Joshi_2026_Naunyn.Schmiedebergs.Arch.Pharmacol__

Amyloid beta (Abeta)-induced neuronal dysfunction is a key pathological feature of Alzheimer's disease (AD), characterized by oxidative stress, mitochondrial impairment, and calcium dyshomeostasis. Transient receptor potential canonical 5 (TRPC5), a calcium-permeable cation channel, has been implicated in neurodegeneration, but its role in AD remains unclear. This study investigated TRPC5 involvement in Abeta-induced neurotoxicity and evaluated the neuroprotective potential of Clemizole, a TRPC5 blocker, in preclinical AD models. In SH-SY5Y cells, Abeta-induced neurotoxicity was assessed by measuring cell viability, intracellular and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential, and calcium influx. In rats, an intracerebroventricular (ICV) Abeta(25-35) (10 microg) induced cognitive impairment model was used. Behavioral tests assessed cognitive function. Hippocampal TRPC5 expression and memory as well as calcium associated protein expressions (p-CaMKII, PSD-95, BDNF, calcineurin A) were analyzed, and acetylcholinesterase (AChE) activity was measured following 3 weeks of Clemizole (10 and 30 mg/kg) treatment. Abeta exposure reduced neuronal survival, increased ROS, disrupted mitochondrial membrane potential, and elevated calcium influx in vitro. Clemizole mitigated oxidative stress, restored mitochondrial function, and restored calcium homeostasis. In vivo, Abeta induced cognitive deficits and upregulated hippocampal TRPC5 expression in rats. Clemizole reduced TRPC5 levels, improved cognitive performance, enhanced p-CaMKII, PSD-95, and BDNF expression, decreased calcineurin A, and reduced AChE activity. TRPC5 contributes to Abeta-induced neurotoxicity and cognitive impairment, and Clemizole-mediated TRPC5 inhibition confers neuroprotection by restoring calcium balance and attenuating the decrease in memory-associated protein expression. These findings support TRPC5 as a potential therapeutic target in AD; however, further studies using a transgenic AD model are warranted before clinical translation.