title: The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling.
abstract: Neuroinflammation remains the primary cause of morbidity and mortality in stroke-induced secondary brain injury. The NOD-like receptor pyrin 3 (NLRP3) inflammasome is involved in diverse inflammatory diseases, including cerebral ischemia, and is thus considered an effective therapeutic target. In the present study, we investigated the neuroprotection of Sinomenine (SINO), a potent natural anti-apoptotic and anti-inflammatory molecule, against cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO) in vivo and in an oxygen glucose deprivation (OGD)-treated astrocytes/microglia model in vitro. SINO administration intraperitoneally alleviated the cerebral infarction, brain edema, neuronal apoptosis, and neurological deficiency after MCAO induction. SINO also attenuated astrocytic and microglial activation in the ischemic hemisphere. NLRP3 inflammasome activation after MCAO and OGD induction, with the up-regulation of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1 and pro-inflammatory cytokines, was significantly inhibited by SINO treatment both in vivo and in vitro. In addition, SINO reversed the OGD-induced inhibition of AMPK phosphorylation in vitro. Further, the suppressive effect of SINO on NLRP3 inflammasomes was blocked by an AMPK inhibitor, Compound C. Our findings demonstrate that SINO exerts a neuroprotective effect in ischemic stroke by inhibiting NLRP3 inflammasomes via the AMPK pathway, which also provides evidence of a novel treatment for clinical stroke therapy.
authors: Department of Neurology, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110016, PR China.
authors: Jing
authors: J
authors: Qiu
authors: Department of Neurology, The 463rd Hospital of PLA, Shenyang, Liaoning 110042, PR China.
authors: Min
authors: M
authors: Wang
authors: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, PR China; Department of Neurosurgery, Dalang Hospital, Dongguan, Guangzhou 523000, PR China.
authors: Jun
authors: J
authors: Zhang
authors: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, PR China.
authors: Qing
authors: Q
authors: Cai
authors: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, PR China.
authors: Dan
authors: D
authors: Lu
authors: Department of Neurology, The 463rd Hospital of PLA, Shenyang, Liaoning 110042, PR China.
authors: Yansong
authors: Y
authors: Li
authors: Department of Neurology, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110016, PR China.
authors: Yushu
authors: Y
authors: Dong
authors: Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710038, PR China. Electronic address: zhaotianzhi1981@163.com.
authors: Tianzhi
authors: T
authors: Zhao
authors: Department of Neurology, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110016, PR China. Electronic address: chsshenyang@sina.cn.
authors: Huisheng
authors: H
authors: Chen
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy*; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009019:Morphinans / Q000627:therapeutic use*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D000066829:Neuroprotection; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy*
chemical_list: D000893:Anti-Inflammatory Agents; D058847:Inflammasomes; D009019:Morphinans; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C009271:sinomenine; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; Glia; Ischemic stroke; NLRP3 inflammasome; Secondary brain injury; Sinomenine