BENEFICIAL EFFECT OF CV-4151 (ISBOGREL), A THROMBOXANE A(2) SYNTHASE INHIBITOR, IN A RAT MIDDLE CEREBRAL-ARTERY THROMBOSIS MODEL

Effects of thromboxane A(2) (TXA(2)) synthase inhibitors (CV-4151 and ozagrel) on cerebral thrombosis and cerebral damage were examined in a rat middle cerebral artery (MCA) thrombosis model and their potencies were compared with the conventional antithrombotic agents, aspirin an d ticlopidine. CV-4151 significantly inhibited photochemically induced MCA thrombosis by oral (1 and 10 mg/kg) and intravenous (1 mg/kg) adm inistration. Ozagrel (10 mg/kg, p.o.) also inhibited it. The potency o f CV-4151 was about 10 times stronger than that of ozagrel, being comp arable with the inhibition of brood TXA(2) generation. Aspirin (100 mg /kg, p.o.) and ticlopidine (300 mg/kg, p.o.) showed an inhibitory tend ency on MCA thrombosis. Twenty-four h after photochemical stimulation, cerebral edema and cerebral infarction were observed, and the lactate content in the brain increased. CV-4151 and ozagrel prevented this ed ema, and the antiedema effects of the drugs were correlated with the a ntithrombotic effect on thrombotic MCA occlusion. CV-4151 (10 mg/kg, p .o.), furthermore, significantly reduced the infarct size and inhibite d the increase in lactate content. These results indicate that TXA(2) synthase inhibitors inhibit cerebral damage by inhibition of MCA occlu sion with thrombosis, probably resulting from the inhibition of TXA(2) generation, and their effects are superior to those of aspirin and ti clopidine. TXA(2) might play an important role in cerebral damage in t he MCA thrombosis model. CV-4151 might be a useful drug for the treatm ent of cerebral thrombosis and for the prevention of cerebral infarcti on.