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We previously demonstrated that treatment with nVNS during middle cerebral artery occlusion (MCAO) reduces infarct volume and BBB disruption. Although nVNS was suggested to play its neuroprotective role by initiating a splenic-sympathetic-nerve anti- inflammatory pathway, human study showed that nVNS could directly regulate the activity of brain regions within MCA territories through VN central project. While studying the mechanism of the neuroprotective role of nVNS, we observed that ischemic neurons, rather than active microglia, are the main resource of interleukin-1 (IL-1), pro- inflammatory cytokine, 24-hour after stroke. This study tested the novel hypothesis that nVNS reduced neuron-derived IL-1 and neuroinflammation in acute ischemic rat brain. Spontaneous hypertensive rats were subjected to a 90-minute MCAO with 24-hour of reperfusion (MCAO/RP). nVNS treated rats received 5 stimulations on the skin overlying the cervical vagus nerve beginning at 30-minute after MCAO onset. Control rats received the same stimulations on the quadriceps femoris muscle. We found that MCO/RP induced a significant increase of active IL-β level in ischemic hemispheres, which was significantly attenuated by nVNS. The activation of the neuronal IL-1 is non-caspase-1-dependent. We further demonstrated an intracellular co-localization of IL-1β and MMP-9 in the ischemic rat brain neurons. Selective MMP-2/9 inhibitor significantly reduces IL-1β expression in cytosol of cultured rat primary neurons subjected to 2-hour oxygen-glucose deprivation with 24-hour reoxygenation. Moreover, nVNS reduced MMP-9 expression and attenuated stroke-induced decrease of nicotinic acetylcholine receptor α7 subtype (α7nAChR) in ischemic neurons. The activation of α7nAChR regulates MMP-9 expression and plays a role in neuroprotection by anti-inflammation. Our findings suggested the possibility that at acute stage, ischemic stroke triggers a unique molecular injury cascade involving activation of the MMPs/IL-1β signaling pathway in neurons, which subsequently contributes to BBB damage, neuroinflammation, and neuron degeneration. nVNS downregulates this signaling pathway leading to reduction of brain injury.

Acknowledgements: This study was supported by electroCore, LLC Research grant, and NIH grants (1R21 NS091710 and1RF1NS110724) to Dr. Yi Yang.



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