Inhibition of the neuronal isoform of nitric oxide synthase significantly attenuates 1-methyl-4-phenylpyridinium (MPP(+)) toxicity in vitro.
The possible protection against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) afforded by inhibitors of nitric oxide synthase (NOS) and the antagonist of N-methyl-D-aspartate receptor function, MK-801, was studied in a brain-slice superfusion system. Significant decreases in levels of dopamine and its metabolites 3,4-dihyroxyphenylacetic acid (DOPAC) and homovanillic acid were observed following incubation of slices with 25 microM MPP(+). The activity of intracellular lactate dehydrogenase (LDH), a marker of cell viability, was also significantly decreased. These effects were attenuated by preincubation with I mM 7-nitroindazole (7NI), a selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS). In contrast, the nonspecific NOS inhibitor N(omega)-nitro-L-arginine, also at 1 mM, had no effect on levels of dopamine metabolites but did show a small attenuation of the levels of dopamine. 7NI alone caused some increase in levels of dopamine and a decrease in the metabolite DOPAC, which is consistent with it also acting as an inhibitor of monoamine oxidase-B. MK-801 afforded no significant protection of aminergic cells, although changes in LDH activity suggested that there may have been some protection of non-aminergic neurons affected by this, relatively high concentration of MPP(+).
Department of Biochemistry, Trinity College, Dublin, Ireland.
M B
MB
O'Byrne
K F
KF
Tipton
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors* / Q000506:poisoning*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007191:Indazoles; D015102:3,4-Dihydroxyphenylacetic Acid; D019335:Nitroarginine; D016291:Dizocilpine Maleate; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D015655:1-Methyl-4-phenylpyridinium; C080122:7-nitroindazole; D006719:Homovanillic Acid