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The Journal of Neuroscience, April 23, 2008, 28(17):4311-4316; doi:10.1523/JNEUROSCI.4720-07.2008
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Brief Communications
The 3-Hydroxy-3-Methylglutaryl-CoA Reductase Inhibitor Lovastatin Reduces Severity of L-DOPA-Induced Abnormal Involuntary Movements in Experimental Parkinson's Disease
Stefan Schuster,1 Agnès Nadjar,2 Jun Tang Guo,3 Qin Li,3 Carina Ittrich,1 Bastian Hengerer,1 andErwan Bezard2 1Boehringer Ingelheim Pharma GmbH, 88397 Biberach, Germany, 2Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, Universite Victor Segalen-Bordeaux 2, 33076 Bordeaux, France, and 3Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, 100021 Beijing, China
Correspondence should be addressed to Erwan Bezard, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, Universite Bordeaux 2, 146 Rue Leo Saignat, 33076 Bordeaux, France. Email: Erwan.bezard{at}u-bordeaux2.fr
Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia (LID), about which the rodent analog, the abnormal involuntary movements (AIMs), has been associated consistently with an activation of the Ras-extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase signaling pathway. Previous studies have shown that lovastatin, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity and subsequently the phosphorylation of ERK1/2 (pERK1/2). We hypothesized that lovastatin treatment-commenced previous L-DOPA exposure could reduce AIM incidence and severity in the 6-hydroxydopamine (6-OHDA) rat model of PD by secondarily preventing the L-DOPA/Benserazide-induced increase in pERK1 levels. The lovastatin-L-DOPA/Benserazide-treated 6-OHDA animals displayed less severe rotational behavior as well as a dramatic reduction in AIM severity than the L-DOPA/Benserazide-treated ones. Such lower AIM severity was associated with a decrease in L-DOPA-induced increase in the following: (1) striatal pERK1 and (2)
FosB levels, and (3) theta/
oscillations of substantia nigra pas reticulata (SNr) neurons as well as (4) a normalization of SNr firing frequency. Those results strongly suggest that lovastatin might represent a treatment option for managing LID in PD.
Key words: Parkinson's disease; statins; dyskinesia; AIMs; LID; 6-hydroxydopamine; substantia nigra pars reticulata; pERK1/2
Received Oct. 18, 2007; revised March 10, 2008; accepted March 11, 2008.
Correspondence should be addressed to Erwan Bezard, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5227, Universite Bordeaux 2, 146 Rue Leo Saignat, 33076 Bordeaux, France. Email: Erwan.bezard{at}u-bordeaux2.fr
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