Correlation between the neostriatal content of the 1-methyl-4-phenylpyridinium species and dopaminergic neurotoxicity following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration to several strains of mice.
In the present study we observed pronounced differences in the capacity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce dopaminergic neurotoxicity in several strains of mice. For example, there was no MPTP-induced decrement in neostriatal dopamine content in Ace Swiss-Webster mice and a 92% decrement in Taconic Farms C57 bl mice. Several parameters which could possibly explain this differential sensitivity to MPTP were studied. These include: 1) neostriatal monoamine oxidase-B (MAO-B) activity; 2) the capacity of neostriatal synaptosomes prepared from the mouse strains to accumulate 1-methyl-4-phenylpyridinium (MPP+), the major metabolite of MPTP formed via oxidation by MAO-B; and 3) the neostriatal MPP+ content after MPTP administration to the mice. There were no significant differences in the Km values for MAO-B in the neostriatum among the strains of mice examined. Neostriatal Vmax values for MAO-B differed somewhat among the strains, with a low of 2915 +/- 172 nmol/g of tissue per hr (CD-1 mice from Charles River) and a high of 3884 +/- 203 nmol/g of tissue per hr (C57 bl mice from Taconic Farms). However, Vmax values for MAO-B in the mouse strains did not correlate significantly with the relative sensitivity of the strains to MPTP. There were no significant differences in the capacity of neostriatal synaptosomes prepared from the mouse strains to accumulate MPP+. Studies on the metabolism of MPTP after peripheral administration revealed that there was a significant (P less than .01) positive correlation between the relative sensitivity of the mouse strains to MPTP and their neostriatal MPP+ content after MPTP administration.(ABSTRACT TRUNCATED AT 250 WORDS)
Giovanni
A
A
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway.
Sieber
B A
BA
Heikkila
R E
RE
Sonsalla
P K
PK
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism; D013045:Species Specificity
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine