Anti-dyskinetic effect of anpirtoline in animal models of L-DOPA-induced dyskinesia.

Abstract

The serotonin system has emerged as a potential target for anti-dyskinetic therapy in Parkinson's disease. In fact, serotonin neurons can convert L-DOPA into dopamine, and mediate its synaptic release. However, they lack a feedback control mechanism able to regulate synaptic dopamine levels, which leads to un-physiological stimulation of post-synaptic striatal dopamine receptors. Accordingly, drugs able to dampen the activity of serotonin neurons can suppress L-DOPA-induced dyskinesia in animal models of Parkinson's disease. Here, we investigated the ability of the 5-HT1A/1B receptor agonist anpirtoline to counteract L-DOPA-induced dyskinesia in L-DOPA-primed 6-OHDA-lesioned rats and MPTP-treated macaques. Results suggest that anpirtoline dose-dependently reduced dyskinesia both in rats and monkeys; however, the effect in MPTP-treated macaques was accompanied by a worsening of the Parkinson's disease score at significantly effective doses (1.5 and 2.0mg/kg). At a lower dose (0.75mg/kg), anpirtoline markedly reduced dyskinesia in 4 out of 5 subjects, but statistical significance was prevented by the presence of a non-responsive subject. These results provide further evidence that the serotonin neurons contribute both to the pro-dyskinetic effect of L-DOPA and to its therapeutic efficacy in the rat and monkey models of Parkinson's disease.

• Authors: Erwan Bézard, Ana Muñoz, Elisabetta Tronci, Elsa Y Pioli, Qin Li, Gregory Porras, Anders Björklund, Manolo Carta
• Journal: Neuroscience research (Neurosci Res) Vol. 77 Issue 4 Pg. 242-6 (Dec 2013) ISSN: 1872-8111 [Electronic] Ireland
• PMID: 24135129 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

Chemical References

• Antiparkinson Agents
• Piperidines
• Pyridines
• Serotonin 5-HT1 Receptor Agonists
• anpirtoline
• Levodopa

Topics

• Animals
• Antiparkinson Agents (adverse effects)
• Dyskinesia, Drug-Induced (drug therapy)
• Female
• Levodopa (adverse effects)
• Macaca fascicularis
• Parkinsonian Disorders (drug therapy)
• Piperidines (therapeutic use)
• Pyridines (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Serotonin 5-HT1 Receptor Agonists (therapeutic use)