Evidence for a dissociation between MPTP toxicity and tyrosinase activity based on congenic mouse strain susceptibility.
The neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most valuable available models for investigating critical aspects of human Parkinson's disease. In order to analyze the relevance of pigmentation for MPTP sensitivity, we compared C57Bl/6 wild-type mice with the albino mutant C57Bl/6J-Tyr(c-2J) of the same strain. These animals were treated either with systemic MPTP or with saline and were examined in behavioral tests. Seven days after treatment, the contents of dopamine and other monoamines were determined postmortem in the neostriatum and ventral striatum. Furthermore, the numbers of tyrosine hydroxylase-positive cells were counted in the substantia nigra and ventral tegmental area. Open field testing showed that rearing activity was drastically reduced as an acute effect of MPTP in both wild type and mutants; however, subsequent recovery to control levels was faster in wild-type mice. Nest building also indicated strain-dependent effects, since it was delayed only in mutants treated with MPTP. Neurochemically, MPTP led to severe neostriatal dopamine depletions, which did not differ significantly between wild-type (72.9%) and mutant mice (82.1%). Less severe dopamine depletions were also found in the ventral striatum. Histologically, a loss of tyrosine hydroxylase-labeled cells was observed only in the substantia nigra of both wild-type and mutant mice (13.3 and 21.3%, respectively), but not in the ventral tegmental area. Together, our data do not provide evidence that tyrosinase-deficient mice are less affected by MPTP treatment than the comparable wild type, thus arguing strongly against the hypothesis that enhanced MPTP sensitivity in pigmented mouse strains is caused by tyrosinase activity.
Hofele
K
K
Department of Neurology, Heinrich-Heine-University of Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
Sedelis
M
M
Auburger
G W
GW
Morgan
S
S
Huston
J P
JP
Schwarting
R K
RK
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000201:enzymology; D009638:Norepinephrine / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D012701:Serotonin / Q000378:metabolism; D013045:Species Specificity; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D014442:Monophenol Monooxygenase; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid