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Ashwagandha in brain disorders: A review of recent developments
Abstract
Ethnopharmacological relevance: Withania somnifera (Family: Solanaceae), commonly known as Ashwagandha or
Indian ginseng is distributed widely in India, Nepal, China and Yemen. The roots of plant consist of active
phytoconstituents mainly withanolides, alkaloids and sitoindosides and are conventionally used for the treatment of multiple brain disorders.
Aim of the review: This review aims to critically assess and summarize the current state and implication of
Ashwagandha in brain disorders. We have mainly focussed on the reported neuroactive phytoconstituents,
available marketed products, pharmacological studies, mechanism of action and recent patents published related
to neuroprotective effects of Ashwagandha in brain disorders.
Materials and methods: All the information and data was collected on Ashwagandha using keywords
“Ashwagandha” along with “Phytoconstituents”, “Ayurvedic, Unani and Homeopathy marketed formulation”,
“Brain disorders”, “Mechanism” and “Patents”. Following sources were searched for data collection: electronic
scientific databases such as Science Direct, Google Scholar, Elsevier, PubMed, Wiley On-line Library, Taylor and
Francis, Springer; books such as AYUSH Pharmacopoeia; authentic textbooks and formularies.
Results: Identified neuroprotective phytoconstituents of Ashwagandha are sitoindosides VII–X, withaferin A,
withanosides IV, withanols, withanolide A, withanolide B, anaferine, beta-sitosterol, withanolide D with key
pharmacological effects in brain disorders mainly anxiety, Alzheimer's, Parkinson's, Schizophrenia, Huntington's
disease, dyslexia, depression, autism, addiction, amyotrophic lateral sclerosis, attention deficit hyperactivity
disorder and bipolar disorders. The literature survey does not highlight any toxic effects of Ashwagandha.
Further, multiple available marketed products and patents recognized its beneficial role in various brain disorders; however, very few data is available on mechanistic pathway and clinical studies of Ashwagandha for
various brain disorders is scarce and not promising.
Conclusion: The review concludes the results of recent studies on Ashwagandha suggesting its extensive potential
as neuroprotective in various brain disorders as supported by preclinical studies, clinical trials and published
patents. However vague understanding of the mechanistic pathways involved in imparting the neuroprotective
effect of Ashwagandha warrants further study to promote it as a promising drug candidate.
ResearchGate has not been able to resolve any citations for this publication.
Ayurveda is a Sanskrit word, which means "the scripture for longevity". It represents an ancient system of traditional medicine prevalent in India and in several other south Asian countries. It is based on a holistic view of treatment which is believed to cure human diseases through establishment of equilibrium in the different elements of human life, the body, the mind, the intellect and the soul [1].
The bioconversion of Withania somnifera extract by the fungus Beauveria bassiana leads to cysteine and glutathione derivatives of withaferin A at the C-6 position. The compounds were purified and fully characterized by 1D-NMR, 2D-NMR, and HRMS analysis. The glutathione derivative CR-777 was evaluated as a neuroprotective agent from damage caused by different neurotoxins mimicking molecular symptoms in Parkinson´s disease (PD), including 1-methyl-4-phenylpyridinium (MPP+), 6-hydroxydopamine (6-OHDA), and α-synuclein (α-Syn). CR-777, at nanomolar concentrations, protected dopaminergic and cortical neurons. In 6-OHDA-treated neurons, CR-777 increased cell survival and neurite network and decreased the expression of α-Syn. Using specific inhibitors of cell toxicity signaling pathways and specific staining experiments, the observed role of CR-777 seemed to involve the PI3K/mTOR pathway. CR-777 could be considered as a protective agent against a large panel of neuronal stressors and was engaged in further therapeutic development steps.
Background:
Systemic inflammation driven neuroinflammation is an event which correlates with pathogenesis of several neurodegenerative diseases. Therefore, targeting peripheral and central inflammation simultaneously could be a promising approach for the management of these diseases. Nowadays, herbal medicines are emerging as potent therapeutics against various brain pathologies. Therefore, in this contemporary study, the neuroprotective activity of Ashwagandha (Withania somnifera) was elucidated against the inflammation associated neurodegeneration and cognitive impairments induced by systemic LPS administration using in vivo rat model system.
Methods:
To achieve this aim, young adult wistar strain male albino rats were randomized into four groups: (i) Control, (ii) LPS alone, (iii) LPS + ASH-WEX, (iv) ASH-WEX alone. Post regimen, the animals were subjected to Rotarod, Narrow Beam Walking and Novel Object Recognition test to analyze their neuromuscular coordination, working memory and learning functions. The rats were then sacrificed to isolate the brain regions and expression of proteins associated with synaptic plasticity and cell survival was studied using Western blotting and Quantitative real time PCR. Further, neuroprotective potential of ASH-WEX and its active fraction (FIV) against inflammatory neurodegeneration was studied and validated using in vitro model system of microglial conditioned medium-treated neuronal cultures and microglial-neuronal co-cultures.
Results:
Orally administered ASH-WEX significantly suppressed the cognitive and motor-coordination impairments in rats. On the molecular basis, ASH-WEX supplementation also regulated the expression of various proteins involved in synaptic plasticity and neuronal cell survival. Since microglial-neuronal crosstalk is crucial for maintaining CNS homeostasis, the current study was further extended to ascertain whether LPS-mediated microglial activation caused damage to neurons via direct cell to cell contact or through secretion of inflammatory mediators. ASH-WEX and FIV pretreatment was found to restore neurite outgrowth and protect neurons from apoptotic cell death caused by LPS-induced neuroinflammation in both activated microglial conditioned medium-treated neuronal cultures as well as microglial-neuronal co-cultures.
Conclusion:
This extensive study using in vivo and in vitro model systems provides first ever pre-clinical evidence that ASH-WEX can be used as a promising natural therapeutic remedial for the prevention of neurodegeneration and cognitive impairments associated with peripheral inflammation and neuroinflammation.
The key objective of this present study was to analyze the effect(s) of Ashwagandharishta on the kidney functions of both male and female Albino rats. Chronic toxicity tests were also done. Following treatments the rats were observed for 51 days to know the effects of Ashwagandharishta on kidney functions considering 3 parameters such as serum urea, creatinine and uric acid. Our results failed to exhibit a significant increase in serum urea level at low dose (P<0.01), medium dose (P<0.05) and at high dose (P<0.001) in male rat groups; but with female rat groups our results showed significant increase in serum urea level at three dose levels. Regarding serum creatinine level male rats and female rats showed a trend of increase in level at different dose but effects were insignificant except medium dose in male rats (P<0.05). Regarding serum uric acid level our results failed to show a significant increase irrespective of dose. Jahangirnagar University J. Biol. Sci. 8(1): 1-7, 2019 (June)
Morphine- and ethanol-induced stimulation of neuronal firing of ventral tegmental area (VTA) dopaminergic neurons and of dopamine (DA) transmission in the shell of the nucleus accumbens (AcbSh) represents a crucial electrophysiological and neurochemical response underlying the ability of these compounds to elicit motivated behaviors and trigger a cascade of plasticity-related biochemical events. Previous studies indicate that the standardized methanolic extract of Withania somnifera roots (WSE) prevents morphine- and ethanol-elicited conditioned place preference and oral ethanol self-administration. Aim of the present research was to investigate whether WSE may also interfere with the ability of morphine and ethanol to stimulate VTA dopaminergic neurons and thus AcbSh DA transmission as assessed in male Sprague-Dawley rats by means of patch-clamp recordings in mesencephalic slices and in vivo brain microdialysis, respectively. Morphine and ethanol significantly stimulated spontaneous firing rate of VTA neurons and DA transmission in the AcbSh. WSE, at concentrations (200–400 μg/ml) that significantly reduce spontaneous neuronal firing of VTA DA neurons via a GABAA- but not GABAB-mediated mechanism, suppressed the stimulatory actions of both morphine and ethanol. Moreover, in vivo administration of WSE at a dose (75 mg/kg) that fails to affect basal DA transmission, significantly prevented both morphine- and ethanol-elicited increases of DA in the AcbSh. Overall, these results highlight the ability of WSE to interfere with morphine- and ethanol-mediated central effects and suggest a mechanistic interpretation of the efficacy of this extract to prevent the motivational properties of these compounds.
Background: Herbal medicines can be novel treatment strategies for management of nicotine addiction. Withania somnifera (Ashwagandha) is an Indian medicinal plant of great medicinal value; used in many clinically proven conditions. Objective: In present study we aimed at investigating the effect of withania somnifera extract (WSE) on preventing nicotine mediated effects attributed for the development of addiction. Materials and Methods: Mice were treated with nicotine and/or WSE and subjected to nicotine induced conditioned place preference (CPP) in male albino mice was checked. Results: Application of two-way ANOVA showed that with preconditioning and post-conditioning values as a within-subjects (column) factor and treatment as an independent between subject (row) factor. Two-way ANOVA revealed significant effect of treatment [F(3,40)=4.119, p<0.05], time [F(1,40)=23.76, p<0.001] and interactiontreatment x time [F(3,40)=5.244, p<0.01] on Intra-peritoneal (ip) administration of nicotine (1 mg/kg). WSE did not produce any changes in the preference to drug-paired compartment. Factors like treatment [F(3,40) = 0.656, p>0.05], time [F(1,40) = 7.383, p<0.01] and interactiontreatment xtime [F(3,40) = 0.5748, p>0.05] showed insignificant effects. Withania somnifera (50,100,200 mg/kg ip) co-administered with nicotine during the 6 days conditioning sessions completely abolished the acquisition of nicotine-induced CPP in mice. Conclusion: Above data indicate that Withania somnifera attenuate nicotine induced CPP. Hence it has potential as an anti-addictive therapy.
Traditional Chinese Medicine (TCM) has a methodical and organized system for the classification of herbal medicines. These classifications have been developed over many hundreds of years of careful observation and documentation of each of the traditional herbs and their effect on the human body. Due to isolation and long distances between different countries and cultures, certain significant herbal medicines (such as Ashwagandha from India) are not currently classified per TCM principles. The systems of Ayurveda and TCM are juxtaposed, herein, to establish a parallel between the two systems. In TCM, each herbal substance has its distinct attributes; therefore, a side-by-side comparison was made between each relevant herb and Ashwagandha. Because of this comparison, in the TCM herbal classification system, Ashwagandha can be categorized as "Tonify Qi" and "Tonify Blood and Essence". This comparison, depicted in (Table 1), provides evidence to classify Ashwagandha in TCM accurately and establishes a methodology by which other relevant herbal medicines can be joined with Chinese medicine and classified under TCM categories and terms.
Withania somnifera (WS; commonly known as Ashwagandha or Indian ginseng) is a medicinal plant whose extracts have been in use for centuries in various regions of the world as a rejuvenator. There is now a growing body of evidence documenting neuroprotective functions of the plant extracts or its purified compounds in several models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Based on the extract's beneficial effect in a mouse model of ALS with TDP-43 proteinopathy, the current study was designed to test its efficacy in another model of familial ALS. Our results show that administration of WS extracts by gavage to mice expressing G93A mutant form of superoxide dismutase (SOD1) resulted in increased longevity, improved motor performance and increased number of motor neurons in lumbar spinal cord. The WS treatment caused substantial reduction in levels of misfolded SOD1whereas it enhanced expression of cellular chaperons in spinal cord of SOD1G93A mice. WS markedly reduced glial activation and prevented phosphorylation of nuclear factor kappaB (NF-κB). The overall immunomodulatory effect of WS was further evidenced by changes in expression of multiple cytokines/chemokines. WS also served as an autophagy inducer which may be beneficial at early stages of the disease. These results suggest that WS extracts might constitute promising therapeutics for treatment of ALS with involvement of misfolded SOD1.
Although recent studies focused on traditional Chinese medicine (TCM) for the treatment of refractory schizophrenia have reported that it may be beneficial, there is still lack of convincing evidence and critical meta-analytic work regarding its effectiveness as an adjunctive therapy. Therefore, we performed a meta-analysis to investigate the effectiveness of TCM in combination with antipsychotics for refractory schizophrenia. Fourteen articles involving 1725 patients published as of December 2016 were included which compared antipsychotic therapies to either TCM alone, or TCM as an adjunctive therapy. TCM was observed to have beneficial effects on aspects of the Positive and Negative Syndrome Scale (PANSS) including total score changes and negative score changes, as well as clinical effects estimated with PANSS or the Brief Psychiatric Rating Scale (BPRS). The changes in extrapyramidal side effects (RSESE) scores from baseline to the end of the treatment period were similar in two groups of related trials. TCM was also reported to mitigate some anti-psychotic related side-effects and overall, TCM adjuvant therapy was generally safe and well tolerated. While, the results indicated the potential utility of TCM as an alternative adjunctive therapeutic for refractory schizophrenia treatment, there remains a need for further high-quality studies.
Background:
Behavioral studies demonstrated that the administration of Withania somnifera Dunal roots extract (WSE), prolongs morphine-elicited analgesia and reduces the development of tolerance to the morphine's analgesic effect; however, little is known about the underpinning molecular mechanism(s). In order to shed light on this issue in the present paper we explored whether WSE promotes alterations of μ (MOP) and nociceptin (NOP) opioid receptors gene expression in neuroblastoma SH-SY5Y cells.
Methods:
A range of WSE concentrations was preliminarily tested to evaluate their effects on cell viability. Subsequently, the effects of 5 h exposure to WSE (0.25, 0.50 and 1.00 mg/ml), applied alone and in combination with morphine or naloxone, on MOP and NOP mRNA levels were investigated.
Results:
Data analysis revealed that morphine decreased MOP and NOP receptor gene expression, whereas naloxone elicited their up-regulation. In addition, pre-treatment with naloxone prevented the morphine-elicited gene expression alterations. Interestingly, WSE was able to: a) alter MOP but not NOP gene expression; b) counteract, at its highest concentration, morphine-induced MOP down-regulation, and c) hamper naloxone-induced MOP and NOP up-regulation.
Conclusion:
Present in-vitro data disclose novel evidence about the ability of WSE to influence MOP and NOP opioid receptors gene expression in SH-SY5Y cells. Moreover, our findings suggest that the in-vivo modulation of morphine-mediated analgesia by WSE could be related to the hindering of morphine-elicited opioid receptors down-regulation here observed following WSE pre-treatment at its highest concentration.
Background
The epidemic of obesity has reached alarming levels in both developing and developed nations. Excessive calorie intake and sedentary lifestyle due to technological advancements are the main causal factors for overweight and obesity among the human population. Obesity has been associated with a number of co-morbidities such as hypertension, type 2 diabetes mellitus, cardiovascular diseases, and neurodegeneration and dementia. The progression of neurological disorders in obese subjects has been mainly attributed to neuroinflammation. Withania somnifera has been used in numerous Ayurvedic formulations owing to its wide array of health-promoting properties. The current study was designed to test the hypothesis whether dry leaf powder of W. somnifera has anxiolytic and anti-neuroinflammatory potential in diet-induced obesity.
Methods
Young adult female rats were divided into four groups: low fat diet group (LFD) fed with regular chow feed, high fat diet group (HFD) fed with diet containing 30% fat by weight, low fat diet plus extract group (LFDE) fed with regular chow feed supplemented with dry leaf powder of W. somnifera 1 mg/g of body weight (ASH), and high fat diet plus extract group (HFDE) fed with diet containing 30% fat by weight and supplemented with ASH. All the animals were kept on respective feeding regimen for 12 weeks; following which, the animals were tested for their anxiety-like behavior using elevated plus maze test. The animals were sacrificed and used to study various inflammatory markers such as GFAP, Iba1, PPARγ, iNOS, MCP-1, TNFα, IL-1β, IL-6, and various markers of NF-κB pathway by Western blotting and quantitative real-time PCR. Serum levels of leptin, insulin and pro-inflammatory cytokines were also assayed.
Results
ASH treated rats showed less anxiety levels as compared to HFD animals. At molecular level, ASH ameliorated the HFD-induced reactive gliosis and microgliosis and suppressed the expression of inflammatory markers such as PPARγ, iNOS, MCP-1, TNFα, IL-1β, and IL-6. Further, ASH ameliorated leptin and insulin resistance and prevented HFD-induced apoptosis.
Conclusions
Dry leaf powder of W. somnifera may prove to be a potential therapeutic agent to attenuate neuroinflammation associated with obesity and may prevent its co-morbidities.
Parkinson’s disease remains as one of the most common debilitating neurodegenerative disorders. With the hopes of finding agents that can cure or reduce the pace of progression of the disease, we studied two traditional medicinal plants: Centella asiatica and Withania somnifera that have been explored in some recent studies. In agreement with the previous work on ethanol extracts of these two plants in mice model, we saw an improvement in oxidative stress profile as well as behavioral performance in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson-like symptoms in Balb/c mice. Given the known potential of both the herbal extracts in improving Parkinson-like symptoms, we expected the combination of the two to show better results than either of the two but surprisingly there was no additivity in either oxidative stress or behavioural recovery. In fact, in some assays, the combination performed worse than either of the two individual constituents. This effect of mixtures highlights the need of testing mixtures in supplements market using enthomedicine. The necessity of comparing multiple groups in this study to get most information from the experiments motivated us to design a ladder-like visualization to show comparison with different groups that we call complete comparison display (CCD). In summary, we show the potential of Centella asiatica and Withania somnifera to ameliorate Parkinson’s disorder.
Neurodegenerative diseases affect not only the life quality of aging populations, but also their life spans. All forms of neurodegenerative diseases have a massive impact on the elderly. The major threat of these brain diseases includes progressive loss of memory, Alzheimer’s disease (AD), impairments in the movement, Parkinson’s disease (PD), and the inability to walk, talk, and think, Huntington’s disease (HD). Oxidative stress and mitochondrial dysfunction are highlighted as a central feature of brain degenerative diseases. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, has been known to play a vital role in the pathophysiology of neurodegenerative diseases including AD, PD, and HD. A large number of studies have utilized oxidative stress biomarkers to investigate the severity of these neurodegenerative diseases and medications are available, but these only treat the symptoms. In traditional medicine, a large number of medicinal plants have been used to treat the symptoms of these neurodegenerative diseases. Extensive studies scientifically validated the beneficial effect of natural products against neurodegenerative diseases using suitable animal models. This short review focuses the role of oxidative stress in the pathogenesis of AD, PD, and HD and the protective efficacy of natural products against these diseases.
Withania somnifera has immense pharmacologic and clinical uses. Owing to its similar pharmacologic activity as that of Korean Ginseng tea, it is popularly called as Indian ginseng. In most cases, extracts of this plant have been evaluated against various diseases or models of disease. However, little efforts have been made to evaluate individual constituents of this plant for neurodegenerative disorders. Present study was carried out to evaluate Withanone, one of the active constituents of Withania somnifera against NMDA-induced excitotoxicity in retinoic acid, differentiated Neuro2a cells. Cells were pre-treated with 5, 10 and 20 μM doses of Withanone and then exposed to 3-mM NMDA for 1 h. MK801, a specific NMDA receptor antagonist, was used as positive control. The results indicated that NMDA induces significant death of cells by accumulation of intracellular Ca2+, generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, crashing of Bax/Bcl-2 ratio, release of cytochrome c, increased caspase expression, induction of lipid peroxidation as measured by malondialdehyde levels and cleavage of poly(ADP-ribose) polymerase-1 (Parp-1), which is indicative of DNA damage. All these parameters were attenuated with various doses of Withanone pre-treatment. These results suggest that Withanone may serve as potential neuroprotective agent.
Background: Alcohol addiction is a social problem leading to both loss of health and economic prosperity among addicted individuals. Common properties of anti‑addictive compounds include anti‑anxiety, anticonvulsants, anti‑depressant, and nootropic actions primarily through modulation of gamma‑aminobutyric acid (GABA) and serotonergic systems. Objective: Here, we screen ashwagandha and shilajit known ethnopharmacologically as nervine tonic and adaptogenic herbs for possible anti‑addictive potential. Materials and Methods: Effect of ashwagandha churna and shilajit was measured on ethanol withdrawal anxiety using elevated plus maze. Role of ashwagandha and shilajit on chronic ethanol consumption (21 days) was measured using two bottle choice protocol of voluntary drinking. We also measured the effect of the above herbs on corticohippocampal GABA, dopamine, and serotonin levels. Results: Both ashwagandha and shilajit were found to reduce alcohol withdrawal anxiety in a dose‑dependent manner. These herbs alone or in combination also decreased ethanol intake and increased water intake significantly after 21 days of chronic administration. Chronic administration of ashwagandha was found to significantly increase GABA and serotonin levels whereas shilajit altered cortico‑hippocampal dopamine in mice. Conclusion: These central nervous system active herbs alone or in combination reduced both alcohol dependence and withdrawal thus showing promising anti‑addictive potential.
Objective: The objective of the present study was to evaluate the ameliorating effect of Withania somnifera on VPA induced autism in BALB/c mice. Materials and Methods: On Post Natal Day (PND), 12 young BALB/c mice were procured from five different litters and segregated into five groups (n = 6). Group I served as control group, received saline on PND 14. Group II served as normal treated, received Withania somnifera (200 mg kg1) from PND 13-40. Group III served as disease control, received VPA (400 mg kg1 s.c.) on PND 14 and vehicle from PND 13-40. Group IV and V served as disease treated, received valproic acid (VPA-400 mg kg1 s.c.) on PND 14 and Withania somnifera (100 and 200 mg kg1 p.o.) from PND 13-40, respectively. All the experiments were preformed in the light phase between 09:00-15:00 h. During the experimental period, various behavioral parameters were evaluated. At the end of the experimental period, all the animals were sacrificed by cervical dislocation and brains were isolated for biochemical estimations and histo-pathological examination of cerebellum for purkinje cell integrity and cerebellar damage. Results: Induction of autism significantly altered behavioral and oxidative stress parameters and altered histo-architecture of cerebellum (decreased number of purkinje fibers, neuronal degeneration and chromatolysis) when compared with normal control group. Pre-treatment with Withania somnifera significantly improved behavioral alterations, altered oxidative stress markers and restored histo-architecture of cerebellum. Conclusion: Withania somnifera ameliorates sodium valporate induced autism in BAL B/C mice and is effective due to its anti-anxiety, anti-oxidant and neuro protective activity.
Withanolide A (steroidal lactone) forms the major constituent of the most popular herbal drug in Ayurvedic medicine, Ashwagandha. It has been used since ancient times as an alternative medicine for the treatment of a variety of age related disorders. Here we provide multiple lines of evidence indicating that Withanolide A improves healthspan, delays age-associated physiological changes and also extends lifespan of C. elegans. We also report several neuroprotective benefits of this natural product, including its anti-amyloidogenic effects, alleviation of α-synuclein aggregation and neuroprotection through modulation of neural mediators like acetylcholine. We observed that Withanolide A mediates lifespan extension and promotes stress resistance via insulin/insulin-like growth factor signaling pathway. Such findings could be helpful to develop a therapeutic medicine from this natural product for the prevention or reversal of age-related ailments and to improve the survival of patients suffering from Alzheimer's or Parkinson's disease.
Withania somnifera (L) Dunal is a well known Indian medicinal plant widely used in the treatment of many clinical conditions in India. It is an important drug commonly known as Asgand which has been used either single or in combination with other drugs in Unani as well as Ayurvedic system of medicine for centuries. It has been described by Dioscorides (78 AD) in his book "Kitab-ul-Hashaish". Asgand consists of the roots of Withania somnifera which has various therapeutic actions such as anti-inflammatory (Muhallil-e-Warm), sedative (Musakkin), alterative (Muaddil) and aphrodisiac (Muqawwi-e-Bah). Keeping in view the medicinal properties of Withania somnifera Dunal (Asgand), an attempt has been made in this review paper to explore various dimensions of the drug including phytochemical and pharmacological studies carried out on this drug.
Stroke management exerts insurmountable societal and economic burden on the patient as well as their caregivers. In the year 2010 alone, the direct and indirect costs of stroke care amounted to 36.5 billion dollars (Go et al., 2014). Despite concentrated efforts to develop a safe, effective drug for stroke, we have not discovered one since the introduction of recombinant tissue plasminogen activator (rtPA)—the standalone FDA-approved therapy for stroke. While rtPA is highly effective, it needs to be given within 3–4.5 hours of the onset of stroke symptoms (Zivin, 2009). This is often complicated by the delay in the commencement of treatment due to preliminary inclusion parameters that are required to be ascertained before rtPA administration.
Maneb (MB) and paraquat (PQ) are environmental
toxins that have been experimentally used to induce
selective damage of dopaminergic neurons leading to the
development of Parkinson’s disease (PD). Although the
mechanism of this selective neuronal toxicity in not fully
understood, oxidative stress has been linked to the pathogenesis
of PD. The present study investigates the mechanisms
of neuroprotection elicited by Withania somnifera
(Ws), a herb traditionally recognized by the Indian system
of medicine, Ayurveda. An ethanolic root extract of Ws
was co-treated with the MB–PQ induced mouse model of
PD and was shown to significantly rescue canonical indicators
of PD including compromised locomotor activity,
reduced dopamine in the substantia nigra and various
aspects of oxidative damage. In particular, Ws reduced the
expression of iNOS, a measure of oxidative stress. Ws also
significantly improved the MB ? PQ mediated induction
of a pro-apoptotic state by reducing Bax and inducing Bcl-
2 protein expression, respectively. Finally, Ws reduced
expression of the pro-inflammatory marker of astrocyte
activation, GFAP. Altogether, the present study suggests
that Ws treatment provides nigrostriatal dopaminergic
neuroprotection against MB–PQ induced Parkinsonism by
the modulation of oxidative stress and apoptotic machinery
possibly accounting for the behavioural effects.
The dependence of man on nature for food, fuel, fodder and medicines goes back to prehistoric times. The oldest civilizations have indication of plants being worshipped by man and different forms of grain are found associated with human beings globally. Initially, man was dependent on plant system for its medical needs, vitality and cure of diseases. The knowledge about plants as a source of medicine was confined to dwellers of high mountains, tribal people, village folk and priests. Now the traditional Indian system of medicine can be broadly classified into the empirical forms of folk medicine which are village based, region-specific, indigenous herb based, local resources based and in many cases, community-specific. At present moment, the pharmaceutical industries are giving much importance to Indian system of medicine to find out possible remedies because synthetic drug preparations take lot of time and is a tedious jobs.
Withania somnifera root extract has been used traditionally in ayurvedic system of medicine as a memory enhancer. Present study explores the ameliorative effect of withanolide A, a major component of withania root extract and its molecular mechanism against hypoxia induced memory impairment. Withanolide A was administered to male Sprague Dawley rats before a period of 21 days pre-exposure and during 07 days of exposure to a simulated altitude of 25,000 ft. Glutathione level and glutathione dependent free radicals scavenging enzyme system, ATP, NADPH level, γ-glutamylcysteinyl ligase (GCLC) activity and oxidative stress markers were assessed in the hippocampus. Expression of apoptotic marker caspase 3 in hippocampus was investigated by immunohistochemistry. Transcriptional alteration and expression of GCLC and Nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) were investigated by real time PCR and immunoblotting respectively. Exposure to hypobaric hypoxia decreased reduced glutathione (GSH) level and impaired reduced gluatathione dependent free radical scavenging system in hippocampus resulting in elevated oxidative stress. Supplementation of withanolide A during hypoxic exposure increased GSH level, augmented GSH dependent free radicals scavenging system and decreased the number of caspase and hoescht positive cells in hippocampus. While withanolide A reversed hypoxia mediated neurodegeneration, administration of buthionine sulfoximine along with withanolide A blunted its neuroprotective effects. Exogenous administration of corticosterone suppressed Nrf2 and GCLC expression whereas inhibition of corticosterone synthesis upregulated Nrf2 as well as GCLC. Thus present study infers that withanolide A reduces neurodegeneration by restoring hypoxia induced glutathione depletion in hippocampus. Further, Withanolide A increases glutathione biosynthesis in neuronal cells by upregulating GCLC level through Nrf2 pathway in a corticosterone dependenet manner.
Withania somnifera (Ashwagandha) is a plant used in medicine from the time of Ayurveda, the ancient system of Indian medicine. The dried roots of the plant are used in the treatment of nervous and sexual disorders. From chemistry point of view, the drug contains group of biologically active constituents known as withanolides. The chemical structures of withanolides have been studied and they are widely distributed in family Solanacae. Withaferin-A is therapeutically active withanolide reported to be present in leaves. In animal studies, withaferin-A has shown significant anticancer activity. Majority of the anticancer drugs like Vinblastine, Vincristine, and Taxol have been derived from green flora. Today there is much interest in natural products with anticancer activity. Withanolides are of under research potential as far treatment of cancer is concerned. The article reviews the scope of studies published in favor of anticancer potential of withaferin-A.
Withania somnifera belongs to the Solanaceae family, commonly known as Ashwagandha, Indian ginseng or Winter cherry. It is an important commercial medicinal crop, considered as similar to Panax ginseng
in Chinese medicine. Different parts of this plant are used in traditional medicine for the treatment of various ailments. It provides defense against diseases, adverse environmental factors and helps to retard the aging process. Ashwagandha exhibits a wide range of therapeutic properties by tuning the endocrine, cardiopulmonary, central nervous system and sexual behavior without any toxicity. The root has been used most frequently for therapeutic uses and is a constituent of over 200 formulations in Ayurveda, Siddha and Unani medicines. There are several reports to establish its immunomodulatory, anti-inflammatory, antistress, memory enhancing, antiparkinsonian, hypolipidemic, antibacterial, cardiovascular, antioxidant, antitumor and adaptogenic properties. These properties stem from the characteristic bioactive phytochemicals such as alkaloids and phytosterols present in the plant. This review presents a detailed survey on various traditional uses, phytochemical composition and pharmacological properties of Withania somnifera
.
Neurodegenerative diseases are characterized by protein aggregates and inflammation as well as oxidative stress in the central nervous system (CNS). Multiple biological processes are linked to neurodegenerative diseases such as depletion or insufficient synthesis of neurotransmitters, oxidative stress, abnormal ubiquitination. Furthermore, damaging of blood brain barrier (BBB) in the CNS also leads to various CNS-related diseases. Even though synthetic drugs are used for the management of Alzheimer's disease, Parkinson's disease, autism, and many other chronic illnesses, they are not without side effects. The attentions of researchers have been inclined towards the phytochemicals, many of which have minimal side effects. Phytochemicals are promising therapeutic agents because many phytochemicals have anti-inflammatory, antioxidative as well as anticholinesterase activities. Various drugs of either synthetic or natural origin applied in the treatment of brain disorders need to cross the BBB before they can be used. This paper covers various researches related to phytochemicals used in the management of neurodegenerative disorders.
Neuropsychiatric symptoms are frequent in obesity. In addition to their substantial economic and health impact, these symptoms significantly interfere with the quality of life and social function of obese individuals. While the pathophysiological mechanisms underlying obesity-related neuropsychiatric symptoms are still under investigation and remain to be clearly identified, there is increasing evidence for a role of inflammatory processes. Obesity is characterized by a chronic low-grade inflammatory state that is likely to influence neuropsychiatric status given the well-known and highly documented effects of inflammation on brain activity/function and behavior. This hypothesis is supported by recent findings emanating from clinical investigations in obese subjects and from experimentations conducted in animal models of obesity. These studies converge to show that obesity-related inflammatory processes, originating either from the adipose tissue or gut microbiota environment, spread to the brain where they lead to substantial changes in neurocircuitry, neuroendocrine activity, neurotransmitter metabolism and activity, and neurogenesis. Together, these alterations contribute to shape the propitious bases for the development of obesity-related neuropsychiatric comorbidities.
Eighteen healthy male Swiss albino mice of specific weight (25–30g) were randomly divided into three groups of six animals each and given specific diets for a period 28 days. Group A was given normal synthetic diet (NSD) and milk; Group B: NSD and Withania somnifera (WS) extract (0.3%) and Group C: NSD supplemented with milk and WS extract (0.3%). The phagocytic activity of peritoneal macrophages and Immunoglobulin G (lgG) level in mice serum increased significantly in comparison to control group in WS-supplemented groups. The lymphocyte proliferation index did not alter significantly (P P WS is able to enhance immunomodulatory and antioxidative properties of milk.
Withania somnifera is an herbal medicine that has been known to possess memory-enhancing properties. The current study involved an assessment of cognitive and psychomotor effects of Withania somnifera extract in healthy human participants.
In this prospective, double-blind, multi-dose, placebo-controlled, crossover study, 20 healthy male participants were randomized to receive 250 mg two capsules twice daily of an encapsulated dried aqueous extract of roots and leaves of Withania somnifera or a matching placebo for a period of 14 days. Cognitive and psychomotor performance was assessed pre-dose (day 1) and at 3 hrs post-dose on day 15 using a battery of computerized psychometric tests. After a washout period of 14 days, the subjects crossed-over to receive the other treatment for a further period of 14 days as per prior randomization schedule. Same battery of test procedures were performed to assess cognitive and psychomotor performance.
Significant improvements were observed in reaction times with simple reaction, choice discrimination, digit symbol substitution, digit vigilance, and card sorting tests with Withania somnifera extract compared to placebo. However, no effect can be seen with the finger tapping test.
These results suggest that Withania somnifera extract can improve cognitive and psychomotor performance and may, therefore, be a valuable adjunct in the treatment of diseases associated with cognitive impairment.
Background
Bisphenol A (BPA), a major endocrine disruptor and a xenobiotic compound is used abundantly in the production of polycarbonate plastics and epoxy resins. Human exposure to this compound is primarily via its leaching from the protective internal epoxy resin coatings of containers into the food and beverages. In addition, the plastics used in dental prostheses and sealants also contain considerable amount of BPA and have a high risk of human exposure. Since it is a well-known endocrine disruptor and closely mimics the molecular structure of human estrogen thereby impairing learning and memory. Withania somnifera (Ws), commonly known as Ashwagandha is known for its varied therapeutic uses in Ayurvedic system of medicine. The present study was undertaken to demonstrate the impairment induced by BPA on the spatial learning, working memory and its alleviation by Ws in Swiss albino mice. The study was conducted on thirty Swiss albino mice, randomly distributed among three groups: control, BPA and BPA + Ws. The behavioral recovery after treatment with Ws was investigated using the Y-maize and Morris water maize test. Whereas, for the estimation of recovery of NMDA receptor which is related to learning and memory in hippocampus region by western blot and immunohistochemistry. Furthermore, the oxidative stress and antioxidant level was assessed by biochemical tests like MDA, SOD and catalase.
Results
The study revealed that administration of Ws alleviated the behavioral deficits induced by BPA. Alongside, Ws treatment reinstated the number of NMDA receptors in hippocampus region and showed anti-oxidative property while ameliorating the endogenous anti-oxidant level in the brain.
Conclusion
These findings suggest that Ws significantly ameliorates the level of BPA intoxicated oxidative stress thereby potentially treating cognitive dysfunction which acts as the primary symptom in a number of neurodegenerative diseases.
Plant based lead compounds have been historically incredible as a source of therapeutic agents for various complex disorders including Alzheimer's disease (AD). AD is one of the leading neurodegenerative disorder in which the underlying risk factors remain largely unclear and presently, there is no disease modifying treatment available. Despite its potential, to date only few compounds have entered for clinical trials. Herein, we described the identification of plant based lead compounds for treatment of AD through an integrative approach of pharmacokinetics and structure bioinformatics approach. In particular we performed screening of lead compounds from 3 traditional medicinal plants namely Withania somnifera, Bacopa monnieri and Morus alba, which are known to have potential for treatment of neurodegenerative disease. We retrieved a total of 210 plant based compounds of which 21 compounds were screened based on their pharmacokinetic properties. Further, Docking study against 7 known AD associated targets were carried out to identify the binding sites and direct interacting residues. In addition we investigate the stable and reliable binding mechanism of top such plant compounds against 3 targets through molecular docking followed by Molecular Dynamic(MD) simulation. The results obtained in the study revealed that 3 drug compounds namely Morusin (MRSN), Withanone (WTHN) and 27-Hydroxywithanolide B (HWTHN) were identified as putative lead compounds against mono amine oxidase (MAOB), Beta-secretase 1(BACE1) and phosphodiesterase 4D.
Background: Now-a-days, herbal treatments are preferred over synthetic drugs for a range of human brain disorders including, Alzheimer’s disease, Parkinson’s disease, depression, epilepsy, schizophrenia, anxiety, etc. Ayurvedic system of medicine has traditionally been used in several neurological conditions. In general, much attention is drawn towards the established traditional systems of herbal remedies for many brain disorders, generating positive hopes for the patients. It is estimated that more than 60 million Indian population suffers from mental disorders. Results: Easy accessibility, negligible incidence of side effects and cost effectiveness of plant products offer considerable advantages. The Ayurvedic prescriptions have been proven to be very useful in mental health. The plant materials prescribed for these problems range from herbs to perennial trees with varied plant parts, ranging from whole plant, roots, stem, bark, leaves, flowers, fruits to seeds. A total of fifty six promising plants have been selected. The chemical structure of the major compounds from these plants range from straight chain fatty acids to terpenoids, steroids, flavonoids, alkaloids, peptides, etc. Conclusion: In the present paper, it has been attempted to review the botanical descriptions, Ayurvedic prescriptions, scientific validations and chemical compositions of the plants which have been in use as an ingredient of Ayurvedic medicine for mental health.
Alzheimer's disease (AD) is a chronic disorder that slowly worsens and impairs the person's memory, learning, reasoning, judgment, communication and familiar tasks with loss of orientation. AD is characterized clinically by cognitive deficit and pathologically by the deposition of β amyloid plaques, neurofibrillary tangles, associated with degeneration of the cholinergic forebrain. Withanone (WS-2), a compound isolated from root extract of Withania somnifera at doses administered orally/day to wistar rats for duration of 21 days showed significant improvement in the cognitive skill by inhibiting amyloid β-42 and attenuated the elevated levels of pro-inflammatory cytokines like TNF alpha, IL-1 beta, IL-6, MCP-1, Nitric oxide, lipid peroxidation and both β- and γ- secretase enzymatic activity. Administration of WS-2 also significantly reversed the decline in acetyl choline and Glutathione (GSH) activity. None of the treatments that are available today alter the underlying causes of this terminal disease. Few preliminary clinical treatments have demonstrated that some plant medicines do ameliorate and improve memory and learning in patients with mild-to-moderate AD. WS-2 showed promise in AD treatment because of cognitive benefits and more importantly, mechanisms of action with respect to the fundamental pathophysiology of the disease, not limited to the inhibition of AChE, but also include the modification of Aβ processing, protection against oxidative stress and anti-inflammatory effects.
Poly (ADP-ribose) polymerase-1 (PARP-1) reverses DNA damage by repairing DNA nicks and breaks in the normal cellular environment. However, during abnormal conditions like stroke and other neurological disorders, overactivation of PARP-1 leads to neuronal cell death via a caspase-independent programmed cell death pathway. Strategies involving inhibition or knockout of PARP-1 have proved beneficial in combating neuro-cytotoxicity. In this study, we performed in-silico analysis of 27 phytochemicals of Withania somnifera (Ashwagandha), to investigate their inhibition efficiency against PARP-1. Out of 27 phytochemicals, we report 12 phytochemicals binding to the catalytic domain of PARP-1 with an affinity higher than FR257517, PJ34 and Talazoparib (highly potent inhibitors of the enzyme). Among these 12 compounds, five phytochemicals namely Stigmasterol, Withacnistin, Withaferin A, Withanolide G and Withanolide B show an exceptionally high binding affinity for the catalytic domain of PARP-1 and bind to the enzyme with similar hydrogen bond formation and hydrophobic interaction pattern as their inhibitors. All of these phytochemicals are BBB permeable so that they can be further developed into potential future neuro-therapeutic drugs against neurodegenerative disorders involving neuronal cell death.
Progress has been made in understanding the genetic defects and the pathophysiology of this crippling motor neuron disease (commonly called Lou Gehrig’s disease). However, this information has not yet led to a successful intervention that alters the course of the disease.
A stroke or cerebrovascular accident is a serious, life-threatening medical condition that occurs when the blood supply to part of the brain is severely reduced or cut off, depriving brain tissue of oxygen and nutrients. Studies suggested that level of gelatinases (MMP-2 and MMP-9) usually increases in the brain after stroke. The elevated activity of gelatinases plays the deleterious role in ischemic stroke, hemorrhagic stroke and perinatal hypoxic–ischemic brain injury. Therefore, matrix metalloproteinase (MMP)-2 and MMP-9 inhibition have therapeutic importance in stroke condition. Present in silico study investigates whether Withania somnifera (WS) phytochemicals inhibit the MMP-2 and MMP-9 by binding to the catalytic domain, as similar to their inhibitor or not. For that, we performed molecular docking study to evaluate the gelatinases-inhibitory potential of 36 WS phytochemicals, which compared with gelatinases inhibitors viz. hydroxamic acid, quercetin, doxycycline, minocycline and reverse hydroxamate. The results suggest that 28 out of 36 WS phytochemicals show higher affinity for MMP-2 owing to bind with active site residues of S1′-pocket with lower binding energy and smaller inhibition constant (Ki) than considered inhibitors. As well as, withanolide G and withafastuosin E show higher affinity for MMP-9 than reverse hydroxamate inhibitor. These phytochemicals have neuroprotective potential as an inherently useful oral drug to combat ischemic and hemorrhagic stroke mediated by gelatinases.
Withania somnifera (Ashawagandha) is very revered herb of the Indian Ayurvedic system of medicine as a Rasayana (tonic). It is used for various kinds of disease processes and specially as a nervine tonic. Considering these facts many scientific studies were carried out and its adaptogenic / anti-stress activities were studied in detail. In experimental models it increases the stamina of rats during swimming endurance test and prevented adrenal gland changes of ascorbic acid and cortisol content produce by swimming stress. Pretreatment with Withania somnifera (WS) showed significance protection against stress induced gastric ulcers. WS have anti-tumor effect on Chinese Hamster Ovary (CHO) cell carcinoma. It was also found effective against urethane induced lung-adenoma in mice. In some cases of uterine fibroids, dermatosarcoma, long term treatment with WS controlled the condition. It has a Cognition Promoting Effect and was useful in children with memory deficit and in old age people loss of memory. It was also found useful in neurodegenerative diseases such as Parkinson’s, Huntington’s and Alzeimer’s diseases. It has GABA mimetic effect and was shown to promote formation of dendrites. It has anxiolytic effect and improves energy levels and mitochondrial health. It is an anti-inflammatory and antiarthritic agent and was found useful in clinical cases of Rheumatoid and Osteoarthritis. Large scale studies are needed to
prove its clinical efficacy in stress related disorders, neuronal disorders and cancers.
Key words: Withania somnifera, rejuvenator, adaptogen / anti-stress, anti-tumor, neuroregenerative, anti-arthritic.
doi: 10.4314/ajtcam.v8i5S.9
Drug addiction represents a dramatic dysregulation of motivational circuits that is caused by a combination of exaggerated incentive salience and habit formation, reward deficits and stress surfeits, and compromised executive function in three stages. The rewarding effects of drugs of abuse, development of incentive salience, and development of drug-seeking habits in the binge/intoxication stage involve changes in dopamine and opioid peptides in the basal ganglia. The increases in negative emotional states and dysphoric and stress-like responses in the withdrawal/negative affect stage involve decreases in the function of the dopamine component of the reward system and recruitment of brain stress neurotransmitters, such as corticotropin-releasing factor and dynorphin, in the neurocircuitry of the extended amygdala. The craving and deficits in executive function in the so-called preoccupation/anticipation stage involve the dysregulation of key afferent projections from the prefrontal cortex and insula, including glutamate, to the basal ganglia and extended amygdala. Molecular genetic studies have identified transduction and transcription factors that act in neurocircuitry associated with the development and maintenance of addiction that might mediate initial vulnerability, maintenance, and relapse associated with addiction.
N-methyl-D-aspartate receptors (NMDARs) mediated excitotoxicity has been implicated in multi-neurodegenerative diseases. Due to lack of efficacy and adverse effects of NMDA receptor antagonists, search for herbal remedies that may act as therapeutic agents is an active area of research to combat these diseases. Withania somnifera (WS) is being used for centuries as a nerve tonic and Nootropic agents. The present study targets the in silico evaluation of the neuroprotective efficacy of W. somnifera phytochemicals by inhibition of NMDA receptor-mediated excitotoxicity through allosteric inhibition of the GluN2B containing NMDARs. We predict Blood Brain Barrier (BBB) penetration, mutagenicity, drug-likeness and Human Intestinal Absorption properties of 25 WS phytochemicals. Further, molecular docking was performed to know whether these phytochemicals inhibit the GluN2B containing NMDARs or not. The results suggest that Anaferine, Beta-Sitosterol, Withaferin A, Withanolide A, Withanolide B and Withanolide D inhibit GluN2B containing NMDARs through allosteric mode similar to the well-known selective antagonist Ifenprodil. These phytochemicals have potential as an essentially useful oral drug to counter NMDARs mediated excitotoxicity and to treat multi-neurodegenerative diseases.
A decade ago, we hypothesized that drug addiction can be viewed as a transition from voluntary, recreational drug use to compulsive drug-seeking habits, neurally underpinned by a transition from prefrontal cortical to striatal control over drug seeking and taking as well as a progression from the ventral to the dorsal striatum. Here, in the light of burgeoning, supportive evidence, we reconsider and elaborate this hypothesis, in particular the refinements in our understanding of ventral and dorsal striatal mechanisms underlying goal-directed and habitual drug seeking, the influence of drug-associated Pavlovian-conditioned stimuli on drug seeking and relapse, and evidence for impairments in top-down prefrontal cortical inhibitory control over this behavior. We further review animal and human studies that have begun to define etiological factors and individual differences in the propensity to become addicted to drugs, leading to the description of addiction endophenotypes, especially for cocaine addiction. We consider the prospect of novel treatments for addiction that promote abstinence from and relapse to drug use. Expected final online publication date for the Annual Review of Psychology Volume 67 is January 03, 2016. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
OBJECTIVES:
Withania somnifera has been in use for several thousand years in Ayurveda to treat various neurological disorders. There is, however, not much scientific data on its protective role in neuronal pathology specifically against brain oxidative stress. Hence, an attempt is made in this work for systematic review and meta-analysis of W. somnifera on neurobehavioural disorders induced by brain oxidative stress in rodents.
METHODS:
A systematic search of the effect of W. somnifera on brain oxidative stress-induced neuronal pathology was performed using electronic databases. The systematic review was performed on neurobehavioural parameters, whereas meta-analysis of W. somnifera effect was done on oxidative stress markers (superoxide dismutase, catalase, glutathione peroxidase, glutathione and lipid peroxidation), nitrite, protein carbonyl, AchE, ChAT and Ach of rodent brain. Data were analysed using Review Manager Software.
KEY FINDINGS:
Twenty-eight studies were selected based upon the inclusion and exclusion criteria. W. somnifera appreciably inhibited the neurological abnormalities due to oxidative stress in rodent brain produced by different physical and chemical stimuli. W. somnifera also significantly restored the altered oxidative and other stress markers in different parts of rodent brain.
SUMMARY:
The systematic review provides scientific evidence for the traditional claim of W. somnifera use in different neurological aliments. However, future clinical trials are mandated to establish the therapeutic efficacy and safety in human beings.
KEYWORDS: Indian ginseng; antioxidant; meta-analysis; neuropathology; oxidative stress
Purpose: To investigate the possible modulatory role of root extract of Withania somnifera (WS) in 3-Nitroproiponic acid (3-NP)-induced cognitive impairment and altered level of oxidative defense in discrete areas of rat brain. Methods: 3-NP was administered in a dose of 10 mg/kg for 14 days where as WS root extract (100 and 200 mg/kg) was administered orally along with 3-NP. Cognitive dysfunctions were assessed in Morris water maze and plus-maze performance task paradigms. On
15th day the animals were scarified and reduced glutathione, total glutathione, oxidized glutathione (GSSG), glutathione-S-transferase (GST) and acetylcholinesterase enzyme levels were estimated in
the striatum, cortex and hippocampus of the rat brian.
Results: Chronic WS root extract (100, 200 mg/kg) treatment for a period of 14 days significantly improved 3-NP-induced cognitive impairment in Morris water and plus maze tests (p<0.05). Further, WS root extract treatment significantly restored GSH, total glutathione, oxidized glutathione, GST and attenuated acetylcholinesterase levels in striatum, cortex and hippocampus regions of brain. Conclusion: There is possible neuroprotective effect of WS root extract against a 3-NP- induced neurotoxicity in rats.
Key words: Huntington’s disease, 3-Nitropropionic acid, Oxidative stress, Withania somnifera
Neurodegenerative diseases commonly induce irreversible destruction of central nervous system (CNS) neuronal networks, resulting in permanent functional impairments. Effective medications against neurodegenerative diseases are currently lacking. Ashwagandha (roots of Withania somnifera Dunal) is used in traditional Indian medicine (Ayurveda) for general debility, consumption, nervous exhaustion, insomnia, and loss of memory. In this review, we summarize various effects and mechanisms of Ashwagandha extracts and related compounds on in vitro and in vivo models of neurodegenerative diseases such as Alzheimer's disease and spinal cord injury.