Neuroprotective effects of resveratrol through modulation of PI3K/Akt/GSK‐3β pathway and metalloproteases

Abstract

AbstractTo analyze the expressional changes in the PI3K/Akt/GSK‐3β pathway and metalloprotease in the cellular Alzheimer's Disease (AD) model with the effect of antioxidant resveratrol. Neuron‐like cells were obtained by a two‐step method of neuronal differentiation by using a combination of retinoic acid (RA) and brain‐derived factor (BDNF) exposure. Then, the application of the amyloid beta peptide 25–35 (Aβ25‐35) to the cell culture mimicked the environmental toxicity observed in AD. Afterward, cell viability and apoptosis assays were performed to determine whether the resveratrol exerts a cytotoxic and apoptotic effect. Finally, the expressional changes in genes in the cellular AD model with the effect of resveratrol were analyzed by Real‐Time PCR. The analysis in silico was assessed using the STRING V12.0 database in each group. Apoptosis data findings were decreased by 1.5‐fold and 2.5‐fold respectively by Differentiated+Resveratrol (RES) and RES when compared to control but no significant difference was observed between RES and AD model groups. Real‐time PCR analysis results revealed PI3K (3.38‐fold), AKT (3.95‐fold), and RELN (1.99‐fold) expressions were significantly higher (p < .001), and also GSK‐3β, TAU, ADAMTS‐4, ADAMTS‐5, and TIMP‐3 gene expression levels were significantly downregulated (2.53‐, 1.79‐, 2.85‐, 4.09‐, and 6.62‐fold, respectively) in the Differentiated+Aβ + RES groups compared to the Differentiated+Aβ group (p < .001). Network analysis shows the functional enrichment of 23 Alzheimer‐related GO terms in the Wnt signaling, proteolysis, and extracellular matrix organization pathways. Resveratrol has inhibited GSK‐3β by activating the PI3K/Akt insulin pathway in a neurotoxic environment. In addition, TAU, RELN, metalloproteases, and their inhibitors associated with Alzheimer's pathology have been regulated supporting the neuroprotective effect of resveratrol.