Remimazolam alleviates hippocampal neuronal injury in an in vitro Alzheimer's disease model by promoting PINK1/Parkin-mediated mitophagy.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated tau proteins. Remimazolam (RMZ), a novel ultra-short-acting benzodiazepine, exhibits neuroprotective effects by enhancing mitochondrial autophagy independently of traditional GABAergic mechanisms. This study investigates the protective role of RMZ against Aβ1-42-induced neuronal damage through PINK1/Parkin-mediated mitophagy. In hippocampal HT22 cells, RMZ significantly attenuated Aβ1-42-induced cytotoxicity, reduced apoptosis, suppressed reactive oxygen species (ROS) production, and decreased lactate dehydrogenase (LDH) release. Moreover, RMZ ameliorated mitochondrial membrane depolarization and tau hyperphosphorylation, while enhancing mitophagy, evidenced by an increased LC3-II/LC3-I ratio, elevated Beclin-1 expression, and decreased P62 levels. Mechanistically, RMZ upregulated PINK1 and Parkin expression, facilitating mitochondrial recruitment and clearance of damaged mitochondria. Importantly, knockdown of PINK1 abolished RMZ's protective effects, confirming the pathway's specificity. These findings suggest that RMZ promotes mitochondrial homeostasis and offers a promising strategy for AD therapy via PINK1/Parkin-mediated mitophagy.