Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson’s disease.
Mov Disord.. 2016-02-12; 31(4): 501-511
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1. Mov Disord. 2016 Apr;31(4):501-11. doi: 10.1002/mds.26475. Epub 2016 Feb 12.
Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models
of Parkinson’s disease.
Pinna A(1), Ko WK(2)(3), Costa G(4), Tronci E(5), Fidalgo C(5), Simola N(4), Li
Q(2)(3), Tabrizi MA(6), Bezard E(2)(3)(7)(8), Carta M(5), Morelli M(1)(4).
(1)National Research Council of Italy, Neuroscience Institute, Cagliari, Italy.
(2)Motac Neuroscience Ltd, Manchester, UK.
(3)Institute of Laboratory Animal Sciences, China Academy of Medical Sciences,
(4)Department of Biomedical Sciences, section of Neuropsychopharmacology,
University of Cagliari, Cagliari, Italy.
(5)Department of Biomedical Sciences, section of Physiology, University of
Cagliari, Cagliari, Italy.
(6)Department of Chemical and Pharmaceutical Sciences, University of Ferrara,
(7)Université de Bordeaux, Institut des Maladies Neurodégénératives, Bordeaux,
(8)CNRS, Institut des Maladies Neurodégénératives, Bordeaux, France.
BACKGROUND: The serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed
dyskinetic-like behavior in animal models of Parkinson’s disease (PD) but
simultaneously reduced levodopa (l-dopa)-induced motility. Moreover, adenosine
A2A receptor antagonists, such as preladenant, significantly increased l-dopa
efficacy in PD without exacerbating dyskinetic-like behavior.
OBJECTIVES: We evaluated whether a combination of eltoprazine and preladenant may
prevent or suppress l-dopa-induced dyskinesia, without impairing l-dopa’s
efficacy in relieving motor signs, in 2 PD models: unilateral
6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
METHODS: Rotational behavior and abnormal involuntary movements, or disability
and l-dopa-induced dyskinesia were evaluated in 6-hydroxydopamine-lesioned rats
and MPTP-treated monkeys, respectively. Moreover, in the rodent striatum,
induction of immediate-early gene zif-268, an index of long-term changes, was
correlated with dyskinesia.
RESULTS: In 6-hydroxydopamine-lesioned rats, combined administration of l-dopa
(4 mg/kg) plus eltoprazine (0.6 mg/kg) plus preladenant (0.3 mg/kg) significantly
prevented or reduced dyskinetic-like behavior without impairing motor activity.
Zif-268 was increased in the striatum of rats treated with l-dopa and l-dopa plus
preladenant compared with vehicle. In contrast, rats treated with eltoprazine
(with or without preladenant) had lower zif-268 activation after chronic
treatment in both the dyskinetic and l-dopa-non-primed groups. Moreover, acute
l-dopa plus eltoprazine plus preladenant prevented worsening of motor performance
(adjusting step) and sensorimotor integration deficit. Similar results were
obtained in MPTP-treated monkeys, where a combination of preladenant with
eltoprazine was found to counteract dyskinesia and maintain the full therapeutic
effects of a low dose of l-dopa.
CONCLUSIONS: Our results suggest a promising nondopaminergic pharmacological
strategy for the treatment of dyskinesia in PD. © 2016 International Parkinson
and Movement Disorder Society.
© 2016 International Parkinson and Movement Disorder Society.
PMID: 26871939 [Indexed for MEDLINE]