Objective: To examine the effects of MEK inhibitors PD98059 and U0126 on L-DOPA-induced dyskinesia and the induced molecular changes.

Background: L-DOPA-induced dyskinesia (LID) represents one of the major problems of the long-term therapy of patients with Parkinson’s disease (PD). Although the pathophysiologic mechanisms underlying LID are not completely understood, activation of the extracellular signal regulated kinase (ERK) is recognized to play a key role. ERK is phosphorylated by mitogen-activated protein kinase kinase (MEK) and could be suppressed by MEK inhibitor.

Methods: Rats with unilateral 6-OHDA lesions of the nigrostriatal pathway received chronic daily L-DOPA treatment for three weeks, and axial, orofacial, forelimb and locomotive abnormal involuntary movements (AIMs) were assessed every other day. U0126 or PD98059 was injected in the lateral ventricle daily for 12 days starting from day 10 of L-DOPA treatment.

Results: The administration of these inhibitors significantly reduced the severity of fully developed AIMs in the rat together with reversal of ERK activation and other associated molecular changes.

Conclusions: These results demonstrate a critical LID mechanism mediated by p-ERK1/2, and indicate that MEK inhibitors may be useful for managing LID.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mek-inhibitors-have-antidyskinetic-effects-in-hemiparkinsonian-rats-that-are-associated-with-critical-neurochemical-alterations-in-the-striatum/