title: Cannabinoid receptor 2 attenuates microglial accumulation and brain injury following germinal matrix hemorrhage via ERK dephosphorylation in vivo and in vitro.
abstract: Microglia accumulation plays detrimental roles in the pathology of germinal matrix hemorrhage (GMH) in the immature preterm brain. However, the underlying mechanisms remain poorly defined. Here, we investigated the effects of a cannabinoid receptor 2 (CB2R) agonist on microglia proliferation and the possible involvement of the mitogen-activated protein kinase (MAPK) family pathway in a collagenase-induced GMH rat model and in thrombin-induced rat microglia cells. We demonstrated that activation of CB2R played a key role in attenuating brain edema, neuronal degeneration, microglial accumulation and the phosphorylated extracellular signal-regulated kinase (p-ERK) protein level 24 h following GMH. In vitro, Western blot analysis and immunostaining indicated that ERK and P38 phosphorylation levels in microglia stimulated by thrombin were decreased after JWH-133 (CB2R selective agonist) treatment in a concentration-dependent manner. Microglia proliferation (EDU + microglia) and inflammatory and oxidative stress responses were attenuated by UO126 (ERK pathway inhibitor) 24 h after thrombin stimulation, an activity that was prevented by AM630 (CB2R selective antagonist). Overall, these findings suggest that activation of the endocannabinoid system might attenuate inflammation-induced secondary brain injury after GMH in rats by reducing microglia accumulation through a mechanism involving ERK dephosphorylation. Enhancing CB2R activation is a potential treatment to slow down the course of GMH in preterm newborns.
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Yihao
authors.initials: Y
authors.lastname: Tao
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Qianwei
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. Electronic address: zhichen@tmmu.edu.cn.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China. Electronic address: gangzhu6666@sina.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D002070:Butadienes / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D020300:Intracranial Hemorrhages / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011897:Random Allocation; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013917:Thrombin; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002070:Butadienes; D002186:Cannabinoids; D007211:Indoles; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D043885:Receptor, Cannabinoid, CB2; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C094023:iodopravadoline
keywords: Cannabinoid receptor 2; MAPK pathway; Microglia; Neonatal stroke; Proliferation