MPTP-induced model of Parkinson's disease in cytochrome P450 2E1 knockout mice.
Evidence for involvement of cytochrome P450 2E1 in the MPTP-induced mouse model of PD has been reported [Vaglini, F., Pardini, C., Viaggi, C., Bartoli, C., Dinucci, D., Corsini, G.U., 2004. Involvement of cytochrome P450 2E1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease. J. Neurochem. 91, 285-298]. We studied the sensitivity of Cyp2e1(-/-) mice to the acute administration of MPTP in comparison with their wild-type counterparts. In Cyp2e1(-/-) mice, the reduction of striatal DA content was less pronounced 7 days after MPTP treatment compared to treated wild-type mice. Similarly, TH immunoreactivity analysis of the substantia nigra of Cyp2e1(-/-) mice did not show any neuronal lesions after MPTP treatment. In contrast to this, wild-type animals showed a minimal but significant lesioning by the toxin as evaluated also by means of non-stereologic computerized assisted analysis of this brain area. Striatal levels of DA metabolites after 7 days were variably affected by the toxin, but consistent differences between the two animal strains were not observed. We evaluated short-term changes in the levels of striatal DA and its metabolites, and we monitored striatal MPP(+) levels. Striatal MPP(+) was cleared more rapidly in Cyp2e1(-/-) mice than in wild-type animals and, consistently, striatal DA content decreased faster in Cyp2e1(-/-) mice than in wild-type animals, and 3-methoxytyramine and HVA levels showed an early and sharp rise. Our findings suggest that Cyp2e1(-/-) mice are weakly sensitive to MPTP-induced brain lesions, markedly in contrast with a protective role of the enzyme as suggested previously. The differences observed between the knockout mice and their wild-type counterparts are modest and may be due to an efficient compensatory mechanism or genetic drift in the colonies.
Viaggi
C
C
Department of Neuroscience, Section of Pharmacology, University of Pisa and Center of Excellence AMBISEN for the Study of Environmental Toxins and CNS Diseases, Pisa, Italy. f.vaglini@drugs.med.unipi.it
Vaglini
F
F
Pardini
C
C
Caramelli
A
A
Corsini
G U
GU
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects*; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D004298:Dopamine / Q000031:analogs & derivatives / Q000032:analysis / Q000172:deficiency; D006719:Homovanillic Acid / Q000032:analysis; D020267:MPTP Poisoning / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D020734:Parkinsonian Disorders / Q000378:metabolism*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000633:toxicity; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D009419:Nerve Tissue Proteins; D011355:Prodrugs; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019392:Cytochrome P-450 CYP2E1; D014446:Tyrosine 3-Monooxygenase; C001746:3-methoxytyramine; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine; D006719:Homovanillic Acid