Activation of the α7 nicotinic acetylcholine receptor mitigates cognitive deficits in mice with sepsis-associated encephalopathy by inhibiting microglial pyroptosis.

Background: While the α7 nicotinic acetylcholine receptor (α7 nAChR) is implicated in sepsis-associated encephalopathy (SAE), its pathophysiological contributions require further investigation.

Methods: SAE was induced in mice via cecal ligation and puncture (CLP), and microglia were treated with lipopolysaccharide (LPS). PHA-543613 (an α7 nAChR agonist) was used to activate α7 nAChR. To study the role of α7 nAChR in mitophagy and pyroptosis, caspase-1-deficient mice and PTEN-induced kinase 1 (PINK1) small interfering RNA (siRNA) were used. Cognitive function, cerebral oxygen extraction ratio (CERO₂), and brain tissue oxygen pressure (PbtO₂) were measured. Blood-brain barrier (BBB) integrity was evaluated via Evan's blue staining. Mitophagy, pyroptosis, and cytokine levels were analyzed via Western blotting and immunofluorescence.

Results: CLP or LPS treatment significantly down-regulated α7 nAChR protein expression in microglia. The administration of PHA-543613 to activate α7 nAChR not only restored its expression post-sepsis, but also notably decreased BBB permeability and mitigated cognitive deficits. Both α7 nAChR activation and caspase-1 knockout effectively suppressed microglial pyroptosis. The activation of α7 nAChR also promoted mitophagy in microglia. This led to an amelioration of brain tissue hypoxia, as shown by elevated PbtO₂ and reduced CERO₂ levels. The suppression of microglial pyroptosis by α7 nAChR was counteracted when mitophagy was inhibited through the siRNA-mediated silencing of PINK1.

Conclusion: The activation of α7 nAChR reduces pyroptosis by enhancing microglial mitophagy, thereby mitigating SAE.