Neuronal nitric oxide synthase inhibition reduces MPP+-evoked hydroxyl radical formation but not dopamine efflux in rat striatum.
Nigral cell degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tertrahydropyridine (MPTP) or its metabolite 1-methyl-4-phenyl pyridinium (MMP+) may involve toxicity induced by nitric oxide. In the present study a microdialysis procedure incorporating salicylate hydroxylation was used to measure striatal hydroxyl radical production through the formation of 2,3-dihydroxybenzoic acid (2,3-DHBA). MPP+ (5-20mM for 20 min) increased 2,3-DHBA formation in the rat striatum in a concentration-dependent manner with a concomitant increase in dopamine release and decrease in 3,4-dihydroxyphenyl acetic acid (DOPAC) formation. Inhibition of NO synthesis following N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mM) and 7-nitroindazole monosodium salt (7-NINA; 1 mM), but not N(G)-nitro-D-arginine methyl ester (D-NAME; 1 mM) attenuated the MPP+-induced increase in hydroxyl radical formation. However, neither L-NAME nor 7-NINA had any effect on the MPP+-induced increase in dopamine efflux measured in vivo by microdialysis or in vitro using superfused striatal slices, although nomifensine (10 microM) abolished the MPP+-evoked dopamine efflux in vitro. These data suggest that NO formation is necessary for the production of hydroxyl radical following MPP+ treatment, but is not involved in the MPP+-evoked dopamine release.
Rose
S
S
Neurodegenerative Diseases Research Centre, King's College London, United Kingdom.
Hindmarsh
J G
JG
Jenner
P
P
D015655:1-Methyl-4-phenylpyridinium / Q000493:pharmacokinetics / Q000633:toxicity*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D062385:Hydroxybenzoates / Q000032:analysis / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D062385:Hydroxybenzoates; D007191:Indazoles; D015102:3,4-Dihydroxyphenylacetic Acid; D017665:Hydroxyl Radical; C009135:2,3-dihydroxybenzoic acid; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D015655:1-Methyl-4-phenylpyridinium; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester; D004298:Dopamine