title: DCPIB, a potent volume-regulated anion channel antagonist, attenuates microglia-mediated inflammatory response and neuronal injury following focal cerebral ischemia.
abstract: Accumulating evidence indicates that extensive microglia activation-mediated local inflammation contributes to neuronal injury in cerebral ischemia. We have previously shown that 4-(2-butyl-6, 7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), a potent volume-regulated anion channel (VRAC) inhibitor, suppresses pathological glutamate release and excitatory neurotoxicity in reversible middle cerebral artery occlusion (rMCAO) model in vivo. In the present study, we sought to determine whether DCPIB also attenuates microglia activation that could contribute to neuronal injury in the cerebral ischemia/reperfusion pathology. We show that oxygen-glucose deprivation (OGD) induced microglia proliferation, migration, and secretion of cytokines and all these pathological changes were effectively inhibited by DCPIB in vitro. In the microglia/neuron co-cultures, OGD induced neuronal damage was reduced markedly in the presence of DCPIB. In rat rMCAO animal model, DCPIB significantly attenuated microglia activation and neuronal death. Activation of mitogen-activated protein kinase (MAPK) signaling pathway is known to be a critical signaling pathway for microglia activation. We further explored a potential involvement of DCPIB in this pathway by western blot analysis. Under the conditions that MAPK pathway was activated either by lipopolysaccharides (LPS) or OGD, the levels of phosphorylated ERK1/2, JNK and p38 were reduced significantly in the presence of DCPIB. Altogether, our study demonstrated that DCPIB inhibits microglia activation potently under ischemic conditions both in vitro and in vivo. The DCPIB effect is likely attributable to both direct inhibition VRAC and indirect inhibition of MAPK pathway in microglia that are beneficial for the survival of neurons in cerebral ischemic conditions.
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Qingdong
authors.initials: Q
authors.lastname: Han
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Shengwen
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Feng
authors.initials: F
authors.lastname: Hu
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, Ohio, 43210, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Jingcao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430030, PR China.
authors.forename: Ting
authors.initials: T
authors.lastname: Lei
authors.affiliation: Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong, University of Science and Technology, Wuhan 430030, PR China. Electronic address: zhanghq_04@yahoo.com.
authors.forename: Huaqiu
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000150:complications* / Q000188:drug therapy / Q000209:etiology; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003517:Cyclopentanes / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D013997:Time Factors
chemical_list: C443139:4-(2-butyl-6,7-dichlor-2-cyclopentyl-indan-1-one-5-yl)oxybutyric acid; D039481:CD11b Antigen; D003517:Cyclopentanes; D016207:Cytokines; D007189:Indans; D019394:Ki-67 Antigen; D005947:Glucose
keywords: 4-(2-butyl-6, 7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid; Cerebral ischemia; DCPIB; ELISA; IF; IL-1β; LPS; MAPK; Microglia; Neuroinflammation; OGD; RVD; TNF-α; VRAC; Volume-regulation anion channels (VRACs); enzyme-linked immunosorbent assay; immunofluorescence; interlukin-1β; lipopolysaccharides; mitogen-activated protein kinase; oxygen-glucose deprivation; rMCAO; regulatory volume decrease; reversible middle cerebral artery occlusion; tumor necrosis factor α; volume-regulated anion channel