ACTIVATION OF COMPLEMENT BY TISSUE-PLASMINOGEN ACTIVATOR, BUT NOT ACUTE CEREBRAL-ISCHEMIA, IN A RABBIT MODEL OF THROMBOEMBOLIC STROKE

Although complement activation is associated with tissue injury during inflammatory and ischemic states, complement activation in states of acute cerebral ischemia before and after administration of tissue plas minogen activator (TPA) has not get been examined and is the focus of this investigation. Twenty-four New Zealand White rabbits weighing 3 t o 3.5 kg were used for this study. Of these, 20 were subjected to intr acranial autologous clot embolization via the internal carotid artery. Three hours postembolization, rabbits received an intravenous infusio n of TPA (6.3 mg/kg, 20% bolus with the remainder infused over a 2-hou r interval; 12 animals) or vehicle (eight animals). All animals were o bserved for a total of 7 or 8 hours postembolization. These two groups were compared to a cohort undergoing sham operation with subsequent T PA infusion (few animals). Plasma samples to quantify complement compo nent C5 hemolytic activity (C5H5O) were obtained at the following time points: 30 minutes before and after clot embolization; 1 hour before and 1 hour after the initiation of therapy with TPA or vehicle and at the completion of the protocol; 7 to 8 hours after clot embolization. The C5 activation was not detected as the result of acute cerebral isc hemia. However, animals receiving TPA with or without concomitant clot embolization exhibited C5 activation as assessed by a reduction in C5 hemolytic function, both 1 hour after initiation of TPA infusion (78. 7 +/- 10.3% and 77.5 +/- 9.9% of baseline value, respectively; mean st andard error of the mean [SEM]) and at the end of the protocol, 2 hour s after the completion of the TPA infusion (72.5 +/- 8.8% and 53.3 +/- 8.1%, respectively; mean +/- SEM, p < 0.05, each group). This study s upports the conclusion that TPA, but not acute cerebral ischemia, may activate the complement cascade in this rabbit model of thromboembolic stroke.