Abstract
BackgroundOur previous research confirmed that electroacupuncture (EA) stimulus elicits neuroprotective effects against cerebral ischemic injury through α7 nicotinic acetylcholine receptor (α7nAChR)-mediated inhibition of high-mobility group box 1 release mechanism. This study investigated whether the signal transducer of α7nAChR and inhibition of NLRP3 inflammasome are involved in the neuroprotective effects of EA stimulus.MethodsIn adult male Sprague-Dawley rats, the focal cerebral ischemic injury was induced by middle cerebral artery occlusion (MCAO) models for 1.5 h. The expression of NLRP3 inflammasome in the penumbral tissue following reperfusion was assessed by western blotting and immunoflourescent staining. The infarct size, neurological deficit score, TUNEL staining and the expression of proinflammatory factors or anti-inflammatory cytokines were evaluated at 72 h after reperfusion in the presence or absence of either α7nAChR antagonist (α-BGT) or agonist (PHA-543,613).ResultsThe contents of inflammasome proteins were gradually increased after cerebral ischemia/reperfusion (I/R). EA stimulus attenuated NLRP3 inflammasome mediated inflammatory reaction and regulated the balance between proinflammatory factors and anti-inflammatory cytokines. The agonist of α7nAChR induced similar neuroprotective effects as EA stimulus. In contrast, α7nAChR antagonist reversed not only the neuroprotective effects, but also the inhibitory effects of NLRP3 inflammasome and the regulatory effects on the balance between proinflammatory factors and anti-inflammatory cytokines.ConclusionsThese results provided compelling evidence that α7nAChR played a pivotal role in regulating the activation and expression of NLRP3 inflammasome in neurons after cerebral I/R. These findings highlighted a novel anti-inflammatory mechanism of EA stimulus by α7nAChR modulating the inhibition of NLRP3 inflammasome, suggesting that α7nAChR-dependent cholinergic anti-inflammatory system and NLRP3 inflammasome in neurons might act as potential therapeutic targets in EA induced neuroprotection against cerebral ischemic injury.
Highlights
Our previous research confirmed that electroacupuncture (EA) stimulus elicits neuroprotective effects against cerebral ischemic injury through α7 nicotinic acetylcholine receptor (α7nAChR)-mediated inhibition of highmobility group box 1 release mechanism
Cerebral ischemia-reperfusion injury increased the expression of NLRP3 inflammasome proteins in rats To observe the expression of NLRP3 inflammasome at different time points after cerebral I/R, rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min
The expression levels of NLRP3 inflammasome such as NLRP3, procaspase-1, Cl.Caspase-1, gasdermin D (GSDMD), GSDMD-N, proIL-1β and mature IL-1β showed
Summary
Our previous research confirmed that electroacupuncture (EA) stimulus elicits neuroprotective effects against cerebral ischemic injury through α7 nicotinic acetylcholine receptor (α7nAChR)-mediated inhibition of highmobility group box 1 release mechanism. This study investigated whether the signal transducer of α7nAChR and inhibition of NLRP3 inflammasome are involved in the neuroprotective effects of EA stimulus. Our previous studies have reported that EA could relieve neurological disorders, reduce infarct volumes after focal cerebral ischemia (Wang et al 2009) and regulate the Reperfusion Injury Salvage Kinase (RISK) signaling pathway (ERKε, PKC, GSK-3β, STAT3) via cannabinoid receptor 1 (CB1R)(Wang et al 2011) and inhibit neuronal apoptosis(Guo et al 2015; Sun et al 2016; Wei et al 2014; Zhou et al 2013). We demonstrated that EA could attenuate cerebral ischemic injury via regulation of α7nAChR-mediated inhibition of HMGB1 release in rats (Wang et al 2012). The detailed underlying mechanism to regulate inflammation after ischemic stroke remains unclear (Goldman et al 2010)
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