Lipid-lowering drugs in the MPTP mouse model of Parkinson's disease: fenofibrate has a neuroprotective effect, whereas bezafibrate and HMG-CoA reductase inhibitors do not.
We tested the ability of simvastatin, atorvastatin, fenofibrate and bezafibrate (two synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists) to prevent dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Tyrosine hydroxylase (TH) immunochemistry was performed 8 days after acute MPTP intoxication. When orally administered for the week prior to intoxication and a week thereafter, fenofibrate prevented the MPTP-induced dopaminergic cell loss in the substantia nigra pars compacta (SNpc) and attenuated the loss of tyrosine hydroxylase immunoreactivity in the striatum. The dosage of 1-methyl-4-phenyl pyridinium (MPP+) in the striatum by high-performance liquid chromatography indicated that fenofibrate did not affect MPTP metabolism. Bezafibrate had no effect and, strikingly, simvastatin and atorvastatin had a negative effect. We also demonstrated the presence of PPAR-alpha in the dopaminergic neurons of the murine substantia nigra. Our data suggest that PPAR-alpha activation by fenofibrate could have a neuroprotective effect in PD through inhibition of inflammation, oxidative stress and/or apoptosis.
Kreisler
Alexandre
A
Department of Pharmacology EA 1046, University of Lille School of Medicine, Lille, France. a-kreisler@chru-lille.fr
Gelé
Patrick
P
Wiart
Jean-François
JF
Lhermitte
Michel
M
Destée
Alain
A
Bordet
Régis
R
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000214:Acyl Coenzyme A / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001629:Bezafibrate / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004347:Drug Interactions; D011345:Fenofibrate / Q000627:therapeutic use*; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008995:Monoamine Oxidase / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology
D000214:Acyl Coenzyme A; D000960:Hypolipidemic Agents; D047493:PPAR alpha; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D011345:Fenofibrate; D001629:Bezafibrate