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

Neurosci Res. 2013 Dec;77(4):242-6. doi: 10.1016/j.neures.2013.10.002. Epub 2013 Oct 14.

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.

Keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 5-HT1A/1B agonists; 6-OHDA; 6-hydroxy-dopamine; AIMs; DA; Dyskinesia; L-DOPA; L-DOPA-induced dyskinesia; LID; MPTP; PD; Parkinson's disease; Serotonin; TH; abnormal involuntary movements; dopamine; tyrosine hydroxylase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

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