Withaferin-A (WA) was evaluated for its neuroprotective efficacy on the dopamine (DA) neurons of the substantia nigra (SN) and striatum (ST) in aged rats. Wistar albino rats were divided into group I, young (3 months old); group II, aged (24 months old); group III, aged rats supplemented with WA (50 mg/kg bodyweight once per day for 30 days), and group IV, young rats supplemented with WA (50 mg/kg bodyweight). At the end of the experiment period, the animals were subjected to various motor behavior analyses, and were sacrificed by transcardial perfusion. The brains were dissected out and subjected to various analyses, including histological, histomorphometrical, and immunolocalization of the tyrosine hydroxylase (TH) enzyme. The data of rotarod analysis (p < 0.001) showed a significant motor impairment in aged rats (number of falls 10.2 ± 0.86) and reduction in retention time (31.23 ± 2.56 s) compared to young controls (2.41 ± 0.35 and 84.05 ± 5.15 s). The stride length was significantly reduced (p < 0.001) in aged rats (4.21 ± 0.57 and 4.38 ± 0.61 cm) when compared to young control rats (6.98 ± 0.25 and 7.13 ± 0.70 cm). The histomorphometric data of the aged animals showed a significant reduction in the neuronal diameter (p < 0.001), density (p < 0.001), and volume (p < 0.001) in the SN of aged rats when compared to young rats. Immunohistology demonstrated a marked reduction in the levels of TH enzyme in both the SN and ST of aged animals when compared to young rats. Both structural and functional impairments were reversed in the aged animals after the supplementation of WA (p < 0.001). The present study clearly indicates that WA attenuates the ageing-mediated motor degenerative changes in the SN and ST of aged rats and ascertains its neuroprotective potential.

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