Interaction Between Inducible Nitric Oxide Synthase And Cyclooxygenase-2 After Cerebral Ischemia
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA(1998)
摘要
Focal cerebral ischemia is associated with expression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), enzymes whose reaction products contribute to the evolution of ischemic brain injury. We tested the hypothesis that, after cerebral ischemia, nitric oxide (NO) produced by iNOS enhances COX-2 activity, thereby increasing the toxic potential of this enzyme. Cerebral ischemia was produced by 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 in the ipsilateral olfactory bulb, The iNOS inhibitor aminoguanidine reduced PGE(2) concentration in the infarct, where both iNOS and COX-2 were expressed, but not in the olfactory bulb, where only COX-2 was expressed. Postischemic PGE(2) accumulation was reduced significantly in iNOS null mice compared with wild-type controls (C57BL/6 or SV129), The data provide evidence that NO produced by iNOS influences COX-2 activity after focal cerebral ischemia, Proinflammatory prostanoids and reactive oxygen species produced by COX-2 may be a previously unrecognized factor by which NO contributes to ischemic brain injury. The pathogenic effect of the interaction between NO, or a derived specie, and COX-2 is likely to play a role also in other brain diseases associated with inflammation.
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关键词
middle cerebral artery occlusion, aminoguanidine, NS-398, gene expression, inducible nitric oxide synthase null mice
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