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Withania somnifera (WS), popularly known as 'Ashwagandha' has been used for centuries as a nerve tonic. Its protective effect has been elucidated in many neurodegenerative pathologies, although there is a paucity of data regarding its effects in ischemic stroke. We examined the neuroprotective properties of an aqueous extract of WS in both pre- and poststroke treatment regimens in a mouse model of permanent distal middle cerebral artery occlusion (pMCAO). WS (200 mg/kg) improved functional recovery and significantly reduced the infarct volume in mice, when compared to those treated with vehicle, in both paradigms. We investigated the protective mechanism/s induced by WS using brain cortices by testing its ability to modulate the expression of key proteins in the ischemic-apoptotic cascade. The Western blots and immunofluorescence analyses of mice cortices revealed that WS upregulated the expression of hemeoxygenase 1 (HO1) and attenuated the expression of the proapoptotic protein poly (ADP-ribose) polymerase-1 (PARP1) via the PARP1-AIF pathway, thus preventing the nuclear translocation of apoptosis-inducing factor (AIF), and subsequent apoptosis. Semaphorin-3A (Sema3A) expression was reduced in WS-treated group, whereas Wnt, pGSK3β, and pCRMP2 expression levels were virtually unaltered. These results indicate the interplay of antioxidant-antiapoptic pathways and the possible involvement of angiogenesis in the protective mechanism of WS while emphasizing the noninvolvement of one of the prime pathways of neurogenesis. Our results suggest that WS could be a potential prophylactic as well as a therapeutic agent aiding stroke repair, and that part of its mechanism could be attributed to its antiapoptotic and antioxidant properties. [ABSTRACT FROM AUTHOR]