title: 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.affiliation: Cajal Institute, Madrid, Spain; Centro Nacional de Biotecnología, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Ruiz-DeDiego
authors.affiliation: Centro Nacional de Biotecnología, Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols all part of Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Britt
authors.initials: B
authors.lastname: Mellstrom
authors.affiliation: CIBERNED, Madrid, Spain; CIBERDEM, Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Vallejo
authors.affiliation: Centro Nacional de Biotecnología, Madrid, Spain; Instituto de Investigaciones Biomédicas Alberto Sols all part of Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Naranjo
authors.affiliation: Cajal Institute, Madrid, Spain; Centro Nacional de Biotecnología, Madrid, Spain. Electronic address: moratalla@cajal.csic.es.
authors.forename: Rosario
authors.initials: R
authors.lastname: Moratalla
mesh_terms: D000107:Acetylation; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000494:pharmacology; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004399:Dynorphins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D004723:Endorphins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D007980:Levodopa / Q000009:adverse effects* / Q000494:pharmacology; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D045442:Rotarod Performance Test
chemical_list: D000978:Antiparkinson Agents; D004399:Dynorphins; D004723:Endorphins; D006657:Histones; D051605:Kv Channel-Interacting Proteins; D007980:Levodopa; D016627:Oxidopamine; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D012097:Repressor Proteins; C496756:Csen protein, mouse; C483819:Fosb protein, mouse; C036200:rimorphin
keywords: Abnormal involuntary movements; Dopaminergic denervation; Dynorphin-B; FosB; Parkinson’s disease; Phospho-GluR1