Abstract
Inflammation and apoptosis play critical roles in the acute progression of ischemic injury pathology. Emerging evidence indicates that vagus nerve stimulation (VNS) following focal cerebral ischemia and reperfusion (I/R) may be neuroprotective by limiting infarct size. However, the underlying molecular mechanisms remain unclear. In this study, we investigated whether the protective effects of VNS in acute cerebral I/R injury were associated with anti-inflammatory and anti-apoptotic processes. Male Sprague-Dawley (SD) rats underwent VNS at 30 min after focal cerebral I/R surgery. Twenty-four h after reperfusion, neurological deficit scores, infarct volume, and neuronal apoptosis were evaluated. In addition, the levels of pro-inflammatory cytokines were detected using enzyme-linked immune sorbent assay (ELISA), and immunofluorescence staining for the endogenous “cholinergic anti-inflammatory pathway” was also performed. The protein expression of a7 nicotinic acetylcholine receptor (a7nAchR), phosphorylated Akt (p-Akt), and cleaved caspase 3 in ischemic penumbra were determined with Western blot analysis. I/R rats treated with VNS (I/R+VNS) had significantly better neurological deficit scores, reduced cerebral infarct volume, and decreased number of TdT mediated dUTP nick end labeling (TUNEL) positive cells. Furthermore, in the ischemic penumbra of the I/R+VNS group, the levels of pro-inflammatory cytokines and cleaved caspase 3 protein were significantly decreased, and the levels of a7nAchR and phosphorylated Akt were significantly increased relative to the I/R alone group. These results indicate that VNS is neuroprotective in acute cerebral I/R injury by suppressing inflammation and apoptosis via activation of cholinergic and a7nAchR/Akt pathways.
Highlights
Acute cerebral ischemia triggered by interruption of blood flow can cause rapid activation of a variety of detrimental cellular processes, including excitotoxicity, oxidative and nitrosative stress, cortical spreading depolarization, inflammation, necrosis, and apoptosis [1,2]
There was no significant difference in heart rate (HR) during baseline between the ischemia and reperfusion (I/R)+vagus nerve stimulation (VNS) group and other groups (p.0.05)
We found that the expression of a7 nicotinic acetylcholine receptor (a7nAchR) in brain could be regulated by VNS treatment after I/R in rats, suggesting that the neuroprotective effect induced by VNS may be partly due to the up-regulation of a7nAchR expression
Summary
Acute cerebral ischemia triggered by interruption of blood flow can cause rapid activation of a variety of detrimental cellular processes, including excitotoxicity, oxidative and nitrosative stress, cortical spreading depolarization, inflammation, necrosis, and apoptosis [1,2]. It is known that revascularization of occluded blood vessels is the most effective treatment for patients with acute ischemic stroke [3]. Reperfusion may cause secondary injury via mitochondrial dysfunction, excessive release of glutamate, and overproduction of pro-inflammatory mediators and reactive oxygen species (ROS). These factors directly influence the prognosis of stroke patients [4], and controlling excessive inflammatory response is an important therapeutic challenge. The molecular mechanisms underlying VNS-mediated neuroprotection are still unknown
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