The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin reduces severity of L-DOPA-induced abnormal involuntary movements in experimental Parkinson's disease.
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.
Schuster
Stefan
S
Boehringer Ingelheim Pharma GmbH, 88397 Biberach, Germany.
Nadjar
Agnès
A
Guo
Jun Tang
JT
Li
Qin
Q
Ittrich
Carina
C
Hengerer
Bastian
B
Bezard
Erwan
E
D000818:Animals; D020820:Dyskinesias / Q000188:drug therapy* / Q000201:enzymology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007980:Levodopa / Q000633:toxicity*; D008148:Lovastatin / Q000627:therapeutic use*; D008297:Male; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007980:Levodopa; D008148:Lovastatin