Remimazolam and dexmedetomidine prevent cognitive decline by affecting lipopolysaccharide-induced brain injury in mice: Possible involvement of the vagus nerve pathway

Sepsis-associated encephalopathy (SAE) is a critical neurological complication of sepsis with limited therapeutic options. This study investigated the neuroprotective potential of remimazolam (REMI) and dexmedetomidine (DEX) in a lipopolysaccharide (LPS)-induced murine model of SAE. We assessed cognitive function via trace fear conditioning, hippocampal CA3 neuronal integrity, neuroinflammatory markers (TNF-α, IL-6, IL-1β), blood-brain barrier (BBB) permeability through hippocampal albumin levels, and lung Netrin-1 expression as an indicator of vagus nerve pathway activity. LPS administration resulted in significant cognitive deficits, CA3 neuronal damage, elevated systemic and central pro-inflammatory cytokines, increased BBB permeability, and reduced lung Netrin-1. Pre-treatment with either REMI or DEX substantially ameliorated these LPS-induced neuropathological changes and cognitive impairments. Notably, the protective effects of both agents on cognitive function were significantly attenuated by the α7 nicotinic acetylcholine receptor (α7nAChR) antagonist, methyllycaconitine. These findings suggest that REMI and DEX exert neuroprotective effects against LPS-induced acute brain injury and cognitive decline, likely mediated, at least in part, through the α7nAChR pathway, highlighting their potential therapeutic relevance in mitigating SAE.