Nitric oxide synthases: targets for therapeutic strategies in neurological diseases.
Glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunctions are common features leading to neuronal death in cerebral ischemia, traumatic brain injury, Parkinson's disease, Huntington's disease, Alzheimer's disease and amyotrophic lateral sclerosis. Nitric oxide (NO) alone or in cooperation with superoxide anion and peroxynitrite is emerging as a predominant effector of neurodegeneration The use of NO synthase (NOS) inhibitors and mutant mice lacking each NOS isoform have provided evidence for the injurious effects of NO derived from neuronal or inducible isoforms. New neuroprotective strategies have been proposed with selective NOS inhibitors for the neuronal (ARL17477) or the inducible (1400 W) isoforms or with compounds combining in one molecule selective nNOS inhibition and antioxidant properties (BN 80933), in experimental ischemia-induced acute neuronal damage. The efficacy of these new strategies is well established in acute neuronal injury but remains to be determined in more chronic neurological diseases.
Chabrier
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PE
Beaufour-Ipsen Research Labs., Les Ulis, France.
Demerlé-Pallardy
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C
Auguet
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D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000578:Amidines / Q000494:pharmacology / Q000627:therapeutic use; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use; D001930:Brain Injuries / Q000188:drug therapy; D002545:Brain Ischemia / Q000188:drug therapy; D004790:Enzyme Induction; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D009422:Nervous System Diseases / Q000188:drug therapy*; D009569:Nitric Oxide / Q000009:adverse effects / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D009928:Organ Specificity; D011109:Polymethacrylic Acids / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use
C102136:ARL 17477; D000578:Amidines; D001596:Benzylamines; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009419:Nerve Tissue Proteins; D011109:Polymethacrylic Acids; D011719:Pyrazines; D013876:Thiophenes; D009569:Nitric Oxide; C091347:vinyl ethyl methacrylate; C120890:BN 80933; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse