Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson's disease.

Abstract

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 (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. 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.

• Authors: Annalisa Pinna, Wai Kin D Ko, Giulia Costa, Elisabetta Tronci, Camino Fidalgo, Nicola Simola, Qin Li, Mojgan Aghazadeh Tabrizi, Erwan Bezard, Manolo Carta, Micaela Morelli
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 31 Issue 4 Pg. 501-11 (Apr 2016) ISSN: 1531-8257 [Electronic] United States
• PMID: 26871939 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 International Parkinson and Movement Disorder Society.

Chemical References

• Antiparkinson Agents
• Piperazines
• Pyrimidines
• Serotonin Receptor Agonists
• Triazoles
• Levodopa
• eltoprazine
• 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine

Topics

• Animals
• Antiparkinson Agents (administration & dosage, adverse effects, pharmacology)
• Behavior, Animal (drug effects)
• Disease Models, Animal
• Drug Therapy, Combination
• Dyskinesia, Drug-Induced (drug therapy, prevention & control)
• Female
• Levodopa (administration & dosage, adverse effects, pharmacology)
• Macaca fascicularis
• Male
• Parkinson Disease (drug therapy)
• Piperazines (administration & dosage, pharmacology)
• Pyrimidines (administration & dosage, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Serotonin Receptor Agonists (administration & dosage, pharmacology)
• Triazoles (administration & dosage, pharmacology)