Resveratrol Activation of SIRT1–PGC-1α–Mitochondrial Biogenesis, Nrf2–Keap1–Redox Signaling, and AMPK–mTOR–Autophagy Pathways in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disease that is characterized by selective destruction of dopaminergic neurons in the substantia nigra and miscalculated 7-synuclein folds. Current treatment measures are mostly symptomatic and fail to prevent the progression of the disease, hence the need to find disease-modifying interventions. It is beginning to be accumulated that the pathogenesis of PD occurs by the interaction of three mutually dependent pathological mechanisms including mitochondrial dysfunction, oxidative stress, and impaired proteostasis, to create a self-amplifying neurodegenerative loop undermining the efficacy of single-target therapy. Therefore, growing scientific interest has been drawn to modulators that are able to effectively deal with several pathways and reestablish cellular homeostasis.  Resveratrol, a naturally occurring polyphenol that is a derivative of grapes and berries, has emerged as a potential candidate owing to its ability to influence simultaneously the evolutionary-preserved stress-response mechanisms involved in PD. The review summarises existing data on the neuroprotective mechanism of resveratrol through the concurrent activation of the SIRT1PGC1-axis, Nrf2Keap1 redox signaling pathway, and AMPK-mTOR autophagy pathways. SIRT1 activation with resveratrol enhances PGC -1 -mediated mitochondrial biogenesis, which restores bioenergetic efficiency and enhances mitochondrial quality control. At the same time, resveratrol increases Nrf2 signaling, leading to strong up-regulation of antioxidant and phase II detoxification enzymes, which eliminate the harmful generation of reactive oxygen species caused by the malfunction of dysfunctional mitochondria and distorted dopamine production. Simultaneously, resveratrol enhances AMPK activity and suppresses mTOR, thus abating autophagic repression and leading to the removal of the toxic aggregates of alpha-synuclein and destroyed organelles.  Notably, these signaling networks are not performing in isolation; they have much crosstalk, providing a neuroprotective synergist program that targets the fundamental pathological causes of PD. Preclinical studies invariably indicate that resveratrol has been shown to suppress dopaminergic neurodegeneration and enhance motor functioning, but its clinical application has been limited by its inability to penetrate the blood-brain barrier and lack of bioavailability. These pharmacokinetic setbacks could be overcome by the development of formulation regimes and the synthesis of resveratrol analogs. Together, resveratrol is an attractive disease-modifying multi-target therapeutic agent for Parkinson's.