In:
Movement Disorders, Wiley, Vol. 31, No. 4 ( 2016-04), p. 501-511
Abstract:
The serotonin 5‐HT 1A/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 A 2A 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 (MPTP)–treated monkeys. 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. Z if‐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
Type of Medium:
Online Resource
ISSN:
0885-3185
,
1531-8257
Language:
English
Publisher:
Wiley
Publication Date:
2016
detail.hit.zdb_id:
2041249-6
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