Resveratrol Alleviates Cognitive Impairment in Chronic Cerebral Hypoperfusion by Targeting Lingo-1, NgR1, p75, and RhoA/ROCK-2 Pathways

Abstract

Background: Chronic cerebral hypoperfusion (CCH), a pathophysiological state linked to vascular dementia and cognitive impairment, involves the NgR1/Lingo-1/p75 signaling complex implicated in neurodegenerative processes. Resveratrol (RES), a neuroprotective compound, was investigated for its potential to mitigate CCH-induced cognitive deficits by targeting this pathway. Objectives: This study examined RES's ability to improve cognitive impairment in CCH by suppressing the NgR1/Lingo-1/p75 complex and downstream RhoA-ROCK2 signaling. Methods: Rats were divided into five groups: Control, CCH + Ethanol (ETH), CCH, CCH + resveratrol (RES), and RES. Chronic cerebral hypoperfusion was induced via permanent bilateral carotid artery occlusion (2VO). Cognitive function was assessed using the Morris Water Maze (MWM). Hippocampal morphology in CA1, CA3, and dentate gyrus (DG) regions was analyzed via H&E staining. The expression levels of Lingo-1, NgR1, P75, RhoA, and ROCK2 signaling pathway were detected by western blot and quantitative real-time PCR (qRT-PCR). Results: Chronic cerebral hypoperfusion rats showed elevated protein expression of Lingo-1, p75, RhoA, and ROCK2, though NgR1 remained unchanged. The RES treatment significantly reduced these protein levels. Similarly, mRNA levels of all five targets increased in CCH, but RES notably lowered Lingo-1 and NgR1 expression. The MWM tests revealed RES improved spatial learning and memory deficits in 2VO rats. H&E staining demonstrated RES’s neuroprotective effects, preserving hippocampal neuron integrity. Conclusions: Resveratrol alleviates CCH-induced cognitive impairment by downregulating the Lingo-1/NgR1/p75 signaling axis and inhibiting RhoA-ROCK2 pathways. These findings highlight RES’s potential as a therapeutic agent for vascular cognitive impairment associated with chronic hypoperfusion.