title: Transgenic mice with high levels of superoxide dismutase activity are protected from the neurotoxic effects of 2'-NH2-MPTP on serotonergic and noradrenergic nerve terminals.
abstract: Administration of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) analog 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP; 4 x 15 mg/kg) to CD-1 mice was found to cause substantial decreases in cortical and hippocampal 5-hydroxytryptamine (5-HT) and norepinephrine (NE) to 20-30% of control 3 weeks after treatment. The magnitude of these depletions was similar to those reported previously in Swiss Webster and C57BL/6 mice given 4 x 20 mg/kg 2'-NH2-MPTP, and in keeping with these prior studies, striatal dopamine levels were unchanged by 2'-NH2-MPTP treatment in CD-1 mice. Subsequently, transgenic CD-1 mice producing high levels of human cytosolic Cu-Zn superoxide dismutase (SOD) were studied to assess the role of oxygen radicals in the mechanism of action of 2'-NH2-MPTP. In contrast to the results described above, 5-HT and NE levels were almost completely unaffected by 2'-NH2-MPTP treatment in homozygous SOD mice bearing 5-fold increases in brain SOD activity. In 2'-NH2-MPTP-treated heterozygous SOD mice, which showed an average 3-fold increase in brain SOD activity, only moderate depletions in cortical and hippocampal 5-HT (50-60% of control) and NE (30-40% of control) were observed. Additionally, the density of [125I]RTI-55-labeled 5-HT uptake sites was studied to further assess possible 5-HT terminal loss. In various cortical and hippocampal subregions of nontransgenic mice, 5-HT uptake sites were reduced to 20-35% of control after 2'-NH2-MPTP treatment, in comparison with homozygous SOD mice, which were affected only minimally by 2'-NH2-MPTP administration, and heterozygous SOD mice, which showed intermediate reductions in 5-HT uptake site density on the order of 55-80% of control. Together, these data indicate that mice genetically endowed with increased SOD activity are protected from 2'-NH2-MPTP-induced toxicity, thereby implicating superoxide radicals in the mechanism of action of a neurotoxin that selectively depletes 5-HT and NE without affecting dopamine.
authors.affiliation: Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Maryland 20892, USA. ama@helix.nih.gov
authors.forename: A M
authors.initials: AM
authors.lastname: Andrews
authors.forename: B
authors.initials: B
authors.lastname: Ladenheim
authors.forename: C J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: J L
authors.initials: JL
authors.lastname: Cadet
authors.forename: D L
authors.initials: DL
authors.lastname: Murphy
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: C079794:1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine; D012701:Serotonin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D013482:Superoxide Dismutase; D008995:Monoamine Oxidase; D009638:Norepinephrine