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Activation of DREAM (Downstream Regulatory Element Antagonistic Modulator), a calcium-binding protein, reduces L-DOPA-induced dyskinesias in mice

AuthorsRuiz de Diego, Irene CSIC ORCID; Mellström, Britt; Vallejo, Mario CSIC ORCID; Naranjo, José Ramón; Moratalla, Rosario CSIC ORCID
Issue Date2015
CitationBiological Psychiatry 77(2): 95-105 (2015)
Abstract[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.
Publisher version (URL)https://doi.org/10.1016/j.biopsych.2014.03.023
Identifiersdoi: 10.1016/j.biopsych.2014.03.023
issn: 0006-3223
e-issn: 1873-2402
Appears in Collections:(IIBM) Artículos
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