title: Possible Role of Raf-1 Kinase in the Development of Cerebral Vasospasm and Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats.
abstract: This study aims to clarify the potential role of Raf-1 kinase in cerebral vasospasm (CVS) and early brain injury (EBI) after subarachnoid hemorrhage (SAH). Two experimental SAH models in rats, including cisterna magna double injection model for CVS study and prechiasmatic cistern single injection model for EBI study, were performed in this research. As a specific inhibitor of Raf-1, BAY 43-9006 was used in this study. In CVS study, time course study showed that the basilar artery exhibited vasospasm after SAH and became most severe at day 5, and the phosphorylation of Raf-1 had the same trends, while both vasospasm and the phosphorylation of Raf-1 induced by SAH were inhibited by BAY 43-9006 treatment. In addition, BAY 43-9006 treatment significantly reversed the phosphorylation of ERK1/2 and the activation of NF-κB induced by SAH and decreased the messenger RNA (mRNA) levels of IL-6 and IL-1β. In EBI study, BAY 43-9006 treatment significantly suppressed the brain injury induced by SAH. Besides, BAY 43-9006 inhibited the phosphorylation of Raf-1 and ERK1/2; decreased the protein levels of COX-2, VEGF, and MMP-9; and reversed the activation of NF-κB induced by SAH. These results demonstrate that Raf-1 kinase contributes to CVS and EBI after SAH by enhancing the activation of the Raf-1/ERK1/2 and Raf-1/NF-κB signaling pathways, and that the inhibition of these pathways might offer new treatment strategies for CVS and EBI.
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, People's Republic of China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, People's Republic of China.
authors.forename: Dai
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, People's Republic of China.
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, People's Republic of China.
authors.forename: Wanchun
authors.initials: W
authors.lastname: You
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, People's Republic of China. Dr.zhongwang@gmail.com.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, 215006, Jiangsu Province, People's Republic of China. nju_neurosurgery@163.com.|Institute of Neuroscience, Soochow University, Suzhou, Jiangsu Province, China. nju_neurosurgery@163.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000503:physiopathology / Q000648:ultrastructure; D001812:Blood-Brain Barrier; D001925:Brain Damage, Chronic / Q000201:enzymology* / Q000209:etiology; D001929:Brain Edema / Q000209:etiology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D013345:Subarachnoid Hemorrhage / Q000150:complications*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D020301:Vasospasm, Intracranial / Q000201:enzymology* / Q000209:etiology
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D009536:Niacinamide; D000077157:Sorafenib; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D019908:Proto-Oncogene Proteins c-raf; C546782:Raf1 protein, rat; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: BAY 43-9006; Cerebral vasospasm; Early brain injury; Raf-1; Subarachnoid hemorrhage