Nogawa S, Forster C, Zhang F, Nagayama M, Ross M E, Iadecola C
Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10966-71. doi: 10.1073/pnas.95.18.10966.
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 micrometer) 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 E2 (PGE2) in the ischemic area and in the ipsilateral olfactory bulb. The iNOS inhibitor aminoguanidine reduced PGE2 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 PGE2 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. Pro-inflammatory 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.
局灶性脑缺血与诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）的表达均有关，这两种酶的反应产物会促使缺血性脑损伤的发展。我们验证了这样一个假说：脑缺血后，iNOS产生的一氧化氮（NO）会增强COX-2的活性，从而增加该酶的毒性潜力。通过大鼠或小鼠大脑中动脉闭塞来制造脑缺血模型。在大鼠缺血24小时后，在梗死灶周边可观察到iNOS免疫反应阳性的中性粒细胞与COX-2阳性细胞紧密相邻（<20微米）。在嗅球中，仅观察到COX-2阳性细胞。脑缺血增加了缺血区域和同侧嗅球中COX-2反应产物前列腺素E2（PGE2）的浓度。iNOS抑制剂氨基胍降低了梗死灶中PGE2的浓度，梗死灶中同时表达iNOS和COX-2，但在仅表达COX-2的嗅球中并未降低。与野生型对照（C57BL/6或SV129）相比，iNOS基因敲除小鼠缺血后PGE2的积累显著减少。这些数据证明，iNOS产生的NO在局灶性脑缺血后会影响COX-2的活性。COX-2产生的促炎前列腺素和活性氧可能是NO导致缺血性脑损伤的一个先前未被认识的因素。NO或其衍生物质与COX-2之间相互作用的致病作用可能在其他与炎症相关的脑部疾病中也发挥作用。
