Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice.
Several studies suggest that nitric oxide (NO.) contributes to cell death following activation of NMDA receptors in cultured cortical, hippocampal, and striatal neurons. In the present study we investigated whether 7-nitroindazole (7-NI), a specific neuronal nitric oxide synthase inhibitor, can block dopaminergic neurotoxicity seen in mice after systemic administration of MPTP. 7-NI dose-dependently protected against MPTP-induced dopamine depletions using two different dosing regimens of MPTP that produced varying degrees of dopamine depletion. At 50 mg/kg of 7-NI there was almost complete protection in both paradigms. Similar effects were seen with MPTP-induced depletions of both homovanillic acid and 3,4-dihydroxyphenylacetic acid. 7-NI had no significant effect on dopamine transport in vitro and on monoamine oxidase B activity both in vitro and in vivo. One mechanism by which NO. is thought to mediate its toxicity is by interacting with superoxide radical to form peroxynitrite (ONOO-), which then may nitrate tyrosine residues. Consistent with this hypothesis, MPTP neurotoxicity in mice resulted in a significant increase in the concentration of 3-nitrotyrosine, which was attenuated by treatment with 7 NI. Our results suggest that NO. plays a role in MPTP neurotoxicity as well as novel therapeutic strategies for Parkinson's disease.
Schulz
J B
JB
Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114.
Matthews
R T
RT
Muqit
M M
MM
Browne
S E
SE
Beal
M F
MF
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D019001:Nitric Oxide Synthase; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D007191:Indazoles; D018696:Neuroprotective Agents; D009498:Neurotoxins; C002744:3-nitrotyrosine; D014443:Tyrosine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; C080122:7-nitroindazole; D004298:Dopamine