RT Journal Article
SR Electronic
T1 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.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1511
OP 1519
VO 50
IS 6
A1 A M Andrews
A1 B Ladenheim
A1 C J Epstein
A1 J L Cadet
A1 D L Murphy
YR 1996
UL http://molpharm.aspetjournals.org/content/50/6/1511.abstract
AB 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.