Molecular pathology of cerebral ischemia: delayed gene expression and strategies for neuroprotection.
The evidence reviewed in this paper suggests that molecular and cellular events occurring in the late stages of cerebral ischemia (> 6 h) play an important role in the evolution of ischemic brain damage. We focused our inquiry on two inflammation-related genes iNOS and COX-2. iNOS is expressed in inflammatory and vascular cells in the post-ischemic brain. Pharmacological inhibition of iNOS activity ameliorates ischemic damage, whereas knockout mice lacking the iNOS gene are relatively protected from the consequences of cerebral ischemia. COX-2 is expressed in neurons at the infarct border and inhibition of COX-2 activity improves ischemic brain damage. These results indicate that expression of iNOS and COX-2 contributes to the late stages of ischemic brain damage. Consequently, inhibition of iNOS and COX-2 could be a valuable addition to treatment strategies for ischemic stroke. Most efforts to date have targeted the acute phase of cerebral ischemia. Inhibition of iNOS or COX-2 offers the prospect of treatments directed to the late stages of the damage. However, additional preclinical studies would be necessary before these new treatment strategies can be tested in human stroke.
Iadecola
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Department of Neurology, University of Minnesota Medical School, Minneapolis 55455, USA. iadec001@maroon.tc.umn.edu
Ross
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D000818:Animals; D001921:Brain / Q000098:blood supply / Q000201:enzymology; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*
D007527:Isoenzymes; D008565:Membrane Proteins; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases