MPTP-induced model of Parkinson's disease in cytochrome P450 2E1 knockout mice

• Published in: Neuropharmacology Vol. 56; no. 8; p. 1075
• Main Authors: Viaggi, C, Vaglini, F, Pardini, C, Caramelli, A, Corsini, G U
• Format: Journal Article
• Language: English
• Published: England 01-06-2009
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacokinetics; 1-Methyl-4-phenylpyridinium - metabolism; Animals; Corpus Striatum - chemistry; Corpus Striatum - drug effects; Cytochrome P-450 CYP2E1 - deficiency; Cytochrome P-450 CYP2E1 - genetics; Cytochrome P-450 CYP2E1 - physiology; Dopamine - analogs & derivatives; Dopamine - analysis; Dopamine - deficiency; Homovanillic Acid - analysis; Male; Mice; Mice, Knockout; MPTP Poisoning - metabolism; Nerve Tissue Proteins - analysis; Neurons - drug effects; Neurons - enzymology; Parkinsonian Disorders - metabolism; Prodrugs - pharmacokinetics; Prodrugs - toxicity; Substantia Nigra - drug effects; Substantia Nigra - metabolism; Tyrosine 3-Monooxygenase - analysis
• ISSN: 1873-7064
• DOI: 10.1016/j.neuropharm.2009.03.003

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.