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Título: | Activation of DREAM (Downstream Regulatory Element Antagonistic Modulator), a calcium-binding protein, reduces L-DOPA-induced dyskinesias in mice |
Autor: | Ruiz de Diego, Irene CSIC ORCID; Mellström, Britt CSIC; Vallejo, Mario CSIC ORCID; Naranjo, José Ramón CSIC ORCID; Moratalla, Rosario CSIC ORCID | Fecha de publicación: | 2015 | Editor: | Elsevier | Citación: | Biological Psychiatry 77(2): 95-105 (2015) | Resumen: | [Background]: Previous studies have implicated the cyclic adenosine monophosphate/protein kinase A pathway as well as FosB and dynorphin-B expression mediated by dopamine D1 receptor stimulation in the development of 3,4-dihydroxyphenyl-L-alanine (L-DOPA)–induced dyskinesia. The magnitude of these molecular changes correlates with the intensity of dyskinesias. The calcium-binding protein downstream regulatory element antagonistic modulator (DREAM) binds to regulatory element sites called DRE in the DNA and represses transcription of target genes such as c-fos, fos-related antigen-2 (fra-2), and prodynorphin. This repression is released by calcium and protein kinase A activation. Dominant-active DREAM transgenic mice (daDREAM) and DREAM knockout mice (DREAM−/−) were used to define the involvement of DREAM in dyskinesias. [Methods]: Dyskinesias were evaluated twice a week in mice with 6-hydroxydopamine lesions during long-term L-DOPA (25 mg/kg) treatment. The impact of DREAM on L-DOPA efficacy was evaluated using the rotarod and the cylinder test after the establishment of dyskinesia and the molecular changes by immunohistochemistry and Western blot. [Results]: In daDREAM mice, L-DOPA-induced dyskinesia was decreased throughout the entire treatment. In correlation with these behavioral results, daDREAM mice showed a decrease in FosB, phosphoacetylated histone H3, dynorphin-B, and phosphorylated glutamate receptor subunit, type 1 expression. Conversely, genetic inactivation of DREAM potentiated the intensity of dyskinesia, and DREAM−/− mice exhibited an increase in expression of molecular markers associated with dyskinesias. The DREAM modifications did not affect the kinetic profile or antiparkinsonian efficacy of L-DOPA therapy. [Conclusions]: The protein DREAM decreases development of L-DOPA-induced dyskinesia in mice and reduces L-DOPA-induced expression of FosB, phosphoacetylated histone H3, and dynorphin-B in the striatum. These data suggest that therapeutic approaches that activate DREAM may be useful to alleviate L-DOPA-induced dyskinesia without interfering with the therapeutic motor effects of L-DOPA. |
Versión del editor: | https://doi.org/10.1016/j.biopsych.2014.03.023 | URI: | http://hdl.handle.net/10261/124594 | DOI: | 10.1016/j.biopsych.2014.03.023 | Identificadores: | doi: 10.1016/j.biopsych.2014.03.023 issn: 0006-3223 e-issn: 1873-2402 |
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ActivationDREAM.pdf | 1,56 MB | Adobe PDF | Visualizar/Abrir |
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