Non-invasive vagus nerve stimulation reduced neuron-derived IL-1β and neuroinflammation in acute ischemic rat brain

Abstract

Abstract Objective We previously demonstrated that non-invasive vagus nerve stimulation (nVNS) provided during middle cerebral artery occlusion (MCAO) reduces infarct volume and blood–brain barrier disruption. However, the neuroprotective mechanisms of nVNS in stroke damages remain to be examined. This study tested the hypothesis that nVNS attenuates neuron-derived interleukin-1β (IL-1β), a pro-inflammatory cytokine, and neuroinflammation in ischemic brain. Methods Spontaneously hypertensive rats were subjected to a 90-minute MCAO with 24-hour reperfusion (RP). nVNS treated rats received 5 doses of nVNS beginning 30\xa0min after MCAO onset. Results 1) MCAO/RP induced a significant increase of active IL-1β at 24\xa0h and ischemic neurons were the main resource of IL-1β, which were significantly attenuated by nVNS. 2) The activation of the neuronal IL-1β was non-caspase-1-dependent. Both in vivo and in vitro data showed a correlation of intracellular matrix metalloproteinase-9 (MMP-9) activation with IL-1β expression in ischemic neurons. 3) nVNS significantly reversed stroke-induced decrease of neuronal nicotinic acetylcholine receptor α7 subtype (α7nAChR) and reduced neurodegeneration. Conclusion The results suggest that acute ischemic insult triggers a unique molecular injury cascade involving in activation of the MMPs/IL-1β signaling pathway in neurons. nVNS downregulates this signaling pathway via α7nAChR to reduce brain injury.