Abstract
L-3,4-dihydroxypheylalanine (L-dopa)-induced dyskinesia represent a debilitating complication of therapy for Parkinson's disease (PD) that result from a progressive sensitization through repeated L-dopa exposures. The MPTP macaque model was used to study the proteome in dopamine-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The present data suggest that the dopamine-depleted striatum is so sensitive to de novo L-dopa treatment that the first ever administration alone would be able (i) to induce rapid post-translational modification-based proteomic changes that are specific to this first exposure and (ii), possibly, lead to irreversible protein level changes that would be not further modified by chronic L-dopa treatment. The apparent equivalence between first and chronic L-dopa administration suggests that priming would be the direct consequence of dopamine loss, the first L-dopa administrations only exacerbating the sensitization process but not inducing it.
Highlights
Involuntary movements, or dyskinesias, represent a debilitating complication of L-3,4-dihydroxyphenylalanine (L-dopa) therapy for Parkinson’s disease (PD), experienced, by the vast majority of the patients [1]
MPTP intoxication procedure and further vehicle or L-dopa treatment for several months at a tailored dose designed to produce a full reversal of parkinsonian condition were performed as described in many occasions [e.g. see 8,9–11] (Note that by L-dopa, we mean the clinical formulation ModoparH, (Roche) that is a combination of L-dopa and carbidopa at a fixed ratio of 4:1)
At odds with this classic view, the present data suggests that the DA-depleted striatum is so sensitive to a de novo acute L-dopa treatment that the first ever administration alone is able to induce rapid post-translational modifications (PTM)-based proteomic changes that do not seem to be modified by chronic L-dopa treatment
Summary
Involuntary movements, or dyskinesias, represent a debilitating complication of L-3,4-dihydroxyphenylalanine (L-dopa) therapy for Parkinson’s disease (PD), experienced, by the vast majority of the patients [1]. The past few years have seen unprecedented progress towards better understanding of the underlying neural mechanisms of existing L-dopa-induced dyskinesia (LID). Priming is classically defined as the process by which the brain becomes sensitized such that administration of dopaminergic therapy modifies the response to subsequent dopaminergic treatments [3]. In this way, over time, with repeated treatment, the chance of dopaminergic stimulation eliciting LID is increased and once LID has been established, the severity of dyskinesia increases. Study of immediate-early gene expression has unraveled that a single administration of a DA agonist induces a complex striatal response [4,5], including components of homeostatic response to excessive stimulation as well as genes subserving cellular and synaptic plasticity [4]
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