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September 16, 2025

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

Key Points

Activation of α7 nAChR leads to reduced cognitive deficits in mice with sepsis-associated encephalopathy, and supports brain health.
Increased brain tissue oxygen pressure and decreased cerebrovascular resistance were noted after α7 nAChR activation, showing enhanced brain function.
Animal study used caspase-1 knockout and siRNA to elaborate on the mechanisms of α7 nAChR and microglial pyroptosis.
Findings suggest that enhancing mitophagy can alleviate symptoms of sepsis-associated encephalopathy, but pathways may need further exploration.

Abstract

While the α7 nicotinic acetylcholine receptor (α7 nAChR) is implicated in sepsis-associated encephalopathy (SAE), its pathophysiological contributions require further investigation. 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. 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. The activation of α7 nAChR reduces pyroptosis by enhancing microglial mitophagy, thereby mitigating SAE.

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