Differing short-term neuroprotective effects of the fibrates fenofibrate and bezafibrate in MPTP and 6-OHDA experimental models of Parkinson's disease.
Earlier study from our group indicated that the peroxisome proliferator-activated receptor-alpha agonist fenofibrate prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss in C57Bl/6 mice. Our objective was to determine whether or not fibratescan improve motor activity in two experimental models of Parkinson's disease: the MPTP C57Bl/6 mouse and the 6-hydroxydopamine (6-OHDA) Wistar rat. Six groups of mice were set up: sham, sham-fenofibrate, sham-bezafibrate, MPTP, MPTP-fenofibrate and MPTP-bezafibrate. Mice were fed a diet containing 0.2% fenofibrate, 0.2% bezafibrate or no hypolipidaemic agent for 2 weeks. Four groups of rats were set up: sham, sham-fenofibrate, 6-OHDA and 6-OHDA-fenofibrate. Rats were fed a diet containing 0.2% fenofibrate or no hypolipidaemic agent for 4 weeks. In mice, motor activity was quantified using actimetry. Nine parameters were recorded. The results were analyzed with a mixed linear model. In rats, behavioural sensitization was studied with repetitive injections of apomorphine. All the actimetry parameters indicated a decrease of locomotion the day after MPTP injections and eight parameters improved in MPTP mice treated with fenofibrate or bezafibrate. The apomorphine-induced rotation behaviour mildly decreased in 6-OHDA rats treated with fenofibrate, but behavioural sensitization was unchanged. The 6-OHDA and MPTP compounds have different toxicity mechanisms, which could explain why we did not observe the same effect in 6-OHDA rats as in MPTP mice. These data suggest that the protective effect of fibrates can be carried through inhibition of inflammation rather than oxidative stress.
Kreisler
Alexandre
A
University Lille Nord de France, Department of Pharmacology, Lille, France. alexandre.kreisler@chru-lille.fr
Duhamel
Alain
A
Vanbesien-Mailliot
Christel
C
Destée
Alain
A
Bordet
Régis
R
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001058:Apomorphine / Q000494:pharmacology; D001629:Bezafibrate / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004347:Drug Interactions; D005106:Exploratory Behavior / Q000187:drug effects; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D018709:Statistics, Nonparametric; D013378:Substantia Nigra / Q000378:metabolism; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000378:metabolism
D000978:Antiparkinson Agents; D018696:Neuroprotective Agents; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine; D011345:Fenofibrate; D001629:Bezafibrate