The cyclooxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury inwild-type mice but not in mice with deletion of the inducible nitric oxidesynthase gene

The authors investigated the role of the prostaglandin-synthesizing enzyme cyclooxygenase-2 (COX-2) in the mechanisms of focal cerebral ischemia and i ts interaction with inducible nitric oxide synthase (iNOS). Focal cerebral ischemia was produced by permanent occlusion of the middle cerebral artery (MCA) in mice. Infarct volume was measured 96 hours later by computer-assis ted planimetry in thionin-stained brain sections. The highly selective COX- 2 inhibitor NS398 (20 mg/kg; intraperitoneally), administered twice a day s tarting 6 hours after MCA occlusion, reduced total infarct volume in C57BL/ 6 (-23%) and 129/SVeV mice (-21%), and ameliorated the motor deficits produ ced by MCA occlusion (P < .05). However, NS398 did not influence infarct vo lume in mice with deletion of the iNOS gene (P < .05). In contrast, the neu ronal NOS inhibitor 7-NI (50 mg/kg; intraperitoneally), administered once 5 minutes after MCA occlusion, reduced neocortical infarct volume by 20% in iNOS -/- mice (P < .05). NS398 did not affect arterial pressure, resting CB F or the CBF reactivity to hypercapnia in anesthetized iNOS null mice (P > .05). The data suggest that COX-2 reaction products, in mouse as in rat, co ntribute to ischemic brain injury. However, the failure of NS398 to reduce infarct volume in iNOS null mice suggests that iNOS-derived NO is required for the deleterious effects of COX-2 to occur. Thus, COX-2 reaction product s may be another mechanism by which iNOS-derived NO contributes to ischemic brain injury.