Resveratrol shows neuroprotective effects in preclinical studies across a number of neurodegenerative illnesses, including Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's disease (HD), and it enhances mitochondrial function through stimulation of the AMPK/SIRT1/PGC-1α pathway, thereby improving mitochondrial oxidative capacity and ATP generation. The natural polyphenol lowers α-synuclein accumulation and affects autophagy; both markers of PD. Combining nano‑resveratrol formulations with L‑DOPA has shown greater therapeutic efficacy in animal models (MPTP mouse), while co‑administration with EGCG has shown synergistic neuroprotection in vitro (SH‑SY5Y cells). These combination strategies offer potential advantages in neuroprotection and symptom alleviation while minimizing adverse drug effects. Resveratrol activates SIRT1 and AMPK signaling in preclinical models, enhancing mitochondrial biogenesis, lowering apoptosis, and restoring cellular resilience. The effectiveness of various models and dosages varies. The primary mechanism by which resveratrol promotes neuronal survival and remyelination in multiple sclerosis is through SIRT1 activation, which does not directly reduce inflammation. As innovative delivery systems, intranasal nanoparticles and exosomes produced from macrophages have shown improved CNS targeting accuracy. Resveratrol slows down neurodegeneration and improves the prognosis of HD by improving motor function and stimulating mitochondrial biogenesis in addition to activating neuroprotective ERK signaling. All of these results point to resveratrol's several pathways as a strong contender for neurodegenerative disease adjunctive treatment. The current evidence base is insufficient to support clinical use of resveratrol for any of the four diseases. Further rigorous preclinical studies (including TDP-43 models for ALS, SIRT1 knockout studies, and human-feasible dosing) and well-designed clinical trials with pharmacokinetic endpoints are required before any clinical recommendations can be made.
