Comparative Effects of Tissue Plasminogen Activator, Streptokinase, and Staphylokinase on Cerebral Ischemic Infarction and Pulmonary Clot Lysis in Hamster Models

Abstract

Background-The effects of alteplase (rtPA), streptokinase, and staphylokinase (rSak) on focal cerebral ischemia (FCI) and on pulmonary clot lysis (PCL) were studied in hamsters. Methods and Results-FCI was produced by ligation of the left middle cerebral artery (MCA) and common carotid artery (CCA) and a 10-minute occlusion of the right CCA. FCI was measured after 24 hours by 2,3,5-triphenyltetrazolium chloride staining. 125 I-fibrin-labeled plasma clots were injected via the jugular vein, and clot lysis was determined from residual radioactivity at 90 minutes. Study drugs were given intravenously over 60 minutes. FCI increased from 1.2 (0.27 to 2.3) mm 3 (median and 17th to 83rd percentile range, nϭ24) in controls to 19 to 27 mm 3 with thrombolytic agent, with maximal rates at 0.13Ϯ0.05 mg/kg rtPA, 0.23Ϯ0.09 mg/kg streptokinase, and 0.037Ϯ0.025 mg/kg rSak. PCL increased from 18Ϯ2% (meanϮSEM, nϭ27) in controls to Ϸ85% with thrombolytics, with maximal rates at 0.12Ϯ0.03 mg/kg rtPA, 0.17Ϯ0.05 mg/kg streptokinase, and 0.018Ϯ0.002 mg/kg rSak. All agents caused maximal FCI and PCL rates at similar doses without ␣ 2 -antiplasmin and fibrinogen depletion. Injection of 6 mg/kg human plasminogen combined with streptokinase caused a "systemic fibrinolytic state" with fibrinogen depletion. Maximal rates of FCI were obtained with 0.097Ϯ0.077 mg/kg streptokinase (Pϭ0.26 versus streptokinase alone) and of PCL with 0.010Ϯ0.002 mg/kg (Pϭ0.006 versus streptokinase alone). Conclusions-Thrombolytic

Depletion of circulating α2-antiplasmin by intravenous plasmin or immunoneutralization reduces focal cerebral ischemic injury in the absence of arterial recanalization

“…In the present study, a 30-minute instead of a 10-minute occlusion period of the right CCA was used to obtain larger lesions. 5 This resulted in the death of one of the control animals but none of the hamsters receiving plasmin.…”

“…5 The MCA was occluded by ligation with 10-0 nylon thread (Ethylon, Neuilly, France), after which the artery was transsected distally and the temporal muscle and skin were sutured back in place. A vertical incision was then made above the sternum, and both CCAs were exposed.…”

“…C57Bl/6 0.07 15 (13-23) [5] 10 (5.7-16) [6] .068 15 (8.0-20) [7] 11 (1.8-14) [6] .063 15 (8.0-23) [12] 11 (1.8-16) [12] .0079…”

“…1,2 However, alteplase infusion increased infarct volume after focal cerebral ischemic injury (FII) induced by occlusion of the middle cerebral artery (MCA) in mice, 3 possibly as a result of plasmin-mediated degradation of laminin, a component of basal lamina playing a role in neuronal survival. 4 The deleterious effects of alteplase on FII in mice were confirmed and extended using alteplase, streptokinase, or staphylokinase in hamsters, 5 indicating that this phenomenon is neither species specific nor agent specific and that it occurs in the absence of systemic fibrinogen breakdown. Thus, one could hypothesize that thrombolytic therapy for ischemic stroke might cause infarct expansion in cases with persistent cerebral arterial occlusion and indeed be harmful to a subgroup of patients.…”

The Neurotoxicity of Tissue Plasminogen Activator?

“…Another study directly compared tPA, streptokinase and rSak in a hamster model (Nagai et al, 1999b). Both focal cerebral ischemia and pulmonary thrombolysis were studied, and it was concluded that all three agents caused similar dose related extension of focal infarction.…”