A preclinical study on the combined effects of repeated eltoprazine and preladenant treatment for alleviating L-DOPA-induced dyskinesia in Parkinson’s disease.
European Journal of Pharmacology. 2017-10-01; 813: 10-16
DOI: 10.1016/j.ejphar.2017.07.030
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1. Eur J Pharmacol. 2017 Oct 15;813:10-16. doi: 10.1016/j.ejphar.2017.07.030. Epub
2017 Jul 21.
A preclinical study on the combined effects of repeated eltoprazine and
preladenant treatment for alleviating L-DOPA-induced dyskinesia in Parkinson’s
disease.
Ko WKD(1), Li Q(2), Cheng LY(2), Morelli M(3), Carta M(4), Bezard E(5).
Author information:
(1)Motac Neuroscience Ltd, Manchester, United Kingdom. Electronic address:
.
(2)Motac Neuroscience Ltd, Manchester, United Kingdom; Institute of Laboratory
Animal Sciences, China Academy of Medical Sciences, Beijing, China.
(3)Department of Biomedical Sciences, Section of Toxicology, University of
Cagliari, University Campus, SS554 km 4.5, 09042 Monserrato, Italy.
(4)Department of Biomedical Sciences, Section of Physiology, University
of Cagliari, University Campus, SS554 km 4.5, 09042 Monserrato, Italy.
(5)Motac Neuroscience Ltd, Manchester, United Kingdom; Institute of Laboratory
Animal Sciences, China Academy of Medical Sciences, Beijing, China; Univ. de
Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux,
France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000
Bordeaux, France.
Eltoprazine, a serotonergic (5-HT)1A/B receptor agonist, is a potential treatment
for L-DOPA-induced dyskinesia (LID) in Parkinson’s disease (PD) but notably
compromises the anti-parkinsonian effects of L-DOPA, as seen in rodent and monkey
models of PD. Preladenant, a selective adenosine A2a receptor antagonist,
mediates modest anti-parkinsonian effects in parkinsonian monkeys. In a recent
investigation, combined eltoprazine and preladenant treatment with a
sub-threshold dose of L-DOPA acutely attenuated dyskinesia without exacerbating
PD disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated
macaques. The aim of this study was to investigate the daily repeated treatment
effects of eltoprazine (1mg/kg) alone, and in combination with preladenant
(5mg/kg), on the motor symptoms of PD and LID in MPTP-treated macaques. The
anti-dyskinetic and -parkinsonian effects of combinative drug administration with
a sub-threshold dose of L-DOPA were measured over 14 days. Eltoprazine treatment
alone produced a near-complete suppression of dyskinesia but consistently
increased parkinsonism. The administration of preladenant with eltoprazine
prevented the increased severity of parkinsonian motor symptoms but was unable to
maintain a reduced expression of dyskinesia with repeated administration. These
data demonstrate the clinical utility of the modulation of the serotonergic and
adenosine neurotransmitter systems with selective pharmacological agents for only
acute treatment of LID. This multi-targeted approach is unsuitable as a long-term
treatment regimen due to unsustainable therapeutic effects on dyskinesia.
Copyright © 2017 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.ejphar.2017.07.030
PMID: 28739086 [Indexed for MEDLINE]