Nitric oxide and MPP+-induced hydroxyl radical generation.
Although neuroprotective effect of nitric oxide (NO) is discussed, NO has a role of pathogenesis of cellular injury. NO is synthesized from L-arginine by NO synthase (NOS). NO contributes to the extracellular potassium-ion concentration ([K(+)](o))-induced hydroxyl radical ((*)OH) generation. Cytotoxic free radicals such as peroxinitrite (ONOO(-)) and (*)OH may also be implicated in NO-mediated cell injury. NO activation was induced by K(+) depolarization. NO may react with superoxide anion (O(2) (-)) to form ONOO(-) and its decomposition generates (*)OH. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) metabolite 1-methyl-4-phenylpyridinium ion (MPP(+)) involve toxicity induced by NO. Intraneuronal Ca(2+) triggered by MPP(+) may be detrimental to the functioning of dopaminergic nerve terminals in the striatum. Although the [K(+)](o)-induced depolarization enhances the formation of (*)OH product due to MPP(+), the (*)OH generation via NOS activation may be unrelated the dopamine (DA)-induced (*)OH generation. Depolarization enhances the MPP(+)-induced (*)OH formation via NOS activation. NOS inhibition is associated with a protective effect due to suppression of depolarization-induced (*)OH generation. ONOO(-) has been implicated as a causative factor under conditions in which DA neurons are damaged. These findings may be useful in elucidating the actual mechanism of free radical formation in the pathogenesis of neurodegenerative brain disorders, including Parkinson's disease and traumatic brain injuries.
Obata
T
T
Department of Analytical Chemistry, Ohu University School of Pharmaceutical Sciences, Koriyama, Fukushima, Japan. t-obata@pha.ohu-u.ac.jp
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D015259:Dopamine Agents / Q000633:toxicity*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004966:Estrogens, Conjugated (USP) / Q000633:toxicity; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism*; D017551:Microdialysis; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018696:Neuroprotective Agents; D009569:Nitric Oxide / Q000494:pharmacology / Q000633:toxicity*; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D016877:Oxidants / Q000737:chemistry*; D011188:Potassium / Q000378:metabolism
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D004966:Estrogens, Conjugated (USP); D018696:Neuroprotective Agents; D016877:Oxidants; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D052248:Nitric Oxide Synthase Type I; D015655:1-Methyl-4-phenylpyridinium; D011188:Potassium; D019331:NG-Nitroarginine Methyl Ester