Role of Inducible Nitric Oxide Synthase and Cyclooxygenase-2 in the Mechanisms of Ischemic Brain Injury

Abstract

There is a growing body of evidence indicating that cerebral ischemic damage is associated with a local inflammatory reaction, which contributes to the development of ischemic brain injury. We review evidence that inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are involved in the mechanisms by which ischemia-induced inflammation contributes to tissue damage. In rodents, as in humans, iNOS is expressed in inflammatory cells infiltrating the ischemic brain and in cerebral blood vessels. Administration of iNOS inhibitors 24h after ischemia reduces the size of the infarct produced by occlusion of the rat middle cerebral artery (MCA). Furthermore, “knockout” mice lacking the iNOS gene have smaller infarcts than wild-type mice. COX-2 is expressed in the postischemic brain with a time course similar to that of iNOS; and it is present in ischemic neurons, inflammatory cells, and blood vessels. Administration of the selective COX-2 inhibitor NS-398 reduces infarct size. Furthermore, NO produced by iNOS activates COX-2, thereby increasing the production of toxic prostanoids and free radicals. The evidence suggests that NO synthesized by iNOS, in part through reaction products of COX-2, contributes to the expansion of the infarct that occurs during the late postischemic period. Thus, the interaction between iNOS and COX-2 plays an important role in the late stages of cerebral ischemic damage. Delayed administration of iNOS and COX-2 inhibitors may be a useful therapeutic strategy to target selectively the progression of ischemic brain injury.