.01) . Conclusion　Gastrodin intervention has a protective effect against hippocampal neuroinflammation in methamphetamine-dependent CPP rats, and is closely related to the function of TLR4/MyD88/NF-κB signal pathway. [ABSTRACT FROM AUTHOR]

Background: Gastrodin has been widely used clinically in China as an antihypertensive drug. However, its effect on hypertensive renal injury is yet to be elucidated. The current study aimed to investigate the effects of gastrodin on hypertensive renal injury and its underlying mechanisms by network pharmacology analysis and validation in vivo and in vitro. Methods: A total of 10 spontaneously hypertensive rats (SHRs) were randomly categorized into the following two groups: SHR and SHR + Gastrodin groups. Wistar Kyoto (WKY) rats were used as the control group (n = 5). The SHR + Gastrodin group was intragastrically administered gastrodin (3.5 mg/kg/day), and the rats in both WKY and SHR groups were intragastrically administered an equal amount of double-distilled water for 10 weeks. Hematoxylin-eosin, Masson’s trichrome, and Sirius red staining were used to detect the pathological changes and collagen content in the renal tissues. Network pharmacology analysis was performed to explore its potential targets and related pathways. In vitro, the CCK-8 assay was used to determine the cell viability. Immunohistochemistry and western-blotting analyses were employed to assess the protein expression associated with renal fibrosis and transforming growth factor-β1 (TGF-β1) pathway-related proteins in the renal tissues or in TGF-β1-stimulated rat kidney fibroblast cell lines (NRK-49F).Results: Gastrodin treatment attenuates renal injury and pathological alterations in SHRs, including glomerular sclerosis and atrophy, epithelial cell atrophy, and tubular dilation. Gastrodin also reduced the accumulation of collagen in the renal tissues of SHRs, which were confirmed by downregulation of α-SMA, collagen I, collagen III protein expression. Network pharmacology analysis identified TGFB1 and SMAD2 as two of lead candidate targets of gastrodin on against hypertensive renal injury. Consistently, gastrodin treatment downregulated the increase of the protein expression of TGF-β1, and ratios of both p-Smad2/Smad2 and p-Samd3/Smad3 in renal tissues of SHRs. In vitro, gastrodin (25–100 μM) treatment significantly reversed the upregulation of α-SMA, fibronectin, collagen I, as well as p-Smad2 and p-Smad3 protein expressions without affecting the cell viability of TGF-β1 stimulated NRK-49F cells. Conclusion: Gastrodin treatment significantly attenuates hypertensive renal injury and renal fibrosis and suppresses TGF-β1/Smad2/3 signaling in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Gastrodia elata exhibits extensive pharmacological activity; its extract gastrodin (GAS) has been used clinically to treat cardiovascular diseases. In the present study, we examined the effect of GAS in a mice model of pathological cardiac hypertrophy, which was induced using transverse aortic constriction (TAC). Male C57BL/6 J mice underwent either TAC or sham surgery. GAS was administered post-surgically for 6 weeks and significantly improved the deterioration of cardiac contractile function caused by pressure overload, cardiac hypertrophy, and fibrosis in mice. Treatment with GAS for 6 weeks upregulated myosin heavy chain α and down-regulated myosin heavy chain β and atrial natriuretic peptide, while insulin increased the effects of GAS against cardiac hypertrophy. In vitro studies showed that GAS could also protect phenylephrine-induced cardiomyocyte hypertrophy, and these effects were attenuated by BAY-876, and increased by insulin. Taken together, our results suggest that the anti-hypertrophic effect of gastrodin depends on its entry into cardiomyocytes through GLUT4.

Gastrodin is one of the most important biologically active components of Gastrodia elata, which has many health benefits as a dietary and health food supplement. However, gastrodin measurement traditionally relies on laboratory and sophisticated instruments. This research was aimed at developing a rapid and non-destructive method based on Fourier transform near infrared (FT-NIR) to predict gastrodin content in fresh Gastrodia elata. Auto-ordered predictors selection (autoOPS) and successive projections algorithm (SPA) were applied to select the most informative variables related to gastrodin content. Based on that, partial least squares regression (PLSR) and multiple linear regression (MLR) models were compared. The autoOPS-SPA-MLR model showed the best prediction performances, with the determination coefficient of prediction (Rp2), ratio performance deviation (RPD) and range error ratio (RER) values of 0.9712, 5.83 and 27.65, respectively. Consequently, these results indicated that FT-NIRS technique combined with chemometrics could be an efficient tool to rapidly quantify gastrodin in Gastrodia elata and thus facilitate quality control of Gastrodia elata.

Gastrodin, the primary bioactive compound found in Gastrodia elata, has been shown to exhibit neuroprotective properties in a range of neurological disorders. However, the precise mechanisms through which gastrodin influences glioma cells remain unclear, and there is a scarcity of data regarding its specific effects. To ascertain the viability of glioma cell lines LN229, U251, and T98, the CCK-8 assay, a colony formation assay, and a 3D culture model were employed, utilizing varying concentrations of gastrodin (0, 5, 10, and 20 μM). Gastrodin exhibited a notable inhibitory effect on the growth of glioma cells, as evidenced by its ability to suppress colony formation and spheroid formation. Additionally, gastrodin induced ferroptosis in glioma cells, as it can increase the levels of reactive oxygen species (ROS) and peroxidized lipids, and reduced the levels of glutathione. Using a subcutaneous tumor model, gastrodin was found to significantly inhibit the growth of the T98 glioma cell line in vivo. Using high-throughput sequencing, PPI analysis, and RT-qPCR, we successfully identified Homeobox D10 (HOXD10) as the principal target of gastrodin. Gastrodin administration significantly enhanced the expression of HOXD10 in glioma cells. Furthermore, treatment with gastrodin facilitated the transcription of ACSL4 via HOXD10. Notably, the inhibition of HOXD10 expression impeded ferroptosis in the cells, which was subsequently restored upon rescue with gastrodin treatment. Overall, our findings suggest that gastrodin acts as an anti-cancer agent by inducing ferroptosis and inhibiting cell proliferation in HOXD10/ACSL4-dependent pathways. As a prospective treatment for gliomas, gastrodin will hopefully be effective.

Gatrodin is an active compound with cardio-protective potentials. In the current study, the mechanism underlying the effects of gastrodin was explored. Myocardial infarction was induced and handled with gastrodin. The role of miR-30a-5p and its downstream effector, ATG5, in the cardio-protective effects of gastrodin was verified. Gastrodin induced the dys-expresseion of 72 miRs in oxygen/glucose deprivation (OGD) cardiomyocytes and miR-30a-5p was selected as the potential therapeutic target. Gastrodin increased viability and suppressed autophagy in OGD cardiomyocytes, which was associated with the induction of miR-30a-5p and deactivation of ATG5. In rat models, gastrodin attenuated structure deterioration and dysfunction in heart, and suppressed autophagy. At molecular level, miR-30a-5p was induced and ATG5 were down-regulated. After the suppression of miR-30a-5p or the overexpression of ATG5, the cardio-protective effects of gastrodin were compromised. Gastrodin induced the expression of miR-30a-5p, which contributed to the attenuation of autophagy in infarcted heart tissues.

BackgroundProphylactic medication in clinical detoxification programs for the treatment of medication overuse headache is still debated. Gastrodin, a main bioactive constituent of Rhizoma Gastrodiae, has been applied clinically to treat primary headache for more than 30 years in China due to its potential analgesic and anti-migraine mechanisms. However, clinical evidence supporting its routing use in MOH is insufficient. The present study aims to investigate the efficacy and tolerability of oral gastrodin in medication overuse headache.MethodsA multicenter, randomized, double-blind, parallel, placebo-controlled trial will be performed. A target sample size of 186 patients who fulfill the International Classification of Headache Disorders 3rd version (ICHD-3) criteria for MOH will be recruited and screened during a baseline screening period of 28 days before being randomly assigned to either the gastrodin or placebo group at a ratio of 1:1. Enrolled patients will be assessed for each 4 weeks during the 12-weeks double-blind phase and followed up at week 24. The primary endpoint is mean change in monthly headache day frequency. Secondary endpoints will be the proportion of remitted MOH, change in headache pain intensity, headache impact test (HIT-6) score, 50% responder rate, treatment failure, monthly acute medication intake days, and Short Form 36-Item Health Survey (SF-36) score. Tolerability will be assessed by drop-out rates though safety monitoring during treatment.DiscussionThe findings of the present study may help to provide new evidence on gastrodin as a prophylaxis treatment with both efficacy and high tolerability for the treatment of MOH.Clinical trail registrationChinese Clinical Trail Registry (ChiCTR2200063719), Protocol Version 1.1, May, 09, 2022.

Background: Neuroinflammation plays a pivotal role in the pathogenesis of Central Nervous System (CNS) diseases. The phenolic glucoside gastrodin (GAS), has been known to treat CNS disorders by exerting anti-inflammatory activities. Our aim was to investigate the potential neuroprotective mechanisms of GAS on lipopolysaccharide (LPS)-induced mice. Methods: Male C57BL/6J mice were treated by LPS, before which GAS was adminisrated. The behavior tests such as forced swim test, tail suspension test, and elevated plus maze were performed to evaluate depressive-anxiety-like behaviors. A high-throughput sequencing (HTS) analysis was performed to screen out distinctive miRNAs which were validated using quantitative real-time PCR. Then, miRNA agomir or NC was injected stereotaxically into hippocampus of mice to explore the role of miRNA on GAS in response to LPS. Furthermore, Immunofluorescence and the hematoxylin and eosin (H&E) staining were employed to observe the cellular morphology. The protein levels of pro-inflammatory factors were evaluated by western blot. Finally, the target mRNA of miRNA was predicted using bioinformatics analysis. GO and KEGG enrichment analyses were conducted to clarify the potential function of target protein, which were visualized by bubble charts. Results: The behavioral data showed that mice in the LPS group had obvious depressive-anxiety-like behaviors, and 100 mg/kg GAS could improve these behavioral changes and alleviate the levels of pro-inflammatory cytokines in the hippocampus when mice were exposed to LPS for 6 h. Meanwhile, LPS-induced microglia and astrocyte activation in the CA1, CA2, CA3, and DG regions of the hippocampus were also reversed by GAS. Furthermore, miR-107-3p were screened out and verified for GAS in response to LPS. Importantly, miR-107-3p overexpression negatively abrogated the neuroprotective effects of GAS. Moreover, KPNA1 might be the target molecular of miR-107-3p. KPNA1 might regulate 12 neuroinflammation-related genes, which were mainly involved in cytokine−mediated signaling pathway. Conclusion: These results suggested that GAS might alleviate the LPS-induced neuroinflammation and depressive-anxiety-like behaviors in mice by downregulating miR-107-3p and upregulating the downstream target KPNA1. The indicates miR-107-3p may provide a new strategy for the treatment of CNS diseases. [ABSTRACT FROM AUTHOR]

Neuroinflammation is the main pathological mechanism of cognitive dysfunction caused by neurodegenerative diseases, and effective preventive and therapeutic measures are not available. We predicted the key targets of gastrodin’s effects upon neuroinflammation through Network Pharmacology and molecular docking. Then the predicted targets were used to study how gastrodin affected cognitive dysfunction triggered by lipopolysaccharide-induced neuroinflammation in rats and its mechanisms. Three-month-old male rats were intraperitoneally injected with lipopolysaccharide for 3 days (d), 7 d and 14 d respectively. Gastrodin improved learning and memory ability of rats with neuroinflammation. Lipopolysaccharide enhanced the levels of pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, in rat hippocampus, which could be reversed by gastrodin. Gastrodin also inhibited the activation of microglia. Our findings suggested that gastrodin exerted neuroprotective effects in rats with neuroinflammation by impacting the TLR4-NF-kB-NLRP3 pathway. Therefore, gastrodin may be a potential therapeutic agent for neuroinflammation-induced cognitive dysfunction. [ABSTRACT FROM AUTHOR]

Gastrodin, the main active ingredient of Gastrodia elata Blume, has been shown to protect against many inflammatory diseases. Our study aimed to investigate the anti-inflammatory role of gastrodin in concanavalin A (ConA)-induced acute hepatitis in mice and to explore its precise mechanism. C57BL/6 mice were administered with gastrodin (50 or 100mg/kg) for 3 days prior to intravenous injection of ConA to induce acute autoimmune hepatitis (AIH). Serum aminotransferases levels and cytokine levels were measured. Liver tissue histology was conducted to assess the degree of liver injury. Splenocytes pretreated with gastrodin were stimulated with ConA to observe splenocyte proliferation. Gastrodin greatly reduced the level of serum aminotransferases, inflammatory cytokine such as IL-6 and TNF-α and histopathological damage in ConA-induced hepatitis. Besides, gastrodin had an inhibitory effect on liver apoptosis, and autophagy. Furthermore, gastrodin inhibited the proliferation of splenocytes in vitro. The protein expression of p-JAK2 and p-STAT3 was markedly affected by gastrodin pretreatment. The present study indicated that gastrodin pretreatment exerted protective effects against ConA-induced acute hepatitis, partly through the inhibition of the IL6/JAK2/STAT3 pathway. Further studies are recommended to determine the potential therapeutic role of gastrodin in acute AIH. [ABSTRACT FROM AUTHOR]

Gastrodiae rhizoma (GR) formula granules and preparations have been used as a popular traditional Chinese medicine for clinical treatment since they have good pharmacological activity to treat nervous system diseases. Gastrodin and parishins have been the main active components in aqueous extracts for GR formula granules, but their pharmacological activities and metabolism are different. For quality control of the extracts, the extraction conditions should be investigated to accurately control the contents of two kinds of components. In this paper, the transfer rate of six index components (including gastrodin, p-hydroxybenzyl alcohol, parishin A, parishin B, parishin C, and parishin E) obtained by HPLC were used as indicators to investigate the effect of pH on the GR extraction process. The results demonstrated that pH is a key factor for preventing transforming parishins into gastrodin and maintaining high content of parishins in the extracts. It can be concluded that the weak acid environment could improve the transfer rate of parishins, thus ensuring the gastrodin and parishins consistency between GR raw materials and its aqueous extracts. Therefore, pH is an essential condition for accurate quality control of the extracts. [ABSTRACT FROM AUTHOR]

Pholidota chinensis Lindl. is an epiphytic or lithophytic perennial herb of Orchidaceae family used as a garden flower or medicinal plant to treat high blood pressure, dizziness and headache in traditional Chinese medicine. Gastrodin (GAS) is considered as a main bioactive ingredient of this herb but the biosynthetic pathway remains unclear in P. chinensis. To elucidate the GAS biosynthesis and identify the related genes in P. chinensis, a comprehensive analysis of transcriptome and metabolome of roots, rhizomes, pseudobulbs and leaves were performed by using PacBio SMART, Illumina Hiseq and Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/ MS). A total of 1,156 metabolites were identified by UPLC-MS/MS, of which 345 differential metabolites were mainly enriched in phenylpropanoid/ phenylalanine, flavone and flavonol biosynthesis. The pseudobulbs make up nearly half of the fresh weight of the whole plant, and the GAS content in the pseudobulbs was also the highest in four tissues. Up to 23,105 Unigenes were obtained and 22,029 transcripts were annotated in the transcriptome analysis. Compared to roots, 7,787, 8,376 and 9,146 differentially expressed genes (DEGs) were identified in rhizomes, pseudobulbs and leaves, respectively. And in total, 80 Unigenes encoding eight key enzymes for GAS biosynthesis, were identified. Particularly, glycosyltransferase, the key enzyme of the last step in the GAS biosynthetic pathway had 39 Unigenes candidates, of which, transcript28360/f2p0/1592, was putatively identified as the most likely candidate based on analysis of co-expression, phylogenetic analysis, and homologous searching. The metabolomics and transcriptomics of pseudobulbs versus roots showed that 8,376 DEGs and 345 DEMs had a substantial association based on the Pearson's correlation. This study notably enriched the metabolomic and transcriptomic data of P. chinensis, and it provides valuable information for GAS biosynthesis in the plant. [ABSTRACT FROM AUTHOR]

Gastrodia elata Bl. has a long edible history and is considered an important functional food raw material. Gastrodin (GAS) is one of the main functional substances in G. elata BI. and can be used as a health care product for the elderly to enhance resistance and delay aging. This study investigated the ameliorative effect and mechanism of GAS on cognitive dysfunction in vascular dementia (VaD) rats, which provides a theoretical basis for development and utilization of functional food. The water maze test shows that GAS improves learning and memory impairment in VaD rats. Meanwhile; GAS significantly decreased the levels of Fe2+ and malondialdehyde (MDA); increased the content of glutathione (GSH); and significantly up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPx4), the key regulatory factors of ferroptosis; while it down-regulated the expression of kelch-like ECH-associated protein (Keap1) and cyclooxygenase 2 (COX2). However, GAS does not directly regulate GPx4 and COX2 to inhibit ferroptosis. Furthermore, compared with GAS alone, GAS combined with Bardoxolone (an agonist of Nrf2) did not further affect the increase in GPx4 levels and decrease in COX2 levels, nor did it further affect the regulation of GAS on the biochemical parameters of ferroptosis in HT22 hypoxia injury. These findings revealed that GAS inhibited ferroptosis in hippocampal neurons by activating the Nrf2/Keap1-GPx4 signaling pathway, suggesting its possible application as a functional food for improving vascular dementia by inhibiting ferroptosis. [ABSTRACT FROM AUTHOR]

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Abstract Background Gastrodin (GAS), is a kind of phenolic compound extracted from the traditional Chinese herbal medicine Gastrodia elata Blume (GEB). This study was aimed at probing into the protective effect of GAS on peripheral nerve injury (PNI) and the underlying mechanism. Methods A rat model with PNI was established, followed by intraperitoneal injection of GAS (20 mg/kg/day). Sciatic nerve function index (SFI) was used to analyze the function of sciatic nerve. The amplitude and latency of compound muscle action potential (CMAP) were examined by electrophysiology. Schwann cells (SCs) were isolated from fetal rats and treated with GAS 200 μg/mL, and H2O2-induced model of oxidative stress injury was established. EdU and Transwell assays were adopted to detect the viability and migration of SCs. Dual-luciferase reporter gene assays were applied to verify the binding site between miR-497 and brain-derived neurotrophic factor (BDNF) 3’UTR. MiR-497 expression was probed by quantitative real-time polymerase chain reaction (qRT-PCR). BDNF, neurofilament-200 (NF-200) and myelin basic protein (MBP) expression levels were detected by Western blotting. Malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, glutathione content (GSH) and catalase (CAT) activity in SCs were also measured. Results GAS treatment could significantly increase the SFI and amplitude of CMAP, shorten the refractory period, and ameliorate muscle atrophy of the rats with PNI. GAS treatment could markedly restrain miR-497 expression and increase the expression levels of BDNF, NF-200 and MBP in SCs. BDNF was confirmed as the target of miR-497 and BDNF overexpression could reverse the impacts of miR-497 overexpression on the proliferation, migration, and oxidative stress response of SCs. Conclusions GAS promotes the recovery of PNI via modulating miR-497 / BDNF axis and inhibiting oxidative stress. Graphical abstract

Cardiovascular diseases cause significant morbidity and mortality worldwide, incurring a major public health burden. Gastrodia elata Blume is a traditional Chinese herbal medicine that has been widely used to treat central nervous system and cardiovascular diseases. Gastrodin, as the major active component in Gastrodia elata Blume, can confer protection against cardiovascular diseases. In this review, we summarize the anti-inflammatory actions, anti-cardiac hypertrophy, anti-hypertension, anti-atherosclerosis, and angiogenic effects of gastrodin, as well as its protective effects on vascular cells and against myocardial ischemia-reperfusion injury. The medical potential of gastrodin in diabetes-related cardiovascular diseases is also discussed.

[Display omitted] • The self-pumping dressing is prepared by integrated electrospinning technology. • Self-pumping properties synergize with anti-inflammatory properties of gastrodin. • Self-pumping dressing reduces inflammation and promotes neovascularization. • Self-pumping dressing improves macrophage immunomodulatory imbalance. • Self-pumping dressing loading with gastrodin accelerates diabetic wound healing. The diabetic wound is often associated with excessive inflammatory exudate, scant neovascularization, and imbalanced macrophage immunomodulation. However, the inflammatory exudate is absorbed by gauze to come into contact with the diabetic wound, which hinders the separation of the inflammatory exudate from the wound without creating effective separation protection. Hence, an electrospun multifunctional self-pumping dressing loading with gastrodin is designed to attenuate inflammation, improve immunomodulation, and promote neovascularization. The absorbent layer and drainage layer of the self-pumping dressing are integrated using electrospinning. The inflammatory exudate in the diabetic wound is unidirectionally drained from the drainage layer to the absorbent layer via the self-pumping structure. In addition, the synergistic effect of the immunomodulatory and anti-inflammatory properties of gastrodin and the self-pumping properties of the self-pumping dressing further promote the rapid healing of diabetic wounds. The diabetic wound healing experiment confirms that the self-pumping dressing loading with gastrodin exhibits the ability to rapidly promote diabetic wound healing within 15 days. The self-pumping dressing with gastrodin can regulate inflammatory exudate in diabetic wounds and promote extremely rapid healing of diabetic wounds, which expands the novel application of gastrodin and self-pumping dressing in the field of biomedical materials. [ABSTRACT FROM AUTHOR]

• GTD opposed dopaminergic neurotoxicity of MPTP/MPP+ in vivo and in vitro. • GTD rescued the dysregulation of dopamine homeostasis in PD models. • GTD restored dopamine homeostasis by upregulating VMAT2. • GTD increased VMAT2 by activating MEK/ERK/CREB pathway. Dysfunction of dopamine homeostasis (DAH), which is regulated by vesicular monoamine transporter 2 (VMAT2), is a vital cause of dopamine (DA) neurotoxicity and motor deficits in Parkinson's disease (PD). Gastrodin (4-hydroxybenzyl alcohol 4-O-β-D-glucoside; GTD), a natural active compound derived from Gastrodia elata Blume, can be used to treat multiple neurological disorders, including PD. However, whether GTD regulates VMAT2-mediated DAH dysfunction in PD models remains unclear. To explore whether GTD confers dopaminergic neuroprotection by facilitating DA vesicle storage and maintaining DAH in PD models. Mice were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and PC12 cells with 1-methyl-4-phenyl-pyridinium (MPP+) to induce PD characteristics. Multiple behavioural tests were performed to evaluate the motor functions of the mice. HPLC was used to measure DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. Transmission electron microscopy was used to observe synaptic vesicles. Molecular docking and molecular dynamics were used to determine the binding affinity of GTD to the target protein. Reserpine (Res, a VMAT2 inhibitor) and PD0325901 (901, a MEK inhibitor) were employed to investigate the mechanism of GTD. Western blotting and immunohistochemistry were used to assess the expression of the target proteins. GTD attenuated motor deficits and dopaminergic neuronal injury, reversed the imbalance of DAH, and increased VMAT2 levels and vesicle volume in MPTP-induced mice. GTD ameliorated cell damage, ROS release, and dysfunction of DAH in MPP+-induced PC12 cells. Moreover, the neuroprotective effects of GTD were reversed by Res in vitro and in vivo. Furthermore, GTD can activate the MEK/ERK/CREB pathway to upregulate VMAT2 in vitro and in vivo. Interestingly, 901 reversed the effects of GTD on VMAT2 and dopaminergic neuronal impairment. GTD relieved PD-related motor deficits and dopaminergic neuronal impairment by facilitating MEK-depended VMAT2 to regulate DAH, which offers new insights into its therapeutic potential. [Display omitted] [ABSTRACT FROM AUTHOR]

Traditionally, gastrodin extracted from Rhizoma Gastrodiae has been used to treat various neurological diseases. The objective of this systematic review with meta-analysis is to evaluate the potential benefits of gastrodin as an adjuvant therapy for the treatment of acute stroke. Relevant literature from multiple medical databases was searched until October 12, 2023, to identify randomised controlled trials investigating the use of gastrodin as an adjuvant therapy for acute stroke treatment. The total response rate and marked improvement rate were defined as >18% and >45% improvement in National Institutes of Health Stroke Scale score, respectively. A total of 12 randomised controlled trials, including 1 174 stroke patients, were identified. Compared to conventional treatment alone, the combination of gastrodin and conventional treatment significantly improved the total response rate (risk ratio 1.24; 95% CI 1.15–1.34) and marked improvement rate (risk ratio 1.37; 95% CI 1.18–1.59). Adjuvant treatment with gastrodin also resulted in a reduction in the National Institutes of Health Stroke Scale score (weighted mean difference [ WMD ] −3.08 points; 95% CI −3.75 to −2.41), haematoma volume (WMD −3.57 cm3; 95% CI −4.26 to −2.87), and blood neuron-specific enolase level (WMD −3.81 μg/l; 95% CI −6.21 to −1.41), as well as an increase in blood brain-derived neurotrophic factor level (WMD 0.81 ng/ml; 95% CI 0.50–1.12). Gastrodin, when used as an adjuvant therapy, may yield additional beneficial effects in patients with acute stroke. However, future high-quality trials are necessary to further support this evidence. • Adjuvant treatment with gastrodin improved 24% total response rate. • Adjuvant treatment with gastrodin improved 37% marked improvement rate. • Addition of gastrodin to the usual treatment led to a decrease of 3.08 points in National Institutes of Health Stroke Scale. • Gastrodin as adjuvant therapy can increase neuroprotective effect in acute stroke patients. • The benefits of gastrodin may be linked to its anti-inflammatory and antioxidant effects. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is characterized by abnormal β-amyloid and tau accumulation, mitochondrial dysfunction, oxidative stress, and synaptic dysfunction. Here, we aimed to assess the mechanisms and signalling pathways in the neuroprotective effect of gastrodin, a phenolic glycoside, on murine neuroblastoma N2a cells expressing human Swedish mutant APP (N2a/APP). We found that gastrodin increased the levels of presynaptic-SNAP, synaptophysin, and postsynaptic-PSD95 and reduced phospho-tau Ser396, APP and Aβ 1-42 levels in N2a/APP cells. Gastrodin treatment reduced reactive oxygen species generation, lipid peroxidation, mitochondrial fragmentation and DNA oxidation; restored mitochondrial membrane potential and intracellular ATP production. Upregulated phospho-GSK-3β and reduced phospho-ERK and phospho-JNK were involved in the protective effect of gastrodin. In conclusion, we demonstrated the neuroprotective effect of gastrodin in the N2a/APP cell line by ameliorating the impairment on synaptic and mitochondrial function, reducing tau phosphorylation, Aβ 1-42 levels as well as reactive oxygen species generation. These results provide new mechanistic insights into the potential effect of gastrodin in the treatment of Alzheimer's disease. [Display omitted] • Gastrodin is neuroprotective in the N2a/APP cell model of Alzheimer's disease. • Effects of gastrodin involve the ERK1/2, GSK-3β and JNK signalling pathways. • Gastrodin ameliorates synaptic, mitochrondrial, ROS damages, modulates APP processing, and tau phosphorylation in N2a/APP cell. [ABSTRACT FROM AUTHOR]

Myocardial ischemia/reperfusion (I/R) injury after percutaneous coronary intervention (PCI) is common in acute myocardial infarction. Aspirin is commonly prescribed as anti-thrombotic therapy with coronary heart disease (CHD). However, long-term use of aspirin causes severe gastric mucosal damage. Gastrodin is a Chinese natural medicine with antiinflammatory and anti-oxidative properties. In this study, we investigated the effects of combined therapy with aspirin and gastrodin on the myocardial and gastric mucosal injury in response to myocardial I/R injury and underlying mechanisms using the Sprague-Dawley (SD) rat model. Our results demonstrated that myocardial I/R caused significant cardiac dysfunction and gastric mucosal damage. Administration of aspirin led to significantly reduce myocardial infarction size and myocardial enzyme release, as well as significantly improved cardiac function through exerting anti-inflammatory effects. However, aspirin exacerbated gastric mucosal damage by increasing the levels of inflammatory mediators and endothelin (ET) while reducing prostaglandin E2 (PGE2) levels. The combined treatment with aspirin and gastrodin not only significantly protected gastric mucosa by normalizing the expression levels of the inflammatory factors, ET and PGE2, but also significantly reduced myocardial infarction size and improved cardiac function by inhibiting inflammation in response to I/R. The combination therapy also dramatically down-regulated the levels of pyroptosis-related proteins in the myocardium and gastric mucosa. The combination therapy showed obviously reduced level of thromboxane B2 (TXB2), which was simultaneously accompanied with increased levels of the tissue plasminogen activator (t-PA). This suggested that gastrodin did not inhibit the anti-thrombotic function of aspirin. Accordingly, aspirin in combination with gasrtodin protected the structural and functional integrity of the heart and stomach by suppressing pyroptosis and inflammation. Therefore, combination of aspirin and gastrodin is a promising treatment for cardiac dysfunction and gastric mucosa injury after myocardial I/R. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the effects of gastrodin combined with anisomine hydrobromate on neurological function in the elderly with cerebral small vessel disease (CSVD) and cognitive dysfunction. METHODS: A total of 104 elderly patients with CSVD and cognitive dysfunction admitted into the Eighth People’s Hospital of Hebei from Aug. 2019 to Dec. 2020 were prospectively extracted to be divided into the control group and the study group according to different administration methods, with 52 cases in each group. Both groups were given routine treatment, the control group was given oral Anisodine hydrobromide tablets on the basis of routine treatment, while the study group received intramuscular injection of gastrodin on the basis of the control group. Both groups were treated for 1 month. Expression levels of neurofunctional indicators and inflammatory factors were detected before and after treatment in two groups, and the mini-mental state examination (MMSE) and montreal cognitive assessment (MoCA) were evaluated. The total effective rate and incidence of adverse drug reactions in two groups were statistically analyzed. RESULTS: The expression of brain-derived neurotrophic factor (BDNF), MMSE and MoCA scores in both groups after treatment were significantly higher than those before treatment; expression levels of neuron-specific enolase (NSE), central nervous system-specific protein (S100β), interleukin-6 (IL)-6 and homocysteine (Hcy) were significantly lower than those before treatment, and the differences were statistically significant (P<0. 05). The expression of BDNF, MMSE and MoCA scores in the study group were significantly higher than those in the control group after treatment; expression levels of NSE, S100β, IL-6 and Hcy were significantly lower than those in the control group, and the differences were statistically significant (P <0. 05). The total effective rate of the study group was 94. 23% (49/52), significantly higher than 67. 31% (35/52) of the control group, the difference was statistically significant (P < 0. 05). The incidence of adverse drug reactions in the study group and the control group were respectively 13. 46% (7/52) and 9. 62% (5/52), with no statistically significant difference (P >0. 05). CONCLUSIONS: Gastrodin combined with anisouline hydrobromate in the treatment of the elderly with CSVD and cognitive dysfunction can effectively improve the neurological function and cognitive function of patients, and the clinical effect is significant. [ABSTRACT FROM AUTHOR]

Gastrodin is a major active phenolic glycoside extract from Gastrodia elata, an important herb used in traditional medicine. Previous research has reported that gastrodin possesses anti-inflammatory and anti-oxidant properties. Therefore, we aimed to investigate its hepatoprotective effects and mechanisms on acetaminophen (APAP)-induced liver injury in a mouse model. Mice included in this study were intraperitoneally administered with a hepatotoxic APAP dose (300 mg/kg). At 30 min after APAP administration, gastrodin was intraperitoneally injected at concentrations of 0, 15, 30, and 45 mg/kg. Then, all mice were sacrificed at 16 h after APAP injection for further analysis. The results showed that gastrodin treatment ameliorated acute liver injury caused by APAP, as indicated by serum alanine aminotransferase level, hepatic myeloperoxidase activity, and cytokine (TNF-α, IL-1β, and IL-6) production. It also significantly decreased hepatic malondialdehyde activity but increased superoxide dismutase activity. In addition, gastrodin decreased ERK/JNK MAPK expression but promoted Nrf2 expression. These results demonstrated that gastrodin may be a potential therapeutic target for the prevention of APAP-induced hepatotoxicity via amelioration of the inflammatory response and oxidative stress, inhibition of ERK/JNK MAPK signaling pathways, and activation of Nrf2 expression levels. [ABSTRACT FROM AUTHOR]

Achilles tendinopathy (AT) is an injury caused by overuse of the Achilles tendon or sudden force on the Achilles tendon, with a considerable inflammatory infiltrate. As Achilles tendinopathy progresses, inflammation and inflammatory factors affect the remodeling of the extracellular matrix (ECM) of the tendon. Gastrodin(Gas), the main active ingredient of Astrodia has anti-inflammatory, antioxidant, and anti-apoptotic properties. The small intestinal submucosa (SIS) is a naturally decellularized extracellular matrix(dECM)material and has a high content of growth factors as well as good biocompatibility. However, the reparative effects of SIS and Gas on Achilles tendinopathy and their underlying mechanisms remain unknown. Here, it is found that SIS hydrogel loaded with gastrodin restored the mechanical strength of the Achilles tendon, facilitated ECM remodeling, and restored ordered collagen arrangement by promoting the translocation of protein synthesis. It also decreases the expression of inflammatory factors and reduces the infiltration of inflammatory cells by inhibiting the NF-κB signaling pathway. It is believed that through further research, Gas + SIS may be used in the future for the treatment of Achilles tendinopathy and other Achilles tendon injury disorders., (© 2024 Wiley‐VCH GmbH.)

The pathway of Janus-activated kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) (termed as JAK2/STAT3) plays an active role in stroke-related inflammation induced by ischemic stress. Gastrodin, the primary compound in Gastrodia elata Bl, has been identified for its notable neuroprotective effects and demonstrated to ameliorate cerebral ischemia-reperfusion but its exact mechanisms governing this defense are still unclear. This study aims to investigate whether gastrodin can regulate mitochondrial function via the JAK2/STAT3 pathway to limit cerebral ischemia-reperfusion. In vivo, gastrodin significantly reduced infarct volume, improved neurobiological function, attenuated neuronal apoptosis, oxidative stress, mitochondrial impairment, mtDNA leakage, and inflammatory responses. At the cellular level, gastrodin administration rescued OGD/R-induced cell apoptosis, oxidative stress, and mitochondrial dysfunction. Mechanistically, gastrodin notably suppressed Toll-like receptor 9 (TLR9) expression, important for the recognition of disrupted endogenous DNA to produce inflammatory reactions. Furthermore, gastrodin mitigated inflammation by inhibiting JAK2/STAT3 signaling, influencing inflammatory factors to aggravate inflammation. Notably, the effects of gastrodin were abolished by Coumermycin A1 (C-A1), a JAK2 agonist, validating the role of JAK2/STAT3 signaling. In summary, gastrodin enhances the protective effect against mitochondrial damage in ischemic stroke by inhibiting JAK2/STAT3 signaling. Gastrodin is a possible therapy for cerebral ischemia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly, is primarily characterized by the degeneration of the retinal pigment epithelium (RPE). However, effective therapeutic options for dry AMD are currently lacking, necessitating further exploration into preventive and pharmaceutical interventions. This study aimed to investigate the protective effects of gastrodin on RPE cells exposed to oxidative stress. We constructed an in vitro oxidative stress model of 4-hydroxynonenal (4-HNE) and performed RNA-seq, and demonstrated the protective effect of gastrodin through mouse experiments. Our findings reveal that gastrodin can inhibit 4-HNE-induced oxidative stress, effectively improving the mitochondrial and lysosomal dysfunction of RPE cells. We further elucidated that gastrodin promotes autophagy and phagocytosis through activating the PPARα-TFEB/CD36 signaling pathway. Interestingly, these outcomes were corroborated in a mouse model, in which gastrodin maintained retinal integrity and reduced RPE disorganization and degeneration under oxidative stress. The accumulation of LC3B and SQSTM1 in mouse RPE-choroid was also reduced. Moreover, activating PPARα and downstream pathways to restore autophagy and phagocytosis, thereby countering RPE injury from oxidative stress. In conclusion, this study demonstrated that gastrodin maintains the normal function of RPE cells by reducing oxidative stress, enhancing their phagocytic function, and restoring the level of autophagic flow. These findings suggest that gastrodin is a novel formulation with potential applications in the development of AMD disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Central nervous system (CNS)-related diseases have a high mortality rate, are a serious threat to physical and mental health, and have always been an important area of research. Gastrodin, the main active metabolite of Gastrodia elata Blume, used in Chinese medicine and food, has a wide range of pharmacological effects, mostly related to CNS disorders. This review aims to systematically summarize and discuss the effects and underlying mechanisms of gastrodin in the treatment of CNS diseases, and to assess its potential for further development as a lead drug in both biomedicine and traditional Chinese medicine. Studies on the pharmacological effects of gastrodin on the CNS indicate that it may exert anti-neurodegenerative, cerebrovascular protective, and ameliorative effects on diabetic encephalopathy, perioperative neurocognitive dysfunction, epilepsy, Tourette's syndrome, depression and anxiety, and sleep disorders through various mechanisms. To date, 110 gastrodin products have been approved for clinical use, but further multicenter clinical case-control studies are relatively scarce. Preclinical studies have confirmed that gastrodin can be used to treat CNS-related disorders. However, important concerns need to be addressed in the context of likely non-specific, assay interfering effects when gastrodin is studied using in vitro and in silico approaches, calling for a systematic assessment of the evidence to date. High-quality clinical trials should have priority to evaluate the therapeutic safety and clinical efficacy of gastrodin. Further experimental research using appropriate in vivo models is also needed, focusing on neurodegenerative diseases, cerebral ischemic and hypoxic diseases, brain damage caused by methamphetamine or heavy metals, and epilepsy., (© 2024 John Wiley & Sons Ltd.)

Background: Gastrodin is the active monomer of the Chinese herb Rhizoma Gastrodiae with the largest quantity of active components. Gastrodin is commonly used in the treatment of central nervous system disorders such as headaches and epilepsy due to its sedating and hypnotic properties. Its pharmacological mechanism and clinical application have been extensively explored due to its low toxicity., Methods: To investigate the molecular mechanism of hepatic uptake of Gastrodin in rats, animals were randomly assigned to three groups: control group, rifampicin (RIF) group, and adrenalone (ADR) group. Blood samples were collected through the cardiac puncture 90, 180, and 300 min after injection, respectively. Rats were sacrificed 300 min after administration, and liver tissue was collected. Gastrodin concentration was determined by HPLC, and the Kp value was calculated., Results: After administering the inhibitors of organic cation transporters (OCTs) and organic anion transporting polypeptides (OATPs), the K P values in the experimental groups were significantly lower compared to the blank control group (P < 0.05)., Conclusions: These findings imply that Gastrodin may be a substrate for both OCTs and OATPs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Synovial inflammation plays a crucial role in osteoarthritis (OA). Gastrodin (GAS), an active ingredient derived from the Gastrodia elata Blume rhizome, possesses antioxidant and anti-inflammatory pharmacological effects. This research aimed to evaluate the function and molecular mechanism of GAS on human fibroblast-like synoviocytes of osteoarthritis (HFLS-OA) induced by interleukin (IL)-1β., Methods: The impact of GAS on the viability of IL-1β-treated HFLS-OA cells was assessed using the cell counting kit-8 (CCK-8). Quantitative real-time reverse transcription PCR (qRT-PCR) was employed to detect changes in IL-8 , IL-6 , monocyte chemotactic protein-1 ( MCP-1 ), tumor necrosis factor ( TNF )-α, and Gremlin-1 mRNA expression in each group. Corresponding kits were utilized to measure the catalase (CAT) and superoxide dismutase (SOD) activities, as well as the nitric oxide (NO) level. Western blot analysis was conducted to examine the expression of extracellular matrix degradation-associated proteins and nuclear factor kappa-B (NF-κB) pathway-correlated proteins in each group., Results: GAS significantly promoted the proliferation of IL-1β-induced HFLS-OA cells and concurrently down-regulated Gremlin-1 mRNA expression ( p < 0.05). Through the down-regulation of Gremlin-1 expression, GAS exhibited the following effects: decreased IL-8 , IL-6 , and TNF-α mRNA expression, as well as NO levels ( p < 0.05); increased SOD and CAT activities ( p < 0.05); down-regulated matrix metallopeptidase 13 (MMP-13) and MMP-1 protein expression levels ( p < 0.01); and up-regulated collagen II protein expression level ( p < 0.01) in IL-1β-treated HFLS-OA cells. Additionally, GAS decreased phospho-inhibitory kappa B (p-IκB)/IκB, phospho-inhibitory kappa B kinase (p-IKK)/IKK, and p-p65/p65 ratios in IL-1β-induced HFLS-OA cells by inhibiting Gremlin-1 expression ( p < 0.01)., Conclusion: GAS demonstrates a positive impact on inflammation, oxidative stress, and extracellular matrix degradation in IL-1β-mediated HFLS-OA cells. This effect is achieved by suppressing Gremlin-1 expression and reducing NF-κB pathway activity.

Xueran Sun, Xin Zhang, Keyu Jiang, Min Wu Department of Traditional Chinese Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Min WuDepartment of Traditional Chinese Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, People’s Republic of ChinaTel + 86-13601884805Email wumin@xinhuamed.com.cnPurpose: This study explored whether gastrodin (Gas) could attenuate the symptoms of Tourette syndrome(TS) via the regulation of glutamate (Glu), its transporters (EAAT1 and EAAT2) and its receptors (NMDAR1, NMDAR2A and NMDAR2B) in rats.Materials and Methods: Seventy-five Wistar male rats were randomly divided into five groups (n=15 each): the control, TS, Tia (tiapride, 25mg/kg), Gas60 (gastrodin, 60mg/kg) and Gas120 groups (gastrodin, 120mg/kg). Rats in all groups except the control group received intraperitoneal injection of 3,3′-iminodipropionitrile (IDPN) for 7 consecutive days to establish the TS model. Thereafter, rats in the Tia, Gas60, and Gas120 groups were gavaged with 25mg/kg Tia, 60mg/kg Gas and 120mg/kg Gas for 28 days. Rats in the control and TS groups were gavaged with 0.9% normal saline. Behavioral evaluation was performed by using stereotypy scoring, nodding experiment and autonomic activity test. The Glu level was measured by UPLC-QqQ-MS analysis. The expression of EAAT1, EAAT2, NMDAR1, NMDAR2A and NMDAR2B was measured by Western blot and quantitative real-time PCR (qRT-PCR) analyses.Results: The results showed that rats with IDPN-induced TS exhibited an increase in stereotypy score, nodding numbers, number of times to enter the central area and autonomic total distance, which could be improved by Tia and Gas treatments. Furthermore, Tia and Gas treatments significantly decreased the IDPN-induced the increase in Glu levels in rats with TS. Furthermore, the decreased expression of EAAT1 and EAAT2 and increased expression of NMDAR1, NMDAR2A, and NMDAR2B in rats with TS induced by IDPN could be substantially altered by Tia and Gas treatments.Conclusion: Gas ameliorated the behavioral dysfunction of rats with TS by maintaining Glu at a normal level, upregulating the expression of EAAT1 and EAAT2, and downregulating the expression of NMDAR1, NMDAR2A and NMDAR2B.Keywords: Tourette syndrome, gastrodin, Glu, EAATs, NMDARs

Betahistine and gastrodin are the first-line medications for vestibular disorders in clinical practice, nevertheless, their amelioration effects on vestibular dysfunctions still lack direct comparison and their unexpected extra-vestibular effects remain elusive. Recent clinical studies have indicated that both of them may have effects on the gastrointestinal (GI) tract. Therefore, we purposed to systematically compare both vestibular and GI effects induced by betahistine and gastrodin and tried to elucidate the mechanisms underlying their GI effects. Our results showed that betahistine and gastrodin indeed had similar therapeutic effects on vestibular-associated motor dysfunction induced by unilateral labyrinthectomy. However, betahistine reduced total GI motility with gastric hypomotility and colonic hypermotility, whereas gastrodin did not influence total GI motility with only slight colonic hypermotility. In addition, betahistine, at normal dosages, induced a slight injury of gastric mucosa. These GI effects may be due to the different effects of betahistine and gastrodin on substance P and vasoactive intestinal peptide secretion in stomach and/or colon, and agonistic/anatgonistic effects of betahistine on histamine H1 and H3 receptors expressed in GI mucosal cells and H3 receptors distributed on nerves within the myenteric and submucosal plexuses. Furthermore, treatment of betahistine and gastrodin had potential effects on gut microbiota composition, which could lead to changes in host-microbiota homeostasis in turn. These results demonstrate that gastrodin has a consistent improvement effect on vestibular functions compared with betahistine but less effect on GI functions and gut microbiota, suggesting that gastrodin may be more suitable for vestibular disease patients with GI dysfunction.

BackgroundGastrodia elata Blume (GEB), a traditional Chinese medicine, has been widely used to treat dizziness, numbness of limbs, and infantile convulsion, among other issues. Gastrodin is the main component of GEB. This meta-analysis aimed to evaluate the efficacy and safety of gastrodin in the treatment of migraine.MethodsTen electronic databases, namely the Cochrane Library, Embase, EBSCO, PubMed, Web of Science, CENTRAL, CNKI (China National Knowledge Infrastructure), CBM (Chinese Biomedicine Database), WanFang, and VIP (Chinese Scientific Journals Database), were searched for randomized controlled trials (RCTs) of gastrodin for migraine published before September 2021. The data were analyzed by RevMan 5.3 software and evaluated by GRADEpro.ResultsA total of 1,332 subjects were included in 16 RCTs. The meta-analysis showed that gastrodin was significantly effective in treating migraine (RR = 1.21, 95%CI = [1.17, 1.27]), reducing the pain degree (MD = −1.65, 95% CI = [−2.28, −1.02]), reducing the frequency of migraine attack (SMD = −2.77, 95% CI = [−3.92, −1.62]), shortening the duration of migraine attack (SMD = −1.64, 95% CI = [−2.35, −0.93]), and slowing average arterial cerebral blood flow velocity (SMD = −3.19, 95% CI = [−5.21, −1.17]), as well as being safe.ConclusionsThis systematic review revealed gastrodin is effective and safe in the treatment of migraine.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=197094, identifier: CRD42020197094.

Background: Gastrodin (Gas) exhibits anti-inflammatory properties against diseases associated with the central nervous system (CNS). This study aimed to investigate the potential neuroprotective role of Gas in traumatic brain injury (TBI). Methods: A rat TBI model was established in male adult Sprague-Dawley (SD) rats by controlled cortical impingement (CCI), and lipopolysaccharide (LPS) was applied to induce the activation of BV2 microglia and HT22 hippocampal neurons. Neurological deficits, motor function and brain water content were evaluated in TBI rats. TUNEL and Nissl’s staining were applied to measure neuronal degeneration and apoptosis. Microglial activation, the mRNA and protein profiles of pro-inflammatory cytokines were tested by immunohistochemistry (IHC), quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Results: Gas significantly reduced neurological deficits, cerebral edema, and neuronal apoptosis and improved motor function in TBI mice. In addition, Gas inactivated microglia and blocked the production of pro-inflammatory cytokines on the damaged side of the TBI rat brain. In vitro, Gas attenuated BV2 microglia inflammation and reduced HT22 hippocampal neuronal apoptosis. On the other hand, Gas activated the PKA/CREB/BDNF pathway both in vivo and in vitro. Conclusions: Gas blocks microglial activation-mediated inflammation through the PKA/CREB/BDNF pathway, thereby improving neurobehavioral function after TBI, which provides a potential therapeutic benefit for treating TBI.

The conformational landscapes of two highly flexible monosaccharide derivatives, namely phenyl β-D-glucopyranoside (ph-β-glu) and 4-(hydroxymethyl)phenyl β-D-glucopyranoside, also commonly known as gastrodin, were explored using a combined experimental and theoretical approach. For the infrared, Raman, and the associated vibrational optical activity (VOA), i.e., vibrational circular dichroism and Raman optical activity, experiments of these two compounds in DMSO and in water were carried out. Extensive and systematic conformational searches were performed using a recently developed conformational searching tool called CREST (conformer-rotamer ensemble sampling tool) in the two solvents. Fourteen and twenty-four low-energy conformers were identified at the DFT level for ph-β-glu and gastrodin, respectively. The spectral simulations of individual conformers were done at the B3LYP-D3BJ/def2-TZVPD level with the polarizable continuum model of the solvents. The VOA spectral features exhibit much higher specificity to conformational differences than their parent infrared and Raman. The excellent agreements achieved between the experimental and simulated VOA spectra allow for the extraction of experimental conformational distributions of these two carbohydrates in solution directly. The experimental percentage abundances based on the hydroxymethyl (at the pyranose ring) conformations G+, G-, and T for ph-β-glu were obtained to be 15%, 75%, and 10% in DMSO and 53%, 40%, and 7% in water, respectively, in comparison to the previously reported gas phase values of 68%, 25%, and 7%, highlighting the important role of solvents in conformational preferences. The corresponding experimental distributions for gastrodin are 56%, 22%, and 22% in DMSO and 70%, 21%, and 9% in water.

Introduction: This study aimed to investigate the possible effect of gastrodin in renal ischemia-reperfusion injury (IRI) and the mechanisms. Methods: Forty-eight male Sprague Dawley rats were randomly divided into 3 groups: sham-operated group, saline-treated IRI group, and gastrodin-treated IRI group. Gastrodin or 0.9% saline (300 mg/kg/day) was intragastrically administrated for 8 days before operation. We analyzed renal function and histological change. The malondialdehyde level, antioxidant enzymes' activities, and markers of inflammation and apoptosis were measured. Statistical analysis was performed using 1-way analysis of variance (ANOVA) or Kruskal-Wallis ANOVA on ranks. Results: Gastrodin pretreatment improved IRI-induced renal dysfunction and histologic injury. Mechanistically, gastrodin reversed the elevation of malondialdehyde level and the reduction of antioxidant enzymes' activities. Gastrodin also reduced the elevated myeloperoxidase activity, TNF-α and IL-1β levels, and the activation of p38 MAPK. Moreover, gastrodin-treated rats exhibited a dramatic reduction in renal tubular apoptosis, along with a decrease in caspase-3 activation and an increase in the Bcl-2/Bax ratio. Conclusion: Gastrodin pretreatment may alleviate renal IRI via the amelioration of oxidative injury, inflammatory response, and renal tubular apoptosis. [ABSTRACT FROM AUTHOR]

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Microglia-mediated neuroinflammation is known to play a pivotal role in the pathogenesis of different neurological diseases. Gastrodin, a phenolic glucoside, has been reported to exert anti-inflammatory effects in activated microglia challenged with lipopolysaccharide (LPS); however, the underlying mechanism has remained obscure. The present study aimed to ascertain if Gastrodin would regulate the Notch signaling pathway involved in microglia activation. We show here that LPS increased the expression of various members of the Notch-1 pathway, including intracellular Notch receptor domain (NICD), recombining binding protein suppressor of hairless (RBP-Jκ) and transcription factor hairy and enhancer of split-1 (Hes-1) in microglia in postnatal rat brain and in BV-2 microglia. Remarkably, Gastrodin was found to markedly attenuate the expression of the above various biomarkers both in vivo and in vitro. Moreover, increased phosphorylation level of ERK, JNK and P38 induced by LPS was attenuated with pretreatment of Notch-1 signaling inhibitor, N-[N-(3,5-difluorophenacetyl)-1-alany1-Sphenyglycinet-butylester (DAPT) as well as Gastrodin. Gastrodin mimicked the effects of DAPT by inhibiting the LPS-induced expression of IL-1β, IL-6, IL-23, TNF-α and NO. Moreover, lentivirus transfection mediated NICD overexpression inhibited the anti-inflammatory effects of Gastrodin. Furthermore, the activation of Notch-1 signaling promoted microglia migration and Gastrodin could inhibit the migration of activated BV-2 microglia by regulating the Notch-1 signaling pathway. In light of the above, our results indicate that Notch-1 signaling pathway is involved in the anti-inflammatory effects of Gastrodin against LPS-induced microglia activation. These findings provide a new biological target of Gastrodin for the treatment of neuroinflammatory disorders. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common chronic neurodegenerative disease globally; however, it lacks effective treatment at present. Focused ultrasound (FUS) combined with microbubbles could increase the efficacy of drug delivery to specific brain regions and is becoming a promising technology for the treatment of central nervous system diseases. In this study, we explored the therapeutic potential of FUS-mediated blood–brain barrier (BBB) opening of the left striatum to deliver gastrodin (GAS) in a subacute PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration of GAS in the left hemisphere was detected by ultra-high performance liquid chromatography electrospray Q-Orbitrap mass spectrometry (UHPLC/ESI Q-Orbitrap) and the distribution of tyrosine hydroxylase (TH) neurons was detected by immunohistochemical staining. The expression of TH, Dopamine transporter (DAT), cleaved-caspase-3, B-cell lymphoma 2 (Bcl-2), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95), and synaptophysin (SYN) protein were detected by western blotting. Analysis showed that the concentration of GAS in the left hemisphere of PD mice increased by approximately 1.8-fold after the BBB was opened. FUS-mediated GAS delivery provided optimal neuroprotective effects and was superior to the GAS or FUS control group. In addition, FUS enhanced GAS delivery significantly increased the expression of Bcl-2, BDNF, PSD-95, and SYN protein in the left striatum (P < 0.05) and reduced the levels of cleaved-caspase-3 remarkably (P = 0.001). In conclusion, the enhanced delivery by FUS effectively strengthened the protective effect of GAS on dopaminergic neurons which may be related to the reinforcement of the anti-apoptotic activity and the expression of synaptic-related proteins in the striatum. Data suggests that FUS-enhanced GAS delivery may represent a new strategy for PD treatment. [ABSTRACT FROM AUTHOR]

This study investigated the effects of gastrodin (GAS) on analgesic, anxiolytic, ferroptosis, and jejunal microbiota in chronic inflammatory pain mice. The chronic inflammatory pain model of C57BL/6J mice was established by hindpaw injection of complete Freund's adjuvant (CFA). After GAS treatment, thermal hyperalgesia test, mechanical allodynia test, elevated plus-maze (EPMT), and open-field test (OFT) were performed to assess the behavioral changes of pain and anxiety. mRNAs of FTHI, GPX4, HO-1, and PTGS2 and jejunal microbiota were measured by qPCR. In CFA-injected C57BL/6 mice, we found that the mechanical and thermal pain threshold were increased with treatment of GAS. In EPMT, the number of entries in open arms and retention times of open arms were increased by GAS. In the OFT, the time spent in the central area was also increased. Furthermore, GAS enhanced mRNA expressions of FTHI, GPX4, and HO-1 but decreased the expression of PTGS2 in a dose-dependent manner. GAS is effective in the treatment of mice chronic inflammatory pain and anxiety-like behaviors. It may be exhibits potential neuroprotective effects through inhibition of ferroptosis independently of the intestinal microbiota. [ABSTRACT FROM AUTHOR]

• We hypothesized that GAS could repair mitochondrial damage and regulate autophagy. • Male C57BL/6 mice and H9C2 cells survived in I/R and H/R injury after GAS treatment. • MI area diminished and cardiac function improved in GAS-treated mice with MIRI. • Viability increased and cardiomyocyte injury was alleviated in GAS-treated cells. • GAS could be a perioperative myocardial protective agent via PINK1/Parkin pathway. Although blood flow is restored after treatment of myocardial infarction (MI), myocardial ischemia and reperfusion (I/R) can cause cardiac injury, which is a leading cause of heart failure. Gastrodin (GAS) exerts protective effects against brain, heart, and kidney I/R. However, its pharmacological mechanism in myocardial I/R injury (MIRI) remains unclear. GAS regulates autophagy in various diseases, such as acute hepatitis, vascular dementia, and stroke. We hypothesized that GAS could repair mitochondrial damage and regulate autophagy to protect against MIRI. Male C57BL/6 mice and H9C2 cells were subjected to I/R and hypoxia-reoxygenation (H/R) injury after GAS administration, respectively, to assess the impact of GAS on cardiomyocyte phenotypes, heart, and mitochondrial structure and function. The effect of GAS on cardiac function and mitochondrial structure in patients undergoing cardiac surgery has been observed in clinical practice. The effects of GAS on cardiac structure and function, mitochondrial structure, and expression of related molecules in an animal model of MIRI were evaluated using immunohistochemical staining, enzyme-linked immunosorbent assay (ELISA), transmission electron microscopy, western blotting, and gene sequencing. Its effects on the morphological, molecular, and functional phenotypes of cardiomyocytes undergoing H/R were observed using immunohistochemical staining, real-time quantitative PCR, and western blotting. GAS significantly reduces myocardial infarct size and improves cardiac function in MIRI mice in animal models and increases cardiomyocyte viability and reduces cardiomyocyte damage in cellular models. In clinical practice, myocardial injury was alleviated with better cardiac function in patients undergoing cardiac surgery after the application of GAS; improvements in mitochondria and autophagy activation were also observed. GAS primarily exerts cardioprotective effects through activation of the PINK1/Parkin pathway, which promotes mitochondrial autophagy to clear damaged mitochondria. GAS can promote mitophagy and preserve mitochondria through PINK1/Parkin, thus indicating its tremendous potential as an effective perioperative myocardial protective agent. [Display omitted] [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is the second most common chronic neurodegenerative disease globally; however, it lacks effective treatment at present. Focused ultrasound (FUS) combined with microbubbles could increase the efficacy of drug delivery to specific brain regions and is becoming a promising technology for the treatment of central nervous system diseases. In this study, we explored the therapeutic potential of FUS-mediated blood–brain barrier (BBB) opening of the left striatum to deliver gastrodin (GAS) in a subacute PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration of GAS in the left hemisphere was detected by ultra-high performance liquid chromatography electrospray Q-Orbitrap mass spectrometry (UHPLC/ESI Q-Orbitrap) and the distribution of tyrosine hydroxylase (TH) neurons was detected by immunohistochemical staining. The expression of TH, Dopamine transporter (DAT), cleaved-caspase-3, B-cell lymphoma 2 (Bcl-2), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95), and synaptophysin (SYN) protein were detected by western blotting. Analysis showed that the concentration of GAS in the left hemisphere of PD mice increased by approximately 1.8-fold after the BBB was opened. FUS-mediated GAS delivery provided optimal neuroprotective effects and was superior to the GAS or FUS control group. In addition, FUS enhanced GAS delivery significantly increased the expression of Bcl-2, BDNF, PSD-95, and SYN protein in the left striatum (P < 0.05) and reduced the levels of cleaved-caspase-3 remarkably (P = 0.001). In conclusion, the enhanced delivery by FUS effectively strengthened the protective effect of GAS on dopaminergic neurons which may be related to the reinforcement of the anti-apoptotic activity and the expression of synaptic-related proteins in the striatum. Data suggests that FUS-enhanced GAS delivery may represent a new strategy for PD treatment.

This study investigated the effects of gastrodin (GAS) on analgesic, anxiolytic, ferroptosis, and jejunal microbiota in chronic inflammatory pain mice. The chronic inflammatory pain model of C57BL/6J mice was established by hindpaw injection of complete Freund’s adjuvant (CFA). After GAS treatment, thermal hyperalgesia test, mechanical allodynia test, elevated plus-maze (EPMT), and open-field test (OFT) were performed to assess the behavioral changes of pain and anxiety. mRNAs of FTHI, GPX4, HO-1, and PTGS2 and jejunal microbiota were measured by qPCR. In CFA-injected C57BL/6 mice, we found that the mechanical and thermal pain threshold were increased with treatment of GAS. In EPMT, the number of entries in open arms and retention times of open arms were increased by GAS. In the OFT, the time spent in the central area was also increased. Furthermore, GAS enhanced mRNA expressions of FTHI, GPX4, and HO-1 but decreased the expression of PTGS2 in a dose-dependent manner. GAS is effective in the treatment of mice chronic inflammatory pain and anxiety-like behaviors. It may be exhibits potential neuroprotective effects through inhibition of ferroptosis independently of the intestinal microbiota.

Gastrodin (Gas) represents the major active component of Gastrodia elata, a Chinese herb. Clinically, Gas is widely used for its sedative, anticonvulsive and neuroprotective properties. This work aimed to assess Gas for its efficacy in Tourette Syndrome (TS) treatment. Twenty-four rats were randomized to the blank control (n = 6) and experimental (n = 18) groups. The experimental group was administered continuous injection of 3, 3′-iminodipropionitrile (IDPN) intraperitoneally for 7 days, and subdivided into the IDPN + NS, IDPN + Hal, and IDPN + Gas groups (n = 6). The control and IDPN + NS groups received saline intragastrically, while the IDPN + Hal and IDPN + Gas groups were administered Gas and Haloperidol, respectively, for 8 weeks. Then, micro-positron emission tomography (PET) was performed for measuring the density and brain distribution of dopamine D2 receptors (D2Rs), dopamine transporters (DATs), 5-HT2A receptors (5-HT2ARs) and 5-HT transporters (SERTs). According to stereotypical behavior experiments, IDPN significantly induced abnormal stereotypical behaviors in rats in comparison with control animals. In addition, micro-PET revealed that by reducing the amounts of D2Rs and increasing those of DATs, Gas could significantly reduce stereotypical TS-like behaviors in this rat model system. Furthermore, Gas treatment reduced the density of SERTs, which could indirectly decrease DA release. The current study demonstrated that Gas could be effective in treating TS.

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The growing burden of psychological stress among diabetes patients has contributed to a rising incidence of depression within this population. It is of significant importance to conduct research on the impact of stress on diabetes patients and to explore potential pharmacological interventions to counteract the stress-induced exacerbation of their condition. Gastrodin is a low molecular weight bioactive compound extracted from the rhizome of Gastrodiae elata Blume, and it may be a preventive strategy for diabetes and a novel treatment for depression symptoms. However, its relevant pharmacological mechanisms for protecting against the impacts of psychological stress in diabetic patients are unclear. In this study, we performed 5 weeks CUMS intervention and simultaneously administered gastrodin (140 mg/kg, once daily) on T2DM mice, to investigate the potential protective effects of gastrodin. The protective effect of gastrodin was evaluated by behavioral tests, biochemical analysis, histopathological examination, RT-qPCR and gut microbiota analysis. We found that the depressive-like behavior and glucolipid metabolism could be deteriorated by chronic stress in type 2 diabetic mice, while gastrodin showed a protective effect against these exacerbations by regulating HPA hormones, activating FXR and Cyp7a1, reducing inflammatory and oxidative stress responses, and regulating ileal gut microbiota abundance. Gastrodin might be a potential therapeutic agent for mitigating the deterioration of diabetes conditions due to chronic stress. [Display omitted] [ABSTRACT FROM AUTHOR]

Gastrodia elata (Orchidaceae) is a medicinal plant used in traditional Chinese medicine. The rhizomes contain numerous active components, of which Gastrodin (p-hydroxymethylphenyl-B-D-glucopyranoside) forms the basis of the traditional medicine Gastrodiae Rhizoma. Gastrodin is also found in other medicinal plants and has neuroprotective, antioxidant, and anti-inflammatory effects. Neuroinflammation plays a crucial role in neurodegeneration. Research indicates that consuming meals and drinks containing Gastrodiaelata can enhance cognitive functioning and memory in elderly patients. The mechanisms relevant to the problem have not been completely understood. The aim was to examine the in vivo and in vitro anti-neuroinflammatory effects of Gastrodin. The neuroprotective effects of Gastrodin on the TLR4/TRAF6/NF-κB pathway and Stat3 phosphorylation in LPS-treated C57BL/6 mice and BV-2 cells were investigated. 1. C57BL/6 mice were assigned to model, gastrodin, donepezil, and control groups (n = 10 per group). The Gastrodin group received 100 mg/kg/d for five days, and the Dopenezil group 1.3 mg/kg/d. A neuroinflammation model was established by administering intraperitoneal injections of 2 mg/kg LPS to all groups, excluding the control. To induce microglial activation in Gastrodin-treated mouse microglial BV-2 cells, 1 µg/ml LPS was introduced for 24 h Morris water mazes were utilized to evaluate learning and spatial memory. Expression and subcellular localization of TLR4/TRAF6/NF-κB axis-related proteins and p-Stat3, Iba-1, GFAP, iNOS, and CD206 were assessed by immunofluorescence, western blots, and ELISA. qRT-PCR was performed to determine and measure IL-1β, TNF-α, cell migration, and phagocytosis. Overexpression of TRAF6 was induced by transfection, and the effect of Gastrodin on IL-1β and p-NF-κB p65 levels was assessed. 1. In mice, gastrodin treatment mitigated LPS-induced deficits in learning and spatial memory, as well as reducing neuroinflammation in the hippocampus, expression of TLR4/TRAF6/NF-κB pathway proteins, activation of microglia and astrocytes, and phosphorylation of Stat3. 2. Gastrodin pretreatment improved LPS-induced inflammation in vitro , reducing expression of TLR4/TRAF6/NF-κB-associated proteins and p-Stat3, inducing microglial transformation from M1 to M2, and inhibiting migration and phagocytosis. Overexpression of TRAF6 inhibited the Gastrodin-induced effects. Gastrodin suppresses neuroinflammation and microglial activation by modifying the TLR4/TRAF6/NF-κB pathway and Stat3 phosphorylation. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction is key to the pathogenesis of vascular dementia (VaD). Sirtuin-3 (SIRT3), an essential member of the sirtuins family, has been proven to be a critical sirtuin in regulating mitochondrial function. The phenolic glucoside gastrodin (GAS), a bioactive ingredient from Gastrodiae Rhizome (known in Chinese as Tian ma) demonstrates significant neuroprotective properties against central nervous system disorders; however, the precise mechanisms through which GAS modulates VaD remain elusive. This study aims to investigate whether GAS confers a protective role against VaD, and to figure out the underlying molecular mechanisms. A bilateral common carotid artery occlusion (BCCAO)-mediated chronic cerebral hypoperfusion (CCH) VaD rat model and a hypoxia model using HT22 cells were employed to investigate pharmacological properties of GAS in mitigating mitochondrial dysfunction. A SIRT3 agonist resveratrol (RES), a SIRT3 inhibitor 3-TYP and SIRT3-knockdown in vitro were used to explore the mechanism of GAS in association with SIRT3. The ability of SIRT3 to bind and deacetylate mitochondrial transcription factor A (TFAM) was detected by immunoprecipitation assay, and TFAM acetylation sites were further validated using mass spectrometry. GAS increased SIRT3 expression and ameliorated mitochondrial structure, mitochondrial respiration, mitochondrial dynamics along with upregulated TFAM, mitigating oxidative stress and senescence. Comparable results were noted with the SIRT3 agonist RES, indicating an impactful neuroprotection played by SIRT3. Specifically, the attenuation of SIRT3 expression through knockdown techniques or exposure to the SIRT3 inhibitor 3-TYP in HT22 cells markedly abrogated GAS-mediated mitochondrial rescuing function. Furthermore, our findings elucidate a novel facet: SIRT3 interacted with and deacetylated TFAM at the K5, K7, and K8 sites. Decreased SIRT3 is accompanied by hyper-acetylated TFAM. The present results were the first to demonstrate that the SIRT3/TFAM pathway is a protective target for reversing mitochondrial dysfunction in VaD. The findings suggest that GAS-mediated modulation of the SIRT3/TFAM pathway, a novel mechanism, could ameliorate CCH-induced VaD, offering a potentially beneficial therapeutic strategy for VaD. [Display omitted] [ABSTRACT FROM AUTHOR]

Depression is a psychiatric disorder and the treatment of depression is an urgent problem that need to be solved. Gastrodin (GAS) is a Traditional Chinese Medicine from an orchid and is used for neurological diseases, including depressive disorders. To assess the effect of GAS on gut microbiota of depressive mice, we established a chronic unpredictable mild stress (CUMS)-induced mouse model, and GAS was administered to one group of the mice. Animal behavior experiments were used to detect depressive-like behaviors, and 16 S rRNA gene analysis was applied to detect the gut microbiota of each group. All raw sequences were deposited in the NCBI Sequence Read Archive under accession number SRP491061. GAS treatment significantly improved depressive-like behaviors as well as the diversity and abundance of the gut microbiota. The depressive-like behaviors of the CUMS-GAS group were improved in different degrees compared with the CUMS group. The linear discriminant analysis (LDA) of the gut microbiota showed that the makeup of the gut microbiota in mice changed dramatically in the CUMS-GAS group, compared with the CUMS group, Bacteroides (LDA = 3.94, P < 0.05) were enriched in the CUMS-GAS group at the genus level. In comparison to the CUMS group, the CUMS-GAS group had a greater concentration numbers of Lactobacillus, Corynebacterium, Staphylococcus, Bacteroides, Psychrobacter, and Alistipes. Our results suggested that GAS improved depressive-like behaviors in mice and impacted the microbial composition of the gut. Our research indicated that dysbiosis of the gut microbiota may be affected by GAS treatment, which improved depressive-like behaviors in the CUMS-induced mouse model of depression. [Display omitted] [ABSTRACT FROM AUTHOR]

Vascular dementia (VD) is the second most common dementia syndrome worldwide, and effective treatments are lacking. Gastrodia elata Blume (GEB) has been used in traditional Chinese herbal medicine for centuries to treat cognitive impairment, ischemic stroke, epilepsy, and dizziness. Gastrodin (p-hydroxymethylphenyl-b-D-glucopyranoside, Gas) and Gastrodigenin (p-hydroxybenzyl alcohol, HBA) are the main bioactive components of GEB. This study explored the effects of Gas and HBA on cognitive dysfunction in VD and their possible molecular mechanisms. The VD model was established by bilateral common carotid artery ligation (2-vessel occlusion, 2-VO) combined with an intraperitoneal injection of sodium nitroprusside solution. One week after modeling, Gas (25 and 50 mg/kg, i.g.) and HBA (25 and 50 mg/kg, i.g.) were administered orally for four weeks, and the efficacy was evaluated. A Morris water maze test and passive avoidance test were used to observe their cognitive function, and H&E staining and Nissl staining were used to observe the neuronal morphological changes; the expressions of Aβ1-42 and p-tau396 were detected by immunohistochemistry, and the changes in energy metabolism in the brain tissue of VD rats were analyzed by targeted quantitative metabolomics. Finally, a Hippocampus XF analyzer measured mitochondrial respiration in H2O2-treated HT-22 cells. Our study showed that Gas and HBA attenuated learning memory dysfunction and neuronal damage and reduced the accumulation of Aβ1-42, P-Tau396, and P-Tau217 proteins in the brain tissue. Furthermore, Gas and HBA improved energy metabolism disorders in rats, involving metabolic pathways such as glycolysis, tricarboxylic acid cycle, and the pentose phosphate pathway, and reducing oxidative damage-induced cellular mitochondrial dysfunction. The above results indicated that Gas and HBA may exert neuroprotective effects on VD by regulating energy metabolism and mitochondrial function.