title: Nitric oxide synthase inhibition and MPTP-induced toxicity in the common marmoset.
abstract: Nitric oxide, produced following activation of N-methyl-D-aspartate (NMDA) receptors, may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity since NMDA receptor antagonists have been shown to prevent MPTP induced nigral cell loss in primates. Common marmosets were treated with either saline or MPTP or L-NGnitro arginine methyl ester (L-NAME) or MPTP and L-NAME. MPTP-treated common marmosets showed motor deficits including bradykinesia, rigidity, and tremor accompanied by a marked loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta and of [3H]-mazindol binding in the caudate-putamen. MPTP treatment also caused an increase in glial fibrillary acidic protein (GFAP) staining in the substantia nigra compared to controls. However, MPTP treatment did not alter the number of constitutive nitric oxide synthase-immunoreactive neurones in the caudate-putamen. Furthermore, neurones or glial cells immunoreactive for inducible nitric oxide synthase were not observed in the substantia nigra pars compacta following MPTP treatment. L-NAME treatment alone did not produce any behavioural changes in marmosets and did not alter the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta, the number of constitutive nitric oxide synthase-immunoreactive neurones or [3H]-mazindol binding in the caudate-putamen compared to saline-treated control animals. Furthermore, L-NAME did not affect the motor deficits, loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta, loss of [3H]-mazindol binding in the caudate-putamen, or the increase in GFAP staining in the substantia nigra induced by MPTP treatment of common marmosets. The failure of L-NAME to protect against MPTP-induced toxicity in the marmoset suggests that nitric oxide does not play a major role in such toxicity and casts doubt over the involvement of the NMDA:nitric oxide system in neurodegeneration in MPTP-treated primates.
authors.affiliation: Neurodegenerative Diseases Research Centre, King's College London, United Kingdom.
authors.forename: G M
authors.initials: GM
authors.lastname: Mackenzie
authors.forename: M J
authors.initials: MJ
authors.lastname: Jackson
authors.forename: P
authors.initials: P
authors.lastname: Jenner
authors.forename: C D
authors.initials: CD
authors.lastname: Marsden
mesh_terms: D018759:Adrenergic Uptake Inhibitors; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002144:Callithrix; D002452:Cell Count; D015259:Dopamine Agents / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006651:Histocytochemistry; D020267:MPTP Poisoning; D008297:Male; D008454:Mazindol; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008454:Mazindol; D019001:Nitric Oxide Synthase; D014446:Tyrosine 3-Monooxygenase; D019331:NG-Nitroarginine Methyl Ester