title: Alteplase treatment does not increase brain injury after mechanical middle cerebral artery occlusion in the rat.
abstract: Recanalization of an occluded vessel with recombinant tissue plasminogen activator is an effective strategy for treating acute ischemic stroke. Recombinant tissue plasminogen activator is administered as alteplase, a formulation containing many excipients including L-arginine, the substrate for nitric oxide production. Most studies fail to compare the effects of alteplase on brain injury to its L-arginine carrier solution. This study aimed to verify the previously reported detrimental effects of alteplase after cerebral ischemia and delineate the contribution of L-arginine. Male Wistar rats, subjected to 90 minutes of intraluminal middle cerebral artery occlusion (MCAO), were administered alteplase, the carrier solution or saline upon reperfusion. Neither alteplase nor the carrier affected cerebral blood flow (CBF) restoration throughout the first 60 minutes of reperfusion. Alteplase treatment was associated with increased mortality after MCAO. Twenty-four hours after MCAO, neurologic function and infarct volume did not differ between rats treated with alteplase, the carrier solution, or saline. Irrespective of treatment group, infarct volume was correlated with CBF during reperfusion, neuroscore, and peri-infarct depolarizations. These results suggest that alteplase treatment, independent of thrombolysis, does not cause increased ischemic injury compared with its appropriate carrier solution, supporting the continued use of alteplase in eligible ischemic stroke patients.
authors: Acute Stroke Programme, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
authors: Brad A
authors: BA
authors: Sutherland
authors: Alastair M
authors: AM
authors: Buchan
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016019:Survival Analysis; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D004337:Drug Carriers; D005343:Fibrinolytic Agents; D001120:Arginine; D010959:Tissue Plasminogen Activator
references: Nat Med. 1998 Feb;4(2):228-31
references: 9461198
references: Brain Res. 1999 Sep 4;840(1-2):194-205
references: 10517971
references: Stroke. 1995 Apr;26(4):627-34; discussion 635
references: 7709410
references: Blood. 2004 Feb 1;103(3):897-902
references: 14512309
references: J Cereb Blood Flow Metab. 2011 Jan;31(1):132-43
references: 20407463
references: Neurology. 1999 Apr 22;52(7):1381-4
references: 10227621
references: Trends Neurosci. 1997 Mar;20(3):132-9
references: 9061868
references: Pharm Biotechnol. 1993;5:91-134
references: 8019701
references: Stroke. 2005 Feb;36(2):332-6
references: 15625301
references: Lancet Neurol. 2009 Dec;8(12):1095-102
references: 19850525
references: J Cereb Blood Flow Metab. 2004 Sep;24(9):945-63
references: 15356416
references: CNS Neurol Disord Drug Targets. 2013 Mar;12(2):155-69
references: 23394532
references: Lancet. 2004 Mar 6;363(9411):768-74
references: 15016487
references: J Physiol. 2011 Sep 1;589(17):4105-14
references: 21708904
references: J Neurosci Methods. 2009 Apr 30;179(1):1-8
references: 19167427
references: Cerebrovasc Brain Metab Rev. 1996 Fall;8(3):195-208
references: 8870974
references: Nat Med. 2008 Jul;14(7):731-7
references: 18568034
references: J Cereb Blood Flow Metab. 2002 Jun;22(6):711-22
references: 12045670
references: Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1073-8
references: 18195371
references: Lancet. 2012 Jun 23;379(9834):2364-72
references: 22632907
references: Stroke. 2000 Apr;31(4):940-5
references: 10754003
references: Cerebrovasc Dis. 2008;25(4):338-43
references: 18303253
references: N Engl J Med. 1995 Dec 14;333(24):1581-7
references: 7477192
references: Thromb Haemost. 1981 Aug 28;46(2):561-5
references: 6795744
references: J Neurosci. 2003 Dec 17;23(37):11602-10
references: 14684862
references: J Cereb Blood Flow Metab. 2010 Nov;30(11):1804-16
references: 20736961
references: J Cereb Blood Flow Metab. 1996 Mar;16(2):195-201
references: 8594050
references: Brain. 2007 Apr;130(Pt 4):995-1008
references: 17438018
references: Biochem Biophys Res Commun. 1988 Jun 30;153(3):1251-6
references: 3390182
references: Stroke. 2001 Nov;32(11):2641-7
references: 11692029
references: J Cereb Blood Flow Metab. 1999 Dec;19(12):1316-21
references: 10598935
references: J Cereb Blood Flow Metab. 2009 Apr;29(4):715-25
references: 19142198