Protective effects and mechanisms of auricular vagus nerve stimulation in the alleviation of acute ischemic cerebral injury in mice

Abstract

Stroke is a major cause of death and long-term disability. Although numerous treatments have shown neuroprotective effects in animal models of ischemic stroke, their clinical efficacy and safety remain to be further investigated. Previous studies have indicated that vagus nerve stimulation (VNS) may reduce cerebral damage in ischemic stroke, but the specific mechanisms by which VNS achieves this effect in murine cerebral ischemic stroke injury are unclear. In this study, an animal model was designed to investigate the therapeutic effects and mechanisms of auricular vagus nerve stimulation (aVNS) in mice with acute ischemic stroke induced by middle cerebral artery occlusion (MCAO) and reperfusion injury. We focused particularly on the involvement of α4-nicotinic acetylcholine receptor (α4-nAChR) and the molecular signaling pathways mediated by aVNS. Mobility of the animals after acute ischemic stroke, infarct volume, and expression of neuroprotective and damaging factors were analyzed to understand the therapeutic effect and protective mechanism of aVNS on ischemic stroke. Our findings demonstrate that aVNS treatment improved mobility and reduced cerebral infarct volume after acute ischemic stroke. Additionally, administration of α4-nAChR antagonists reversed the protective effects of aVNS on ischemic stroke. Our mechanistic investigations revealed that aVNS mediates protective effects against acute ischemic stroke by reducing inflammatory and apoptotic factors, while enhancing neuronal regeneration factors, through activation of α4-nAChR and the GSK3β/β-catenin pathway. Our results provide clear evidence supporting the use of aVNS as a neuroprotective treatment for ischemic stroke in mice.