title: Suppression of the Rho/Rho-kinase pathway and prevention of cerebral vasospasm by combination treatment with statin and fasudil after subarachnoid hemorrhage in rabbit.
abstract: The Rho/Rho-kinase pathway is considered important in the pathogenesis of sustained smooth muscle cell contraction during cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The aims of this study were to investigate whether combination treatment, with pitavastatin as an inhibitor of RhoA and fasudil as an inhibitor of Rho-kinase, prevents the cerebral vasospasm. SAH was simulated using the double-hemorrhage rabbit model, and pitavastatin, or fasudil, or both (combination treatment) were administrated. The basilar artery (BA) cross-sectional area only in the combination treatment group was statistically larger than in the SAH group (p<0.05). BA Rho-kinase, as measured by ELISA, was statistically reduced only in the combination treatment group compared with the SAH group (p<0.05). In the other two treatment groups, pitavastatin or fasudil treatment group showed larger BA cross-sectional areas and lower value for BA Rho-kinase, but there were no statistically significant differences compared with the SAH group. The expression of endothelial nitric oxide synthase (eNOS), evaluated by immunohistochemistry in the pitavastatin group and the combination group, was higher than in the SAH group. Results indicate that combination treatment could extensively prevent cerebral vasospasm due to the synergic effect of combining pitavastatin and fasudil on the Rho/Rho-kinase pathway and on eNOS.
authors: Department of Neurosurgery, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8216 Japan.
authors: Masato
authors: M
authors: Naraoka
authors: Akira
authors: A
authors: Munakata
authors: Naoya
authors: N
authors: Matsuda
authors: Norihito
authors: N
authors: Shimamura
authors: Hiroki
authors: H
authors: Ohkuma
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001488:Basilar Artery / Q000473:pathology; D004338:Drug Combinations; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007150:Immunohistochemistry; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000473:pathology; D020301:Vasospasm, Intracranial / Q000473:pathology / Q000517:prevention & control*; D054460:rho-Associated Kinases / Q000187:drug effects*
chemical_list: D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; C108475:pitavastatin; C049347:fasudil
keywords: Cerebral vasospasm; Fasudil; Pitavastatin; Rho/Rho-kinase pathway; eNOS
references: Stroke. 2011 Mar;42(3):776-82
references: 21317271
references: Acta Neurochir Suppl. 2011;110(Pt 2):9-11
references: 21125437
references: J Cardiovasc Pharmacol. 2000 Feb;35(2):203-11
references: 10672851
references: J Biochem. 2000 Nov;128(5):719-22
references: 11056381
references: Circ Res. 2000 Aug 4;87(3):195-200
references: 10926869
references: Biofactors. 2012 Sep-Oct;38(5):329-37
references: 22674845
references: Am J Physiol Gastrointest Liver Physiol. 2010 Jun;298(6):G962-9
references: 20378830
references: Stroke. 2004 Aug;35(8):1862-6
references: 15218156
references: J Biochem. 2011 Oct;150(4):357-69
references: 21873336
references: Neurosurgery. 1994 Jan;34(1):108-12; discussion 112-3
references: 8121547
references: J Biol Chem. 1996 Aug 23;271(34):20246-9
references: 8702756
references: Stroke. 2002 Dec;33(12):2950-6
references: 12468796
references: Neurol Med Chir (Tokyo). 2008 Jun;48(6):241-7; discussion 247-8
references: 18574328
references: J Physiol. 2010 May 15;588(Pt 10):1747-62
references: 20351047
references: Stroke. 2007 Dec;38(12):3259-65
references: 17962603
references: Stroke. 2001 Dec 1;32(12):2913-9
references: 11739995
references: Science. 1996 Jul 12;273(5272):245-8
references: 8662509
references: Nat Clin Pract Neurol. 2007 May;3(5):256-63
references: 17479073
references: Vascul Pharmacol. 2007 Apr;46(4):286-92
references: 17178255
references: Circ J. 2009 Feb;73(2):361-70
references: 19060417
references: J Cereb Blood Flow Metab. 2011 Jan;31(1):190-9
references: 20517322
references: Neurocrit Care. 2011 Sep;15(2):298-301
references: 21826581
references: J Neurotrauma. 2009 Jul;26(7):1157-65
references: 19226196
references: Cell Signal. 2012 Jul;24(7):1375-80
references: 22430126
references: Stroke. 2006 Aug;37(8):2174-80
references: 16809566
references: J Neurosci Res. 2008 Dec;86(16):3635-43
references: 18683242
references: J Pharmacol Sci. 2008 Dec;108(4):426-32
references: 19098389
references: J Pharmacol Sci. 2012;118(1):92-8
references: 22186620
references: J Neurosurg. 1992 Apr;76(4):571-7
references: 1545249
references: Stroke. 2009 Feb;40(2):591-6
references: 19095985
references: Trends Biochem Sci. 1995 Jun;20(6):227-31
references: 7543224
references: Trends Pharmacol Sci. 2011 Mar;32(3):167-73
references: 21242007
references: World Neurosurg. 2010 Jun;73(6):646-53
references: 20934152
references: Neurol Med Chir (Tokyo). 2006 Sep;46(9):421-8
references: 16998274
references: Biol Pharm Bull. 2011;34(11):1684-9
references: 22040880
references: Br J Pharmacol. 2007 Dec;152(7):1131-9
references: 17767169
references: Trends Pharmacol Sci. 2007 Jun;28(6):252-6
references: 17466386
references: J Cereb Blood Flow Metab. 2009 Aug;29(8):1444-53
references: 19458605
references: Neurol Res. 1989 Jun;11(2):101-4
references: 2569679
references: Hypertension. 2012 Jul;60(1):145-53
references: 22615115
references: J Cereb Blood Flow Metab. 2012 Feb;32(2):341-52
references: 21952110