An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models

Neuropharmacology. 2016 Nov;110(Pt A):48-58. doi: 10.1016/j.neuropharm.2016.07.012. Epub 2016 Jul 14.


Istradefylline (KW-6002), an adenosine A2A receptor antagonist, is used adjunct with optimal doses of L-3,4-dihydroxyphenylalanine (l-DOPA) to extend on-time in Parkinson's disease (PD) patients experiencing motor fluctuations. Clinical application of istradefylline for the management of other l-DOPA-induced complications, both motor and non-motor related (i.e. dyskinesia and cognitive impairments), remains to be determined. In this study, acute effects of istradefylline (60-100 mg/kg) alone, or with optimal and sub-optimal doses of l-DOPA, were evaluated in two monkey models of PD (i) the gold-standard 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque model of parkinsonian and dyskinetic motor symptoms and (ii) the chronic low dose (CLD) MPTP-treated macaque model of cognitive (working memory and attentional) deficits. Behavioural analyses in l-DOPA-primed MPTP-treated macaques showed that istradefylline alone specifically alleviated postural deficits. When combined with an optimal l-DOPA treatment dose, istradefylline increased on-time, enhanced therapeutic effects on bradykinesia and locomotion, but exacerbated dyskinesia. Istradefylline treatment at specific doses with sub-optimal l-DOPA specifically alleviated bradykinesia. Cognitive assessments in CLD MPTP-treated macaques showed that the attentional and working memory deficits caused by l-DOPA were lowered after istradefylline administration. Taken together, these data support a broader clinical use of istradefylline as an adjunct treatment in PD, where specific treatment combinations can be utilised to manage various l-DOPA-induced complications, which importantly, maintain a desired anti-parkinsonian response.

Keywords: Cognition; Istradefylline; KW-6002; MPTP; Parkinson's disease; l-DOPA-induced dyskinesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists / administration & dosage
  • Animals
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / physiopathology
  • Cognition Disorders / psychology
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical / methods
  • Drug Therapy, Combination
  • Dyskinesia, Drug-Induced / drug therapy*
  • Dyskinesia, Drug-Induced / physiopathology
  • Dyskinesia, Drug-Induced / psychology
  • Female
  • Hypokinesia / drug therapy
  • Hypokinesia / physiopathology
  • Hypokinesia / psychology
  • Levodopa / administration & dosage*
  • Levodopa / toxicity
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / physiopathology
  • MPTP Poisoning / psychology
  • Macaca fascicularis
  • Motor Skills Disorders / drug therapy
  • Motor Skills Disorders / physiopathology
  • Motor Skills Disorders / psychology
  • Purines / administration & dosage*
  • Treatment Outcome


  • Adenosine A2 Receptor Antagonists
  • Purines
  • istradefylline
  • Levodopa