In vitro screening of neuroprotective activity of Indian medicinal plant Withania somnifera

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Canine cognitive dysfunction (CCD) and Alzheimer's disease (AD) are the most common age-related neurodegenerative disorders affecting millions of pets and people worldwide. It is now well established that both oxidative stress and A[...]peptide have been implicated in the pathogenesis of CCD and AD⁽¹⁾. A[...]peptide is formed and released after the sequential cleavage of the amyloid precursor protein by[...]- and[...]-secretases, respectively. A[...]peptide, a 40-42 amino acid-long peptide, is an important component of senile plaque formation in AD brain⁽²⁾and its toxicity is mediated through the generation of hydrogen peroxide (H₂O₂)^(3,4). Reactive oxygen species (ROS), on the other hand, generate highly electrophilic[...],[...]-unsaturated carbonyl derivatives including acrolein, 4-hydroxy-2-nonenal, and 4-oxononenal from the peroxidation of membrane lipids⁽⁵⁾. In AD brain, levels of acrolein were found to be significantly higher in several brain regions such as in the hippocampus, amygdala, middle temporal gyrus and cerebellum^(6,7). In primary neuronal cultures from the hippocampus, the toxicity of acrolein was higher than 4-hydroxy-2-nonenal⁽⁸⁾. We have recently established on a neuronal cell line SK-N-SH the details of the multiprocess step of the toxicity of acrolein⁽⁹⁾. We showed that, in addition to being a byproduct of lipid peroxidation, acrolein could also potentiate oxidative damage and activate several redox-sensitive pathways.

Incidence rates of age-specific AD in rural India are at least three times lower than those of an age-matched American reference population⁽¹⁰⁾, which could be attributed to genetic, environmental or dietary causes. Withania somnifera (WS) is one of the most important medicinal plants used in the Indian system of traditional medicine as a nootropic agent and brain tonic to restore age-related decline in mental abilities⁽¹¹⁾. The major biochemical constituents of WS are steroidal alkaloids and steroidal lactones saponins, together called withanolides⁽¹²⁾. Presently more than twelve alkaloids and forty withanolides have been identified and characterised from the leaves, roots and berries of Withania species which either exist in free form, i.e. withanone, withaferin A, withanolide A, withanolides...