Striatal inhibition of calpains prevents levodopa-induced neurochemical changes and abnormal involuntary movements in the hemiparkinsonian rat model

Abstract

Pharmacological dopamine replacement with l-3,4-dihydroxyphenylalanine (l-DOPA) remains the most effective approach to treat the motor symptoms of Parkinson's disease (PD). However, as the disease progresses, the therapeutic response to l-DOPA gradually becomes erratic and is associated with the emergence of dyskinesia in the majority of patients. The pathogenesis of l-DOPA-induced dyskinesia (LID) is still unknown. In the current study, using the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, we demonstrated that the calcium-dependent proteins calpains and cdk5 of the striatum play a critical role in the behavioral and molecular changes evoked by l-DOPA therapy. We first confirmed that l-DOPA reversed PD symptoms, assessed by the cylinder, stepping and vibrissae-elicited reaching tests in this animal model, and elicited robust abnormal involuntary movements (AIMs) reminiscent of LID. Interestingly, intrastriatal infusion of the calpains inhibitor MDL28170, and to a lower extent the cdk5 inhibitor roscovitine, reduced the severity and amplitude of AIMs without affecting l-DOPA's antiparkinsonian effects. Notably, the calpains and cdk5 inhibitors totally reversed the striatal molecular changes attributed to l-DOPA therapy, such as ERK1/2 and dynamin phosphorylation. Another fascinating observation was that l-DOPA therapy, in combination with intrastriatal infusion of MDL28170, augmented tyrosine hydroxylase levels in the striatum of lesioned rats without affecting the number of dopaminergic cells in the substantia nigra. These findings disclose a novel mechanism underlying the maladaptive alterations induced by l-DOPA therapy in the 6-OHDA rat model of PD.