Citronellal improves ischemia-induced pathological senescence of hippocampal neurons and cognitive impairment via regulation of the TRPM2/NMDAR pathway.

Vascular dementia (VaD) is associated with chronic cerebral hypoperfusion, oxidative stress, mitochondrial dysfunction, and hippocampal neuronal senescence. Citronellal (CT) ameliorates cognitive impairment in 2VO-induced VaD rats. CT improved spatial learning and working memory, reduced in vivo oxidative stress, restored hippocampal dendritic spine density, upregulated hippocampal myelin basic protein (MBP), and decreased P-p53, p21, and SA-β-gal. CT also restored mitochondrial membrane potential and reduced Drp1/FIS1 expression. Mechanistically, CT suppressed TRPM2 and restored NMDAR1; TRPM2 deficiency weakened CT-mediated NMDAR1 regulation. These findings suggest that CT ameliorates VaD-related cognitive impairment by inhibiting hippocampal aging through TRPM2/NMDAR-associated oxidative stress-mitochondrial pathways.