Beneficial effect of CV-4151 (isbogrel), a thromboxane A 2 synthase inhibitor, in a rat middle cerebral artery thrombosis model

Abstract

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 and ticlopidine. CV-4151 significantly inhibited photochemically induced MCA thrombosis by oral (1 and 10 mg/kg) and intravenous (1 mg/kg) administration. Ozagrel (10 mg/kg, p.o.) also inhibited it. The potency of CV-4151 was about 10 times stronger than that of ozagrel, being comparable with the inhibition of blood TXA 2 generation. Aspirin (100 mg/kg, p.o.) and ticlopidine (300 mg/kg, p.o.) showed an inhibitory tendency 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 edema, and the antiedema effects of the drugs were correlated with the antithrombotic effect on thrombotic MCA occlusion. CV-4151 (10 mg/kg, p.o.), furthermore, significantly reduced the infarct size and inhibited the increase in lactate content. These results indicate that TXA 2 synthase inhibitors inhibit cerebral damage by inhibition of MCA occlusion with thrombosis, probably resulting from the inhibition of TXA 2 generation, and their effects are superior to those of aspirin and ticlopidine. TXA 2 might play an important role in cerebral damage in the MCA thrombosis model. CV-4151 might be a useful drug for the treatment of cerebral thrombosis and for the prevention of cerebral infarction.