Vagus nerve stimulation protects against cerebral injury after cardiopulmonary resuscitation by inhibiting inflammation through the TLR4/NF-κB and α7nAChR/JAK2 signaling pathways

BACKGROUND: Our previous research proved that vagus nerve stimulation (VNS) improved the neurological outcome after cardiopulmonary resuscitation (CPR) by activating alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) in a rat model, but the underlying mechanism of VNS in neuroprotection after CPR remains unclear.METHODS: In vivo, we established a mouse model of cardiac arrest (CA)/CPR to observe the survival rate, and the changes in inflammatory factors and brain tissue after VNS treatment. In vitro, we examined the effects of alpha 7nAChR agonist on ischemia/reperfusion (I/R)-induced inflammation in BV2 cells under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions. We observed the changes in cell survival rate, the levels of inflammatory factors, and the expressions of alpha 7nAChR/ Janus kinase 2 (JAK2) and toll-like receptor 4 (TLR4) /nuclear factor-kappa B (NF-kappa B).RESULTS: In vivo, VNS preconditioning enhanced functional recovery, improved the survival rate, and reduced hippocampal CA1 cell damage, and the levels of inflammatory mediators after CA/CPR. The application of alpha 7nAChR agonists provided similar effects against cerebral injury after the return of spontaneous circulation (ROSC), while alpha 7nAChR antagonists reversed these neuroprotective impacts. The in vitro results mostly matched the findings in vivo. OGD/R increased the expression of tumor necrosis factor-alpha (TNF-alpha), TLR4 and NF-kappa B p65. When nicotine was added to the OGD/R model, the expression of TLR4, NF-kappa B p65, and TNF-alpha decreased, while the phosphorylation of JAK2 increased, which was prevented by preconditioning with alpha 7nAChR or JAK2 antagonists.CONCLUSION: The neuroprotective effect of VNS correlated with the activation of alpha 7nAChR. VNS may alleviate cerebral IR injury by inhibiting TLR4/NF-kappa B and activating the alpha 7nAChR/JAK2 signaling pathway.