Transient Receptor Potential Vanilloid 4 Antagonist Eliminated Age-Related Spatial Memory Deficit in Female Sprague Dawley Rats.

Abstract

The expression of transient receptor potential vanilloid 4 (TRPV4) channels in the brains of normal-aging individuals significantly increases. However, the involvement of TRPV4 activity in age-related memory impairment remains unknown. This study aimed to investigate the role of TRPV4 in spatial memory tasks, hippocampal inflammation, and hippocampal autophagy in adolescent, adult, and aged female rats. Rats of different ages were used: 5, 10, 19, and 19 months treated with a TRPV4 inhibitor. Memory performance was assessed using the Morris water maze (MWM). Molecular changes were evaluated through western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). The hippocampal TRPV4 expression was significantly increased in the aged rats. Furthermore, aged rats exhibited spatial memory decline, which was normalized with TRPV4 antagonist GSK2193874 (GSK219) injection. The senescence-associated β-galactosidase (SA-β-Gal) activity and hippocampal inflammatory cytokine and microglial activation marker levels in the hippocampus of aged rats were significantly increased. Similarly, the phosphoprotein marker levels of autophagy in the hippocampus of aged rats were significantly increased. GSK219 treatment effectively normalized hippocampal SA-β-Gal activity, inflammation, and autophagy in aged rats. TRPV4 hyperactivity was found to induce hippocampal inflammation and neuronal death, leading to spatial memory impairment in normal aging.