Activation of DREAM (downstream regulatory element antagonistic modulator), a calcium-binding protein, reduces L-DOPA-induced dyskinesias in mice.

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.

• Authors: Irene Ruiz-DeDiego, Britt Mellstrom, Mario Vallejo, Jose R Naranjo, Rosario Moratalla
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 77 Issue 2 Pg. 95-105 (Jan 15 2015) ISSN: 1873-2402 [Electronic] United States
• PMID: 24857398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antiparkinson Agents
• Csen protein, mouse
• Endorphins
• Fosb protein, mouse
• Histones
• Kv Channel-Interacting Proteins
• Proto-Oncogene Proteins c-fos
• Receptors, AMPA
• Repressor Proteins
• Levodopa
• Dynorphins
• rimorphin
• Oxidopamine
• glutamate receptor ionotropic, AMPA 1

Topics

• Acetylation
• Animals
• Antiparkinson Agents (adverse effects, pharmacology)
• Blotting, Western
• Corpus Striatum (drug effects, physiopathology)
• Dynorphins (metabolism)
• Dyskinesia, Drug-Induced (physiopathology)
• Endorphins (metabolism)
• Histones (metabolism)
• Immunohistochemistry
• Kv Channel-Interacting Proteins (genetics, metabolism)
• Levodopa (adverse effects, pharmacology)
• Mice, Knockout
• Motor Activity (drug effects, physiology)
• Oxidopamine
• Parkinsonian Disorders (drug therapy, physiopathology)
• Phosphorylation
• Proto-Oncogene Proteins c-fos (metabolism)
• Receptors, AMPA (metabolism)
• Repressor Proteins (genetics, metabolism)
• Rotarod Performance Test