Abstract
Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson’s disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L-DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets.
Highlights
Luca Pagliaroli and Joanna Widomska have equal contribution.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Chronic administration of the dopamine precursor L-DOPA— the first-line treatment of dystonic symptoms manifesting in childhood or in Parkinson’s disease (PD) [1]—often leads to the development of so-called abnormal involuntary movements (AIMs)
To confirm the degree of dopaminergic denervation in the unilateral 6-OHDA-lesioned rats, total dopamine (DA) tissue content in the ipsilateral and contralateral striatum relative to the lesion was assayed by high-performance liquid chromatography (HPLC) coupled to electrochemical detection (ECD). 6-OHDA lesion induced a marked decrease (76%) in DA concentration in the ipsilateral striatum compared with the contralateral side (Supplementary Fig. 1)
465 genes were overlapping in that they were differentially expressed in both comparisons (Supplementary Fig. 2), and all of these genes were differentially expressed in the opposite direction in the two comparisons
Summary
Literature evidence indicates that chronic L-DOPA administration affects multiple neurotransmitter systems [4,5,6], but mainly the dopaminergic system, i.e., L-DOPA activates striatal dopamine 1 receptors (D1Rs), resulting in the overstimulation of the Bdirect^ nigrostriatal pathway [7, 8]. This hypersensitivity of D1Rs in striatal neurons triggers a number of downstream signaling cascades involving—among others—cyclic AMP (cAMP)-activated protein kinase A (PKA) [9, 10], the phosphatase inhibitor
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