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Chronic l-3,4-dihydroxyphenylalanine ( l-DOPA) treatment of Parkinson's disease (PD) often results in debilitating involuntary movements known as l-DOPA-induced dyskinesia ( lID), which is the main obstacle in PD. The abnormal involuntary movements (AIMs) are consistently involved with the activation of the Ras-extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) signaling pathway. Previous research has also shown that blockade of ERK phosphorylation could reduce the induction of lID. Consequently, inhibitors of MAPK signaling cascade that block the aberrant supersensitive response of direct pathway striatal neurons could provide a novel therapeutic adjunct to l-DOPA in the treatment of PD. Statins, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, can also inhibit Ras isoprenylation and activity, and the subsequent phosphorylation of ERK1/2 (pERK1/2). Simvastatin, a representative of statins, could reduce l-DOPA-induced AIM incidence and severity in the 6-hydroxydopamine (6-OHDA) rat model of PD by preventing the l-DOPA/benserazide-induced increase in pERK1/2 levels in our study. The simvastatin- l-DOPA/benserazide-treated 6-OHDA animals displayed less severe rotational behavior and a dramatic reduction in AIM severity than the l-DOPA/benserazide-treated ones. This lower AIM severity was related to a decrease in l-DOPA-induced increase in the following: (1) striatal pERK1/2 and (2) FosB levels. These results suggest that simvastatin could represent a treatment option for managing lID in PD. [ABSTRACT FROM AUTHOR]