Resveratrol Analogs Ameliorate Mitochondrial Impairment and Insulin Resistance in a Streptozotocin-Induced In Vitro Model of Alzheimer’s Disease

Alzheimer's disease (AD) is characterized by mitochondrial dysfunction, oxidative stress, insulin resistance, and aberrant protein aggregation. Neurodegeneration model with neuronal insulin resistance was induced in SH-SY5Y human neuroblastoma cells by streptozotocin (STZ). We evaluated the neuroprotective effects of resveratrol (RZV) and three structural analogs: oxyresveratrol (OXI), monomethyl resveratrol (MONO), and trimethyl resveratrol (TRI). Mitochondrial function, plasma membrane integrity, oxidative stress) and autophagy were studied by fluorescent assays. Phosphorylated GSK3 levels were measured by ELISA as an indicator of insulin sensitivity. TRI exhibited significant mitochondrial protective effects and strongly induced autophagy. OXI demonstrated excellent antioxidant activity but showed no detectable mitochondrial protective or autophagy-inducing effects. RZV and MONO exhibited moderate antioxidant effects along with strong insulin-sensitizing and autophagy-inducing properties. Insulin sensitivity was most potently restored by RZV (IC₅₀ = 54 pM) and MONO (IC₅₀ = 50 pM), whereas TRI (IC₅₀ = 160 pM) was less potent, and OXI (IC₅₀ = 97 pM) showed moderate potency. Our findings suggest that the neuroprotective effects of resveratrol analogs significantly depend on their molecular structure and that they exert their beneficial effects through distinct mechanisms. This research may contribute to the development of novel, multi-target compounds for the treatment of neurodegenerative diseases.