DCPIB, a potent volume-regulated anion channel antagonist, Attenuates microglia-mediated inflammatory response and neuronal injury following focal cerebral ischemia
| Autor: | Shengwen Liu, Jing-cao Chen, Feng Hu, Qiang Zhang, Qingdong Han, Ting Lei, Huaqiu Zhang, Min Zhou, Zhengwei Li |
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| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Time Factors p38 mitogen-activated protein kinases Cyclopentanes Pharmacology Hippocampus Mice medicine Animals Hypoxia Molecular Biology Cells Cultured Neuroinflammation Neurons CD11b Antigen biology Microglia business.industry General Neuroscience Glutamate receptor Neurotoxicity Infarction Middle Cerebral Artery medicine.disease Coculture Techniques Rats Disease Models Animal Glucose Ki-67 Antigen medicine.anatomical_structure Animals Newborn nervous system Brain Injuries Mitogen-activated protein kinase Indans biology.protein Cytokines Neurology (clinical) Neuron business Neuroscience Developmental Biology |
| Zdroj: | Brain Research. 1542:176-185 |
| ISSN: | 0006-8993 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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