[NO synthases: new pharmacological targets in cerebrovascular accident?].
In cerebral ischemia, the disappointment related to anti-glutamate strategies in clinical trials has led to examine new targets for the treatment of stroke. In vitro studies demonstrated that overactivation of glutamate receptors leads to nitric oxide (NO) production that contributes to the excitotoxic neuronal death. The role of NO was then studied in in vivo models of cerebral ischemia. In the early phase after ischemia, NO is produced by the constitutive endothelial and neuronal isoforms of NO-synthase (NOS 3 and NOS 1) while in the later phase, the inducible NOS (NOS 2) is responsible for the delayed production of NO. NOS 3 appears beneficial via vasodilatation and inhibition of leukocyte adhesion and platelet aggregation. By contrast NOS 1 and NOS 2 were demonstrated deleterious in cerebral ischemia. This was shown by three distinct strategies: selective inhibitors, mutant mice deficient in NOS 1 or NOS 2, and antisenses directed to one of these isoforms. Moreover it is now thought that NO-induced neuronal death is mainly mediated through the formation of peroxynitrite anions resulting from the reaction between NO and superoxyde anion. Peroxynitrites indeed damage lipids, proteins and nucleic acids. DNA strand breaks in turn activate poly(ADP-ribose) polymerase (PARP). Overactivation of this enzyme in pathological conditions such as cerebral ischemia seems deleterious by depleting ATP stores. Thus inhibition of the NO-peroxynitrites-PARP pathway may lead to neuroprotective therapeutics in stroke.
Plotkine
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UPRES EA2510, Laboratoire de Pharmacologie, Université René Descartes, Paris, France.
Margaill
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I
D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D007527:Isoenzymes; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D018696:Neuroprotective Agents; D009569:Nitric Oxide; C496320:NOS1 protein, human; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II