Withania somnifera Regulates Mitochondrial Biogenesis and Energetics in Rat Cortical Neurons: Role of BDNF and SIRT1

Withania somnifera, a psychoactive plant with putative neuroprotective actions, is used in Indian traditional medicine for the treatment of neuropsychiatric and neurodegenerative disorders. However, the key mechanisms underlying the pleiotropic actions of Withania somnifera on the nervous system remain poorly understood. Given converging evidence suggests a critical role for mitochondrial dysfunction in the pathophysiology of neuropsychiatric and neurodegenerative diseases, we hypothesized that Withania somnifera may exert pleiotropic effects via targeting mitochondria. Treatment with Withania somnifera root extract (RE) or the withanolide-withanoside rich fraction (WLS) enhanced cellular ATP levels in rat cortical neurons in vitro and in the neocortex in vivo. In vivo respirometry performed on mitochondria isolated from the neocortex following RE or WLS treatment revealed increased mitochondrial respiration and OxPhos efficiency. Furthermore, WLS treatment evoked increases in mitochondrial mass, and RE and WLS treatments enhanced expression of brain derived neurotrophic factor (BDNF) and Sirtuin 1 (SIRT1), both in vitro and in vivo. Pharmacological inhibitor studies support an important role for BDNF and SIRT1 in the mitochondrial effects of Withania somnifera. Experiments with distinct phytochemical components of WLS identified withanolide A and withanoside IV as key constituents that enhance mitochondrial biogenesis and neuroenergetics. The neuroprotective actions of WLS, withanolide A and withanoside IV against corticosterone-induced neuronal cell death in vitro, required signaling via BDNF and SIRT1. Collectively, these results indicate that Withania somnifera root extract and specific phytochemical constituents robustly influence mitochondria in cortical neurons, contributing to stress adaptation and neuroprotection via BDNF and SIRT1 signaling.