Introduction
Acute stroke is characterized by the abrupt onset of significant impairment of the nervous system within a vascular area that affects the brain, spinal cord, and retina, stemming from underlying cerebrovascular disorders.1 Stroke is prevalent among diverse patient populations and can result in substantial morbidity and mortality. Strokes are categorized into two primary types: ischemic and hemorrhagic. Hemorrhagic strokes can be further classified into intracerebral and subarachnoid hemorrhages. Ischemic stroke occurs due to the obstruction of blood vessels, while hemorrhagic stroke is attributed to the rupture of blood vessels or bleeding within the brain. Subarachnoid hemorrhage refers to bleeding in the area surrounding the brain, whereas intracerebral hemorrhage pertains to bleeding that occurs within the brain tissue itself. The incidence of stroke has significantly increased from 1990 to 2021, with a 70.0% rise in prevalence and a 44.0% increase in mortality rates.2 Additionally, the global cost of managing stroke patients is quite high.
The risk factors for stroke include non-modifiable and modifiable factors. Gender, age, sex, and genetic factors are non-modifiable risk factors.3 Obesity, hypertension, diabetes, improper diet, atrial fibrillation, and smoking and alcohol consumption are modifiable risk factors. The pathophysiology of ischemic and hemorrhagic stroke leads to cellular and physiological alterations, which include neuroinflammation, increased oxidative stress, excitotoxicity, and angiopathy. Post-stroke neuroinflammation causes glial cell activation, increased leukocyte infiltration, blood–brain barrier breakdown, and increased cytokine production. Oxidative stress-induced tissue damage includes mitochondrial dysfunction, increased reactive oxygen species formation and lipid peroxidation, and reduced ATP synthesis. In addition, increased cellular Ca2+/Na+ influx, reduced glutamate uptake, and necrosis lead to excitotoxicity. Furthermore, post-stroke pathophysiology includes interrupted blood flow, cerebral edema, and elevated intracranial pressure. These cellular and physiological alterations ultimately lead to cerebral damage and neuronal death.4
A variety of complications are associated with stroke patients, including post-stroke seizures, mobility disabilities, hemiplegic pain, cognitive deficits, emotional fluctuations, and depression.5 The strategies for post-stroke treatment depend on prehospital patient care, emergency diagnostic assessments, and intravenous and intra-arterial therapies.6 Nevertheless, extensive research is currently being conducted to investigate the effectiveness of natural and readily available herbal remedies and Ayurveda for the recovery of neural damage.7W. somnifera is a potential medicinal plant that is used traditionally in Ayurveda. It has numerous therapeutic applications to prevent inflammation, cancer, diabetes, microbial infection, etc. However, extensive research shows that W. somnifera is effective against neurodegenerative diseases.8 The administration of root powder in a rat model demonstrates enhancements in post-traumatic stress disorder, as well as in memory impairments induced by post-traumatic stress disorder in the hippocampus.9W. somnifera has gained significant attention for its potential in addressing post-stroke complications due to its remarkable neuroprotective properties.10 Additionally, W. somnifera extract significantly improves cognitive impairments and reaction time.11 The present article aims to elucidate the role of W. somnifera in post-stroke recovery by enhancing neural functions.
Data curation
Peer-reviewed research articles, such as original research articles, reviews, and case studies, were obtained from databases including PubMed, Web of Science, Scopus, Google Scholar, Medline, and Embase. Only full-length articles published in the English language up to July 2025 were included in this study. The searching strategy included keywords such as W. somnifera, Ashwagandha, stroke, cerebral ischemia, neurodegeneration, neuronal loss, and post-stroke recovery, which were employed for literature searches.
Botanical and taxonomical description of W. somnifera
W. somnifera, commonly known as Ashwagandha, Indian ginseng, winter cherry, and suranjan, flourishes extensively in areas such as India, Africa, Sri Lanka, Pakistan, and the Mediterranean (Fig. 1).12 This species, W. somnifera, is classified under the family Solanaceae and the genus Withania. The growth of this crop necessitates semi-tropical climates characterized by an annual rainfall of 650–750 mm and an optimal temperature range of 20°C to 35°C. Every part of the plant, including the leaves, bark, stem, seeds, and flowers, is rich in various phytochemicals that may enhance neuronal function (Table 1).12,13–17 A recent study has reported the cytotoxic effect of a single bioactive compound, withaferin A, at a minimum concentration of 0.6 µM on SH-SY5Y cells.18 Nevertheless, the hydroalcoholic extract of W. somnifera root, administered at a dosage of 2,000 mg/kg body weight per day, has been demonstrated to be safe, as evidenced in Wistar rats.19 Thus, normalization of dose is crucial for the safe application of W. somnifera phytochemicals and therapeutic accuracy.
Table 1List of phytochemicals reported in different plant parts of W. somnifera
| Plant parts | Name of phytochemicals | Reference |
|---|
| Root | Basic alkaloids: anahygrine, cuscohygrine, pseudotropine, tropine, anaferine, isopelletierine, pseudo-withanine, withananinine, withananine somnine, somniferine, somniferinine. Neutral alkaloids: 3-tropyltigloate. Other alkaloids: Withasomnine, withanine, and visamine. Free amino acids: Glycine, alanine, tyrosine, proline, cystine, glutamic acid, tryptophan, and aspartic acid | 13 |
| Leaf | Withanolides, alkaloids, free amino acids, chlorogenic acid, glycosides, glucose, condensed tannins, and flavonoids, withaferin A | 13 |
| Fruit | Condensed tannins, proteolytic enzymes, and flavonoids. Alanine, glycine, proline, valine, glutamic acid, cystine, tyrosine, hydroxyproline, aspartic acid, and cysteine | 13 |
| Shoots | Crude protein, calcium and phosphorous, Coumarin: scopoletin | 13 |
| Stem | Condensed tannins and flavonoids | 13 |
| Bark | Free amino acids | 13 |
| Root | Steroids, Terpenoids, Alkaloids, Flavonoids, Tannins, Phenol, Anthraquinone, Catechin | 14 |
| Root | withanolide A, 12-deoxywithastromonolide and withaferin A | 15 |
| Leaf and root | Withanolide-A, withanone, withaferin A, withastramonolide, 27-hydroxywithanone, withanoside, physagulin | 16 |
| Root | Phenolic compounds, flavonoids, coumarins tannins, saponins, protein, steroid glycosides, alkaloids, reducing sugars | 17 |
Pathophysiology of stroke
Stroke is the second leading cause of death globally and a significant contributor to disability. Considerable advancements have been made in stroke research through various in vivo and in vitro studies aimed at elucidating the underlying mechanisms of stroke pathogenesis.20 A stroke is characterized by a sudden and unforeseen alteration in neurological function resulting from impaired blood flow to the brain. The primary blood supply to the brain is facilitated by the circle of Willis, which comprises two anterior, two middle, and two posterior cerebral arteries, in addition to the anterior and posterior communicating arteries. Ischemic stroke, which occurs due to insufficient blood and oxygen supply to the brain, accounts for 85% of strokes, in contrast to hemorrhagic stroke, which accounts for 10%–15%. The obstruction of blood vessels in the brain may result from plaque buildup or blood clots. Localized blood clot formation is referred to as thrombosis, while a movable clot is termed embolism.
In atherosclerosis, plaque accumulates on the inner walls of arteries, leading to the narrowing of blood vessels. This results in diminished blood flow, reduced oxygen supply to brain tissue, increased stress, and ultimately cell death or necrosis. Necrosis causes the leakage of cellular debris into the extracellular space, resulting in the loss of neural functions. Neuroinflammation is a significant biological response observed following a stroke. This process involves the activation of resident immune cells (microglia), which is modulated by fibroblast growth factors. These cells subsequently release proinflammatory and anti-inflammatory cytokines, leading to neural damage.21 Furthermore, increased oxidative stress contributes to the formation of cerebral edema. Additionally, excessive influx of Ca2+ and Na+ ions into neurons may lead to cellular damage. Dysfunction of the blood–brain barrier may be observed in both ischemic and hemorrhagic strokes, serving as a major factor in the functional loss of neurons.22 However, blood–brain barrier disruption in the case of ischemic strokes is mediated by acute hyperpermeability largely due to MMP-9,23 while hemorrhagic strokes often exhibit delayed or subtype-specific disruption.20
Neuroprotective functions of W. somnifera
Extensive studies have been conducted to investigate the neuroprotective properties of W. somnifera. It has been observed that W. somnifera facilitates the recovery of neurons by reducing inflammation, oxidative stress, and apoptosis, while also promoting cell proliferation and neurogenesis. Furthermore, W. somnifera mitigates oxidative stress by reducing the production of free radicals, reactive oxygen species, and lipid peroxidation. Additionally, it enhances the activity of superoxide dismutase and catalase. W. somnifera also bolsters antioxidant defense by elevating levels of vitamins A, C, and E, as well as essential metal ions such as Cu2+, Fe2+, and Zn2+.13
Various parts of the W. somnifera plant, including the root, leaf, fruit, shoots, and bark, are abundant in active constituents and secondary metabolites such as alkaloids, flavonoids, phenolics, saponins, steroids, and glycosides (Table 1).24 It possesses a diverse array of withanolide alkaloids that are potentially associated with the activation of the cytoprotective PI3K/mTOR pathway, as well as the reduction of inflammation and oxidative stress.12W. somnifera counteracts the effects of β-amyloid1–42 and modulates acetylcholine and acetylcholinesterase (AChE), thereby decreasing neurotoxicity.25 The bioactive compounds found in W. somnifera, including stigmasterol, withaferin A, withanolide G, and withanolide B, exhibit a strong binding affinity for PARP-1. In this context, the inhibition of PARP-1 is associated with a decrease in neuronal cell death.26 The advantageous effects of W. somnifera against various neurological disorders, such as schizophrenia, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease, have already been documented.27
Roles of W. somnifera in post-stroke pathophysiology
Various studies have already been conducted demonstrating the beneficial effects of W. somnifera in the recovery of stroke outcomes (Fig. 2). Mice subjected to middle cerebral artery occlusion (MCAO) exhibit significant recovery in the infarct region when treated with an aqueous extract of W. somnifera.28 This research indicates that W. somnifera can modulate the expression of key proteins associated with the ischemic–apoptotic cascade. The administration of a root extract of W. somnifera (200 mg/kg body weight) in C57BL/6 mice following permanent distal MCAO in the contralateral cortex demonstrates a significantly reduced infarct volume in the W. somnifera pre-treatment group compared to the vehicle group (23.1 ± 3.4% versus 35.5 ± 2.5%). Furthermore, the W. somnifera-pretreated mice exhibit enhanced locomotor activity after 24 h and one week, indicating a potential for functional recovery following MCAO.28W. somnifera enhances the expression of HO-1 while reducing levels of PARP-1 and Sema3A. HO-1 plays a crucial role in ischemic stroke through its antioxidant, anti-inflammatory, and antiapoptotic properties.29 Among the downstream products of HO-1, previous studies have reported a reciprocal relationship between serum bilirubin levels and carotid atherosclerosis.30 Conversely, PARP-1 is significant in the progression of ischemic stroke and cell death, suggesting that targeting PARP-1 could be a promising therapeutic approach for post-stroke neurodegeneration.31 Furthermore, the vascular permeability factor Sema3A is vital for neuroprotection by regulating immune responses and angiogenesis following ischemic stroke.32 Mice pre-supplemented with the root extract of W. somnifera demonstrate a reduction in tissue inflammation and an increase in neurotransmitters such as serotonin, dopamine, norepinephrine, and GABA after MCAO.33 In this context, the modulation of inhibitory neurotransmitters such as GABA is essential for neuronal plasticity and post-stroke recovery.34 Additionally, serotonergic and dopaminergic medications are utilized to enhance motor functions following a stroke.35 Pretreatment with a hydroalcoholic extract of W. somnifera in Wistar rats over a period of 30 days results in significant improvements in motor function and a decrease in malondialdehyde levels two hours after MCAO.36 Reports indicate that rats pre-supplemented with W. somnifera (300 mg/kg body weight) maintain normal AChE levels, increase thiols, alleviate neurobehavioral deficits, and reduce lipid peroxidation following MCAO.37 In this context, elevated levels of AChE correlate with increased mortality rates in stroke patients and those experiencing post-stroke cognitive decline.38 Thiols serve as cellular antioxidant defense molecules. A decrease in thiol levels leads to heightened oxidative stress, which is linked to the severity of post-stroke conditions.39 Neurobehavioral deficits refer to dysfunctions in locomotor abilities typically observed following cerebral ischemia–reperfusion injury (hereinafter referred to as I/R injury). Likewise, an increase in lipid peroxidation has been documented in both the ipsilateral and contralateral hemispheres of the brain after MCAO.40 Sood et al.41 have shown that pre-supplementation with W. somnifera in MCAO models may alleviate mitochondrial dysfunction, apoptosis, oxidative stress, and cognitive deficits. The liposomal delivery of the ethanolic root extract from the W. somnifera chemotype variety NMITLI-118 exhibits neuroprotective properties against I/R injury following MCAO.42 An in silico study conducted by Kumar et al.43 shows that 28 out of 36 phytochemicals derived from W. somnifera inhibit binding to the catalytic domain of matrix metalloproteinases, specifically MMP-2 and MMP-9. However, this needs to be validated using in vivo experiments. In rodent models, it has been reported that MMP-9 expression peaks during the acute phase of stroke, while MMP-2 expression is elevated in the later stages post-stroke. The heightened levels of MMP-2 and MMP-9 are associated with disruption of the blood–brain barrier.44 Furthermore, MMP-9 is linked to hemorrhagic transformation and neutrophil infiltration within the infarct area.23
W. somnifera and functional recovery of neurons
Cerebral ischemia results in immediate tissue loss in the area affected by stroke, a phenomenon known as infarction. Furthermore, secondary neurodegeneration develops over time due to the ongoing tissue loss in regions connected to the infarct area. Following a stroke, neurons experience stress from inflammation, ischemia, and excitotoxicity. The pathophysiology of stroke onset involves the release of molecules such as ATP and phosphatidylserine, and the binding of complement components (C1q and C3b), along with microglia, to stressed neurons. Consequently, microglial phagocytosis is linked to neuronal loss following a stroke.45 In this context, W. somnifera has been reported to be advantageous in protecting neurons and mitigating neuronal loss (Fig. 3). Research conducted on human neuroblastoma cells (SH-SY5Y) indicates that the root extract of W. somnifera (20 µg/mL) is effective in reducing apoptotic markers (annexin V), terminal cell death parameters such as lactate dehydrogenase, and cell death markers such as Bax (Bcl-2-like protein 4).46 A study performed on the brains of rats with Parkinson’s disease demonstrates that the root extract of W. somnifera leads to a decrease in inflammation, oxidative stress, and microglial activity, ultimately resulting in reduced neuronal degeneration in the cerebral cortex.47 The excessive production of glutamate, an excitatory neurotransmitter, in the brain leads to glutamate excitotoxicity following a stroke, which significantly contributes to neuronal damage and cell death.48 In this context, a study performed on a rat model of Alzheimer’s disease indicates that the aqueous extract of W. somnifera root may offer protection against neurotoxicity induced by glutamate and prevent neuronal loss in the cerebral cortex and hippocampal regions.49 It has been reported that the aqueous extract of W. somnifera leaf, along with its active fractions, is advantageous for synaptic plasticity and the survival of neuronal cells against neuroinflammation and neurodegeneration caused by bacterial lipopolysaccharide. Furthermore, it mitigates apoptotic cell death in neurons and promotes the restoration of neurite outgrowth.50 However, a nanoemulsion could be developed to enhance the delivery of the leaf extract across the blood–brain barrier. TGF-β1 and Smad2 are crucial in the pathogenesis of acute and post-stroke conditions, as these molecules are essential for regulating neuroinflammation, microglial activation, and angiogenesis.51 In this context, the nanoemulsion of W. somnifera leaf extract may be vital in downregulating the TGF-β1 and Smad2 signaling pathways to safeguard against neuronal damage and apoptosis.52 The accumulation of β-amyloid in the brain is regarded as neurotoxic, leading to neuronal loss.53 It is hypothesized that cerebral ischemia contributes to the buildup of β-amyloid in the brain.54 In this context, the methanol:chloroform (3:1) root extract of W. somnifera has been reported to counteract β-amyloid-induced neurotoxicity in human neuronal SK-N-MC cells.25 Corticosterone is known to induce neuronal cell death during cerebral ischemia.55 Reports indicate that the root extract of W. somnifera is effective in protecting against corticosterone-induced neuronal cell death by upregulating the expression of brain-derived neurotrophic factor (hereinafter referred to as BDNF) and SIRT1, which leads to mitochondrial biogenesis and enhances neuroenergetics.56 It has been demonstrated in a mouse model that withanolide A, isolated from W. somnifera, promotes synaptic reconstruction in neurons and facilitates the regeneration of axons and dendrites.57 The leaf extract of W. somnifera has been reported to play a role in neuroregeneration and memory recovery in a mouse model. Research indicates that the W. somnifera leaf extract enhances KLK8 and MAP2 levels, thereby promoting dendritic growth, which is crucial for receiving signals from other neurons.58 The inhibition of the PI3K/Akt pathway is linked to neuronal cell death. In this context, withanolide A activates the PI3K/Akt pathway while inhibiting mitogen-activated protein kinases, leading to neuroprotection.59 Under normal physiological conditions, glutamate plays a crucial role in neural development and synaptic plasticity. However, excessive release and accumulation of glutamate can activate the N-methyl-D-aspartate (NMDA) receptor. NMDA is a postsynaptic receptor that induces excitotoxicity through lipid peroxidation, ultimately resulting in neuronal cell death. In this regard, withanone has been reported to mitigate NMDA-induced excitotoxicity in neuron-like cells.60
Limitations and future research directions
Extensive research indicates that phytochemicals derived from various parts of W. somnifera are effective in reducing neuronal death and promoting neuroprotection by modifying various cellular and physiological processes. However, these investigations have primarily been carried out through in vitro, in silico, and in vivo methodologies. Consequently, the effects of W. somnifera phytochemicals must be experimentally validated in humans to improve therapeutic efficacy. Therefore, it is essential to conduct clinical trials with large cohorts to establish a safe dosage of W. somnifera phytochemicals for human use. Additionally, in vivo studies and behavioral experiments must be performed to elucidate functional recovery metrics, disability, quality of life, recurrent stroke, mortality, and other related factors. Furthermore, future research is necessary to investigate the physiological pathways targeted by W. somnifera to enhance the understanding of post-stroke recovery.
Conclusions
The rising mortality rates associated with stroke and the subsequent neuronal loss are significant concerns for healthcare professionals. This study illustrates how the neuroprotective properties of W. somnifera can facilitate recovery after a stroke. A thorough review of the literature and analysis indicates that W. somnifera is instrumental in enhancing post-stroke recovery. Extracts from various parts of the plant, including fruits, flowers, roots, and leaves, are rich in diverse bioactive compounds. The neuroprotective effects of W. somnifera may aid in post-stroke recovery by mitigating neuroinflammation, apoptosis, and oxidative stress. Furthermore, W. somnifera may enhance post-stroke recovery by reducing mitochondrial dysfunction and neuronal loss, and by promoting neuronal plasticity. Additionally, it may contribute to increased neurotransmitter levels and improved motor functions. The plant also protects the infarct area from neutrophilic infiltration. Utilizing W. somnifera may enhance memory and functional recovery following a stroke. W. somnifera may play a significant role in mitochondrial biogenesis and neuroregeneration. Therefore, it is essential to determine the target-specific effects of W. somnifera on HO-1, BDNF, SIRT1, KLK8, and MAP2. Additionally, future research at the molecular level and clinical trials are recommended to investigate the biological pathways influenced by the active compounds in W. somnifera.
Declarations
Funding
None.
Conflict of interest
No potential conflict of interest was reported by the authors.
Authors’ contributions
Conceptualization, data curation, study design, data compilation, interpretation, original draft writing, formatting, editing and review (SS, AD, MS), original draft editing and review (RPS, SC, AS, SKS). All authors have approved the final version and publication of the manuscript.