Abstract
Dyskinesias are characterized by abnormal repetitive involuntary movements due to dysfunctional neuronal activity. Although levodopa-induced dyskinesia, characterized by tic-like abnormal involuntary movements, has no clinical treatment for Parkinson’s disease patients, animal studies indicate that Riluzole, which interferes with glutamatergic neurotransmission, can improve the phenotype. The rat model of Levodopa-Induced Dyskinesia is a unilateral lesion with 6-hydroxydopamine in the medial forebrain bundle, followed by the repeated administration of levodopa. The molecular pathomechanism of Levodopa-Induced Dyskinesia is still not deciphered; however, the implication of epigenetic mechanisms was suggested. In this study, we investigated the striatum for DNA methylation alterations under chronic levodopa treatment with or without co-treatment with Riluzole. Our data show that the lesioned and contralateral striata have nearly identical DNA methylation profiles. Chronic levodopa and levodopa + Riluzole treatments led to DNA methylation loss, particularly outside of promoters, in gene bodies and CpG poor regions. We observed that several genes involved in the Levodopa-Induced Dyskinesia underwent methylation changes. Furthermore, the Riluzole co-treatment, which improved the phenotype, pinpointed specific methylation targets, with a more than 20% methylation difference relative to levodopa treatment alone. These findings indicate potential new druggable targets for Levodopa-Induced Dyskinesia.
Highlights
Dyskinesias arise from widely different etiologies, ranging from neurodevelopmental alterations, genetic abnormalities, neurodegenerative diseases, and administration of drugs (e.g., Levodopa-Induced Dyskinesia in Parkinson’s disease) [1]
The phenotype was partially rescued by the administration of Riluzole
Our results showed both in groups, there was an enrichment of relative to a that both in levodopa treatment (L-DOPA) and L-DOPA + R groups, there was an enrichment of Differentially Methylated Sites (DMS) relative random distribution within bp distance, i.e., CpGs in close proximity tend to undergo to a random distribution within 100 bp distance, i.e., CpGs in close proximity tend to unsignificant methylation changeschanges suggesting most probably the co-occurrence of similarof dergo significant methylation suggesting most probably the co-occurrence changes
Summary
There are different strategies to manage the manifestation of LID: administration of lower doses of L-DOPA, treatment with (extended-release) amantadine, and antiepileptic [4,5,6,7,8], antipsychotic [9], or anti-glutamatergic drugs [10,11]. All these treatments show inconsistent results coupled with side effects indicating the need for better solutions. Deepbrain stimulation is a further, but rarely used, strategy due to its invasive nature [12,13]
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