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      Kv1.3 channel blockade alleviates cerebral ischemia/reperfusion injury by reshaping M1/M2 phenotypes and compromising the activation of NLRP3 inflammasome in microglia.

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          Abstract

          After cerebral ischemia/reperfusion injury, pro-inflammatory M1-like and anti-inflammatory M2-like phenotypes of microglia are involved in neuroinflammation, in which NLRP3 inflammasome plays an essential role. Kv1.3 channel has been recognized as neuro-immunomodulatory target, but it is not clear as to its role in the neuroinflammation after cerebral ischemic injury. The current study aimed to investigate the issue. Middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and oxygen-glucose deprivation/ reoxygenation (OGD/R) in primary microglia were utilized to mimic disease state of ischemic stroke. Treatment with PAP-1, a Kv1.3 channel blocker, produced a significant improvement in neurological deficit scores and a decrease in infarct volume in MCAO/R model. An increased number of M2-like phenotypic microglia and a reduced number of M1-like phenotypic microglia were observed by immunofluorescent staining in the in vivo model, which was further validated by flow cytometry in vitro. Western blot showed that PAP-1 treatment profoundly reduced cleavage of caspase-1 and IL-1β in vivo and in vitro. Furthermore, PAP-1 administration reduced the number of NLRP3+/Iba1+ cells and NLRP3 protein levels in vivo, while reduced mRNA and protein expression levels of NLRP3 in vitro. Reduced mRNA expression levels of IL-1β in vitro and protein level of IL-1β in vivo were also observed. Taken together, our findings suggested that Kv1.3 channel blockade effectively alleviated cerebral ischemic injury, possibly by reshaping microglial phenotypic response from M1 towards M2, compromising the activation of NLRP3 inflammasome in microglia, and inhibiting release of IL-1β.

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          Author and article information

          Journal
          Exp Neurol
          Experimental neurology
          Elsevier BV
          1090-2430
          0014-4886
          Oct 2020
          : 332
          Affiliations
          [1 ] Graduate College, Liaoning University of Traditional Chinese Medicine, China; Department of neurology, General Hospital of Northern Theater Command, China.
          [2 ] Department of neurology, General Hospital of Northern Theater Command, China.
          [3 ] Department of neurology, General Hospital of Northern Theater Command, China. Electronic address: chszh@aliyun.com.
          Article
          S0014-4886(20)30230-2
          10.1016/j.expneurol.2020.113399
          32652099
          47e2ed0f-2f29-4d26-b98e-6c3bc1f10a59
          History

          Cerebral ischemia/reperfusion injury,NLRP3 inflammasome,Phenotypes,Microglia,Kv1.3 channel

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