Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces clinical, biochemical and neuropathologic changes reminiscent of those which occur in idiopathic Parkinson's disease. 7-Nitroindazole (7-NI) is a relatively selective inhibitor of the neuronal isoform of nitric oxide synthase (NOS) that blocks MPTP neurotoxicity in mice. We now show that 7-NI protects against profound striatal dopamine depletions and loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated baboons. Furthermore, 7-NI protected against MPTP-induced motor and frontal-type cognitive deficits. These results strongly implicate a role of nitric oxide in MPTP neurotoxicity and suggest that inhibitors of neuronal NOS might be useful in treating Parkinson's disease.
Hantraye
P
P
Unité de Recherche Associé Commissariat á l'Energie Atomique, Centre National de la Recherche Scientifique 2210, Service Hospitalier Frederic Joliot, Orsay, France.
Brouillet
E
E
Ferrante
R
R
Palfi
S
S
Dolan
R
R
Matthews
R T
RT
Beal
M F
MF
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D018476:Hypokinesia; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity; D009460:Neurologic Examination; D009474:Neurons / Q000187:drug effects / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010215:Papio; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D014743:Videotape Recording
D004791:Enzyme Inhibitors; D007191:Indazoles; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole; D004298:Dopamine; D006719:Homovanillic Acid