The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin reduces severity of L-DOPA-induced abnormal involuntary movements in experimental Parkinson’s disease.
Journal of Neuroscience. 2008-04-23; 28(17): 4311-4316
DOI: 10.1523/jneurosci.4720-07.2008
Read on PubMed
1. J Neurosci. 2008 Apr 23;28(17):4311-6. doi: 10.1523/JNEUROSCI.4720-07.2008.
The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin reduces
severity of L-DOPA-induced abnormal involuntary movements in experimental
Parkinson’s disease.
Schuster S(1), Nadjar A, Guo JT, Li Q, Ittrich C, Hengerer B, Bezard E.
Author information:
(1)Boehringer Ingelheim Pharma GmbH, 88397 Biberach, Germany.
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) DeltaFosB levels, and (3) theta/alpha 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.
DOI: 10.1523/JNEUROSCI.4720-07.2008
PMID: 18434508 [Indexed for MEDLINE]