Neuroprotection by Resveratrol in Chronic Cerebral Hypoperfusion: A Study on Synaptogenesis Enhancement and Apoptosis Inhibition

Background: Chronic cerebral hypoperfusion (CCH) is a key contributor to vascular dementia (VaD) and Alzheimer’s disease. Resveratrol (RSV), a polyphenol with potential neuroprotective properties, may mitigate CCH-induced neuronal damage, but its mechanisms remain unclear. Objectives: This study investigated RSV’s effects on memory enhancement through synaptogenesis and apoptosis inhibition in the hippocampus in a rat CCH model. Methods: Forty male rats were randomly divided into four groups: Sham, 2-VO (bilateral carotid artery occlusion), 2-VO+RSV (2.5 mg/kg), and 2-VO+RSV (5 mg/kg). Initial group sizes (n = 10 each) were maintained by replacing deceased animals (2-VO: 7, 2-VO+RSV2.5: 4, 2-VO+RSV5: 6 deaths). The RSV was administered via intraperitoneal injection (ip) for 35 days post-surgery. Cognitive function was assessed using Morris water maze (MWM) and shuttle box tests. Hippocampal mRNA/protein levels of B-cell lymphoma 2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase-3, Ras homolog family member A (RhoA), Rho-associated coiled-coil containing protein kinase 2 (ROCK2), calcium/calmodulin-dependent protein kinase II alpha (CaMKII-α), and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B) were measured. Results: The RSV (5 mg/kg) significantly improved spatial memory in the MWM. Also, RSV at doses of 2.5 and 5 mg/kg significantly increased the entrance latency to the dark compartment (P < 0.05 and P < 0.01 vs 2-VO, respectively). There was a downregulation of pro-apoptotic markers (Bax, Caspase-3) and Rho/ROCK gene expressions, and an upregulation of anti-apoptotic Bcl-2 gene expression and synaptic proteins (CaMKII-α, NMDAR2B) after RSV treatment. The RSV at 5 mg/kg significantly reduced the Bax/Bcl-2 ratio compared to the 2-VO group. Conclusions: The RSV protects against CCH-induced neuronal damage by inhibiting apoptosis and enhancing synaptic plasticity. These findings highlight RSV’s therapeutic potential for vascular cognitive impairment.