EFFECT OF A NOVEL THROMBOXANE-A(2) RECEPTOR ANTAGONIST, S-1452, ON POSTISCHEMIC BRAIN INJURY IN RATS

Background and Purpose: Arachidonate metabolites have been implicated in the development of cerebral injury after ischemia. Particular impor tance has been placed on the balance of thromboxane A2 and prostagland in 12 because of its regulative activity on platelet functions and art erial tone. The purpose of the present study was to shed light on the role of thromboxane A2 in postischemic brain injury. Methods: We evalu ated the effects of S-1452, a novel thromboxane A2 receptor antagonist , on brain edema, infarct areas, and survival rate in rats with middle cerebral artery occlusion. A transient middle cerebral artery occlusi on model was produced by inserting a piece of silicon-coated nylon thr ead into the internal carotid artery. Results: The ratio of plasma thr omboxane B2 to 6-keto-prostaglandin F1alpha significantly rose at 0 ho ur (P<.05), 1 hour (P<.01), 3 hours (P<.05), and 12 hours (P<.05) and then nearly returned to the normal level at 24 hours after reperfusion following 1-hour occlusion. Pretreatment with S-1452 (5, 10, or 50 mg /kg PO) significantly attenuated the increase in postischemic water co ntent in the cerebral cortex perfused by the anterior cerebral artery and the cerebral cortex perfused by the middle cerebral artery in a do se-dependent manner but slightly attenuated it in the caudate putamen 24 hours after reperfusion following 1-hour occlusion. Pretreatment wi th S-1452 (10 mg/kg PO) also significantly decreased the areas of infa rction in the front parts of the cerebrum. The survival rate of animal s after 2 hours of occlusion tended to be improved by treatment with S -1452 (10 mg . kg-1 . d-1 PO), although there was no statistical signi ficance. Conclusions: Our results suggest that thromboxane A2 is close ly related to postischemic brain injury in the early phase of recircul ation and that S-1452 may have a protective effect on postischemic bra in injury.