INTERACTION BETWEEN INDUCIBLE NITRIC-OXIDE SYNTHASE AND CYCLOOXYGENASE-2 AFTER CEREBRAL-ISCHEMIA

Focal cerebral ischemia is associated with expression of both inducibl e nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), enzymes w hose reaction products contribute to the evolution of ischemic brain i njury. We tested the hypothesis that, after cerebral ischemia, nitric oxide (NO) produced by iNOS enhances COX-2 activity, thereby increasin g the toxic potential of this enzyme. Cerebral ischemia was produced b y middle cerebral artery occlusion in rats or mice. Twenty-four hours after ischemia in rats, iNOS-immunoreactive neutrophils were observed in close proximity (<20 mu m) to COX-2-positive cells at the periphery of the infarct, In the olfactory bulb, only COX-2 positive cells were observed. Cerebral ischemia increased the concentration of the COX-2 reaction product prostaglandin E-2 (PGE(2)) in the ischemic area and i n the ipsilateral olfactory bulb, The iNOS inhibitor aminoguanidine re duced PGE(2) concentration in the infarct, where both iNOS and COX-2 w ere expressed, but not in the olfactory bulb, where only COX-2 was exp ressed. Postischemic PGE(2) accumulation was reduced significantly in iNOS null mice compared with wild-type controls (C57BL/6 or SV129), Th e data provide evidence that NO produced by iNOS influences COX-2 acti vity after focal cerebral ischemia, Proinflammatory prostanoids and re active oxygen species produced by COX-2 may be a previously unrecogniz ed factor by which NO contributes to ischemic brain injury. The pathog enic effect of the interaction between NO, or a derived specie, and CO X-2 is likely to play a role also in other brain diseases associated w ith inflammation.