Abstract
Cumulative evidence suggests that pyroptosis, a new sort of programmed cell death, is closely related to cerebral ischemia/reperfusion (I/R) injury. Our previous studies have testified that vagus nerve stimulation (VNS) was involved in many different neuroprotective and neuroplasticity pathways via α7 nicotinic acetylcholine receptor (α7nAchR), a vital node of the cholinergic anti-inflammatory pathway during cerebral I/R injury. We aimed to determine the neuroprotective effects of VNS through α7nAchR-mediated inhibition of pyroptosis. Focal cerebral ischemic stroke rat models were obtained by middle cerebral artery occlusion for 120 min. Expression of the NLRP3 inflammasome was evaluated using western blotting and immunofluorescence (IF) staining. The neurological deficit score, infarct volume, TUNEL staining findings, transmission electron microscopy findings, and expression of inflammatory cytokines were assessed 3 days after I/R injury. Our findings suggested that the protein expression levels of NLRP3, GSDMD-N, cleaved caspase-1, and ASC gradually increased until they peaked on day 3 after I/R injury. VNS inhibited the expression of pyroptosis-related molecules and decreased the number of pyroptotic cells and membrane pores. Administration of α7nAchR-antagonist and agonist helped in further assessment of the role of α7nAchR in pyroptosis. α7nAchR-agonist mimicked VNS’s neuroprotective effects on the improvement of neurological deficits, the reduction of infarct volumes, and the inhibition of neuronal pyroptosis after cerebral I/R injury. Conversely, the neuroprotection provided by VNS could be reversed by the administration of α7nAchR-antagonist. In conclusion, VNS-induced neuroprotection via inhibition of neuronal pyroptosis was α7nAchR-dependent, highlighting the pivotal role of α7nAChR in suppressing cellular pyroptosis and neuroinflammation. These findings may allow a better understanding of treatment principles for cerebral I/R injury.
Highlights
Ischemic stroke is one of the well-known leading causes of death and long-term disability globally [1,2,3]
As compared to the MCAO groups, GTS-21 downregulated the expression of IL-1β and IL-18 (Fig. 6D, E). These findings suggest that following the cerebral I/R damage, vagus nerve stimulation (VNS) may enhance the levels of α7 nicotinic acetylcholine receptor (α7nAchR)
In the present study, we demonstrated that VNS alleviated cerebral I/R injury by suppressing NLRP3 inflammasome activation and cellular pyroptosis
Summary
Ischemic stroke is one of the well-known leading causes of death and long-term disability globally [1,2,3]. Several studies have focused on neuroinflammation since it plays a crucial role in the pathogenesis of ischemic stroke [4]. Pyroptosis, known as cellular inflammatory necrosis, is a newly discovered type of programmed cell death characterized by cellular swelling and lysis, plasma membrane rupture, and release of pro-inflammatory cytokines, which amplify the inflammatory response [5,6,7]. NLRP3 inflammasome is the most researched and plays a pivotal role in inducing pyroptosis. Many endogenous danger signals produced by cerebral ischemia/reperfusion (I/R) injury activate NLRP3 inflammasome and convert pro-caspase 1 into cleaved caspase-
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