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Glibenclamide Directly Prevents Neuroinflammation by Targeting SUR1-TRPM4-Mediated NLRP3 Inflammasome Activation In Microglia.
He, Yihua; Chang, Yuan; Peng, Yuqin; Zhu, Juan; Liu, Kewei; Chen, Jiancong; Wu, Yongming; Ji, Zhong; Lin, Zhenzhou; Wang, Shengnan; Gupta, Sohan; Zang, Nailiang; Pan, Suyue; Huang, Kaibin.
Afiliação
  • He Y; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Chang Y; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Peng Y; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Zhu J; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Liu K; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Chen J; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Wu Y; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Ji Z; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Lin Z; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Wang S; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Gupta S; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Zang N; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China.
  • Pan S; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China. pansuyue@smu.edu.cn.
  • Huang K; Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou North Avenue 1838#, 510515, Guangzhou, China. hkb@smu.edu.cn.
Mol Neurobiol ; 59(10): 6590-6607, 2022 Oct.
Article em En | MEDLINE | ID: mdl-35972671
ABSTRACT
Glibenclamide (GLB) reduces brain edema and improves neurological outcome in animal experiments and preliminary clinical studies. Recent studies also suggested a strong anti-inflammatory effect of GLB, via inhibiting nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation. However, it remains unknown whether the anti-inflammatory effect of GLB is independent of its role in preventing brain edema, and how GLB inhibits the NLRP3 inflammasome is not fully understood. Sprague-Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. The Trpm4 siRNA and GLB were injected to block sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel in rats. Western blotting, quantitative real-time polymerase chain reaction, behavioral analysis, and histological examination were used to evaluate the role of GLB in preventing NLRP3-mediated neuroinflammation through inhibiting SUR1-TRPM4, and corresponding neuroprotective effect. To further explore the underlying mechanism, BV2 cells were subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion. Here, in rat model of cardiac arrest with brain edema combined with neuroinflammation, GLB significantly alleviated neurocognitive deficit and neuropathological damage, via the inhibition of microglial NLRP3 inflammasome activation by blocking SUR1-TRPM4. Of note, the above effects of GLB could be achieved by knockdown of Trpm4. In vitro under circumstance of eliminating distractions from brain edema, SUR1-TRPM4 and NLRP3 inflammasome were also activated in BV2 cells subjected to lipopolysaccharides, or oxygen-glucose deprivation/reperfusion, which could be blocked by GLB or 9-phenanthrol, a TRPM4 inhibitor. Importantly, activation of SUR1-TRPM4 in BV2 cells required the P2X7 receptor-mediated Ca2+ influx, which in turn magnified the K+ efflux via the Na+ influx-driven opening of K+ channels, leading to the NLRP3 inflammasome activation. These findings suggest that GLB has a direct anti-inflammatory neuroprotective effect independent of its role in preventing brain edema, through inhibition of SUR1-TRPM4 which amplifies K+ efflux and promotes NLRP3 inflammasome activation.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Edema Encefálico / Fármacos Neuroprotetores / Canais de Cátion TRPM / Parada Cardíaca Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Edema Encefálico / Fármacos Neuroprotetores / Canais de Cátion TRPM / Parada Cardíaca Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article