WIN55, 212-2 promotes differentiation of oligodendrocyte precursor cells and improve remyelination through regulation of the phosphorylation level of the ERK 1/2 via cannabinoid receptor 1 after stroke-induced demyelination

• Published in: Brain research Vol. 1491; no. 23; pp. 225 - 235
• Main Authors: Sun, Jing, Fang, Yinquan, Chen, Tao, Guo, Jingjing, Yan, Jun, Song, Shu, Zhang, Luyong, Liao, Hong
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 23.01.2013; Elsevier
• Subjects: 212-2; adults; Animals; Antimetabolites; Benzoxazines - pharmacology; Biological and medical sciences; Blotting, Western; brain; Brain Ischemia - pathology; Bromodeoxyuridine; Cannabinoid receptor 1; Cannabinoid Receptor Antagonists - pharmacology; cannabinoids; Cell Differentiation - drug effects; Cell Survival - drug effects; death; Demyelinating Diseases - etiology; Demyelinating Diseases - pathology; Immunohistochemistry; Indicators and Reagents; ischemia; Male; MAP Kinase Signaling System - drug effects; Medical sciences; Microscopy, Electron; Morpholines - pharmacology; myelin basic protein; Myelin basic protein (MBP); Myelin Basic Protein - biosynthesis; myelin sheath; Myelin Sheath - drug effects; Naphthalenes - pharmacology; Neurology; Neuropharmacology; Oligodendroglia - drug effects; Oligodendroglia - ultrastructure; Pharmacology. Drug treatments; Phospho-extracellular signal-regulated kinase 1/2 (p-ERK 1/2); Phosphorylation; Piperidines - pharmacology; protein kinases; Psychodysleptics: hallucinogen; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrazoles - pharmacology; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - drug effects; Rimonabant; signal transduction; stroke; Stroke - complications; Stroke - pathology; Transient middle cerebral artery occlusion (t-MCAO); ultrastructure; Vascular diseases and vascular malformations of the nervous system; Western blotting; WIN55; BD; DAPI: 4; phosphatidylinositol-3 kinase; transient middle cerebral artery occlusion; CNS; Transient middle cerebral artery occlusion (t-MCAO); mitogen-activated protein kinase; oligodendrocyte precursor cells; OPCs; PI3K; transmission electronmicroscopy; ERK 1/2; MBP; phospho-extracellular signal-regulated kinase 1/2; Borna disease; dpi; extracellular signal-regulated kinase 1/2; MCAO; 5-Bromo-2'-deoxyuridine; 6-diamidino-2-phenylindole; Myelin basic protein (MBP); p-ERK 1/2; myelin basic protein; MAPK; t-MCAO; central nervous system; GFAP; nuclear factor; 212-2; WIN55; days post injection; Cannabinoid receptor 1; NF; Phospho-extracellular signal-regulated kinase 1/2 (p-ERK 1/2); glial fibrillary acidic protein; TEM; BrdU; middle cerebral artery occlusion; Phosphorylation; Extracellular signal-regulated protein kinase; Neuroglia; Cardiovascular disease; Vascular disease; Oligodendrocyte; Demyelination; Basic protein; Cannabinoid receptor; Cerebrovascular disease; Nervous system diseases; Stroke; Enzyme; Myelin; Precursor cell; Cerebral disorder; Myelination; Central nervous system disease; Brain ischemia; Differentiation
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2012.11.006

Abstract In stroke, a common cause of neurological disability in adults is that the myelin sheaths are lost through the injury or death of mature oligodendrocytes, and the failure of remyelination may be often due to insufficient proliferation and differentiation of oligodendroglial progenitors. In the current study, we used middle cerebral artery occlusion (MCAO) to induced transient focal cerebral ischemia, and found that WIN55, 212-2 augmented actively proliferating oligodendrocytes measured by CC1 immunoreactive cells within the peri-infarct areas. To establish whether these effects were associated with changes in myelin formation, we analyzed the expression of myelin basic protein (MBP) and myelin ultrastructure. We found that WIN55, 212-2 showed more extensive remyelination than vehicle at 14 days post injection (dpi). The extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway may be involved in OPCs differentiation. To determine the regulatory effect of WIN55, 212-2 post-treatment on phospho-ERK 1/2 (p-ERK 1/2) after ischemia/reperfusion, Western blot analysis was performed. We found that WIN55, 212-2 regulated the phosphorylation level of the ERK 1/2 to promote OPCs survival and differentiation. Notably, cannabinoid receptor 1 is coupled to the activation of the ERK cascade. Following rimonabant combined treatment, the effect of WIN55, 212-2 on regulating the phosphorylation level of the ERK 1/2 was reversed, and the effect of accelerated myelin formation was partially inhibited. Together, we first found that WIN55, 212-2 promoted OPCs differentiation and remyelination through regulation of the level of the p-ERK 1/2 via cannabinoid receptor 1.