Remimazolam mitigates cerebral ischemia/reperfusion injury by concurrently alleviating damage to the blood-brain barrier and RIP3/MLKL-driven necroptosis

Abstract

The pathogenesis of cerebral ischemia-reperfusion injury centers on neuroinflammation and oxidative stress-induced programmed cell death. Although remimazolam(REM) is a clinically used benzodiazepine sedative, its neuroprotective effects against various cell death modalities remain incompletely characterized. Cerebral ischemia-reperfusion injury induced significant cerebral edema, marked oxidative stress, elevated inflammatory factor expression, and substantial blood-brain barrier disruption. REM treatment significantly improved neurological deficits, reduced cerebral infarction volume, enhanced ZO-1 and occludin expression in the cerebral cortex, decreased Evans blue leakage, protected blood-brain barrier integrity, In the hippocampus, REM treatment also significantly inhibited neuroinflammation and oxidative stress, lowered pro-inflammatory factors (TNF-α and IL-1β), mitigated ROS-induced damage, blocked NLRP3 inflammasome activation, suppressed caspase-1 cleavage and GSDMD channel formation, downregulated RIP3/MLKL expression, reduced necroptosis, and improved motor function in rats. REM ameliorates cerebral ischemia-reperfusion injury through dual inhibition of the neuroinflammatory-oxidative stress cascade and concurrent blockade of both NLRP3/GSDMD-mediated pyroptosis and RIP3/MLKL-driven necroptosis.

Keywords: Blood-brain barrier; Necroptosis; Neuroinflammation; Pyroptosis; Remimazolam.