A preclinical study on the combined effects of repeated eltoprazine and preladenant treatment for alleviating L-DOPA-induced dyskinesia in Parkinson's disease

Eur J Pharmacol. 2017 Oct 15:813:10-16. doi: 10.1016/j.ejphar.2017.07.030. Epub 2017 Jul 21.

Abstract

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.

Keywords: 5-HT; Adenosine; L-DOPA-induced dyskinesia; Parkinson's disease.

MeSH terms

  • Animals
  • Antiparkinson Agents / adverse effects*
  • Antiparkinson Agents / therapeutic use
  • Behavior, Animal / drug effects
  • Drug Interactions
  • Dyskinesia, Drug-Induced / drug therapy*
  • Dyskinesia, Drug-Induced / metabolism
  • Dyskinesia, Drug-Induced / physiopathology
  • Female
  • Levodopa / adverse effects*
  • Levodopa / therapeutic use
  • Macaca fascicularis
  • Motor Activity / drug effects
  • Parkinson Disease / complications
  • Parkinson Disease / drug therapy*
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use
  • Time Factors

Substances

  • Antiparkinson Agents
  • Piperazines
  • Levodopa
  • eltoprazine