Therapeutic Potential of Withania somnifera (L.) Dunal (Ashwagandha) in Neuronal Plasticity and Recovery after Stroke

Stroke incidence and mortality are rising, and post‑stroke neuronal loss with long‑term disability remains a major challenge. Natural herbal remedies offer a cost‑effective option for recovery. Withania somnifera (Ashwagandha) has documented neuroprotective properties. This review summarizes its role in enhancing neuronal plasticity and post‑stroke recovery. Preclinical studies show that W. somnifera reduces infarct volume, mitigates neuroinflammation, oxidative stress, and apoptosis, while promoting neurotransmitter levels, motor function, and memory. It modulates key proteins (HO‑1, PARP‑1, Sema3A), activates PI3K/Akt pathway, and restores BDNF and SIRT1. However, clinical trials are needed to confirm efficacy in humans.

Introduction
Stroke is a leading cause of death and disability, with increasing global prevalence. Ischemic stroke (85% of cases) results from vessel obstruction, leading to neuroinflammation, oxidative stress, excitotoxicity, and blood‑brain barrier disruption. Post‑stroke complications include cognitive deficits, motor disabilities, and depression. Current treatments are costly and often insufficient, driving interest in affordable herbal remedies. Withania somnifera (Ashwagandha), used in Ayurveda, has shown neuroprotective effects in neurodegenerative diseases. This review explores its potential in post‑stroke recovery.

Botanical and Taxonomical Description
W. somnifera (Solanaceae) grows in tropical regions. Every part (root, leaf, fruit, stem, bark) contains bioactive compounds: alkaloids (withanine, somniferine), withanolides (withaferin A, withanolide A), flavonoids, phenolics, and saponins (Table 1). The hydroalcoholic root extract up to 2000 mg/kg/day is safe in rats, but withaferin A shows cytotoxicity at 0.6 µM, highlighting the need for dose normalization.

Pathophysiology of Stroke
Ischemic stroke causes energy failure, necrosis, inflammation (microglial activation, cytokine release), oxidative stress (ROS, lipid peroxidation), Ca²⁺ overload, and excitotoxicity (glutamate). Blood‑brain barrier disruption (MMP‑9 mediated) worsens damage. These events lead to neuronal death and functional loss.

Neuroprotective Functions of W. somnifera
W. somnifera reduces free radicals, ROS, and lipid peroxidation, while increasing superoxide dismutase, catalase, and vitamins A, C, E. It counteracts β‑amyloid toxicity, modulates AChE, and binds to PARP‑1 (reducing neuronal death). Its bioactive compounds (stigmasterol, withaferin A, withanolide G/B) inhibit PARP‑1. It also upregulates cytoprotective PI3K/mTOR pathway.

Roles in Post‑Stroke Pathophysiology

• In MCAO mice, W. somnifera root extract (200 mg/kg) reduced infarct volume (23.1% vs 35.5%) and improved locomotor activity.

• It increased HO‑1 (antioxidant, anti‑inflammatory) and decreased PARP‑1 (pro‑death) and Sema3A (vascular permeability factor).

• Pretreatment maintained normal AChE levels, increased thiols, reduced lipid peroxidation, and alleviated neurobehavioral deficits.

• It attenuated mitochondrial dysfunction, apoptosis, and cognitive deficits.

• It reduced tissue inflammation and increased neurotransmitters (serotonin, dopamine, norepinephrine, GABA).

• It inhibited gelatinases (MMP‑2/9) in silico, suggesting blood‑brain barrier protection.

W. somnifera and Functional Recovery of Neurons

• In SH‑SY5Y cells, root extract reduced apoptotic markers (annexin V), LDH, and Bax.

• In Parkinson’s models, it reduced microglial activity and neuronal degeneration.

• Aqueous extract protected against glutamate‑induced neurotoxicity in Alzheimer’s models.

• Leaf extract nanoemulsion downregulated TGF‑β1/Smad2 signaling, protecting against neuroinflammation.

• Methanol:chloroform extract counteracted β‑amyloid neurotoxicity.

• Root extract upregulated BDNF and SIRT1, promoting mitochondrial biogenesis and neuroenergetics.

• Withanolide A promoted synaptic reconstruction, axon and dendrite regeneration, and activated PI3K/Akt while inhibiting MAPK.

• Withanone mitigated NMDA‑induced excitotoxicity.

Limitations and Future Directions
Most evidence comes from in vitro, in silico, and animal studies. High‑quality clinical trials are needed to confirm efficacy, establish safe dosing, and evaluate functional recovery, quality of life, and mortality. Further molecular studies should explore HO‑1, BDNF, SIRT1, KLK8, and MAP2 pathways.

Conclusions
W. somnifera exhibits strong neuroprotective properties by reducing inflammation, oxidative stress, apoptosis, and neuronal loss, while promoting neuroplasticity, neurotransmitter levels, and motor recovery. It holds promise as an adjunctive therapy for post‑stroke recovery, but rigorous clinical validation is required before clinical recommendation.

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https://www.xiahepublishing.com/2472-0712/ERHM-2025-00048

The study was recently published in the Exploratory Research and Hypothesis in Medicine.

Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.

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