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.
Keywords
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Article info
Publication history
Published online: March 28, 2014
Accepted:
March 20,
2014
Received in revised form:
March 5,
2014
Received:
October 4,
2013
Identification
Copyright
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