title: Adenosine A₂A-receptor antagonist istradefylline enhances the motor response of L-DOPA without worsening dyskinesia in MPTP-treated common marmosets.
abstract: The adenosine A₂A-receptor antagonist istradefylline decreases OFF time in patients with Parkinson's disease who are already treated with optimal doses of dopaminergic medication but can cause an increase in non-troublesome dyskinesia. Preclinical experiments have shown that A₂A antagonists are most effective in potentiating motor function when combined with sub-maximal doses of L-DOPA. However, the effects of combining istradefylline with sub-optimal L-DOPA treatment on established dyskinesia have not been studied. We now examine the effects of acute and repeated administration of istradefylline on dyskinesia in MPTP-treated common marmosets previously primed to exhibit involuntary movements by prior exposure to L-DOPA. In these animals, single dose acute oral administration of istradefylline (10 mg/kg) enhanced and prolonged the anti-parkinsonian effects of a sub-optimal dose of L-DOPA (2.5 mg/kg). The chronic co-administration of istradefylline (10 mg/kg) with L-DOPA (2.5 mg/kg) for 21 days did not worsen the severity of existing dyskinesia. Rather, the severity of dyskinesia tended to be reduced over the 21-day treatment period. These results suggest that istradefylline can be used to potentiate the effects of sub-optimal doses of L-DOPA in the treatment of Parkinson's disease without causing or worsening dyskinesia.
authors.affiliation: Development Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Uchida
authors.forename: Tomomi
authors.initials: T
authors.lastname: Tashiro
authors.forename: Mika
authors.initials: M
authors.lastname: Kawai-Uchida
authors.forename: Akihisa
authors.initials: A
authors.lastname: Mori
authors.forename: Peter
authors.initials: P
authors.lastname: Jenner
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kanda
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002144:Callithrix; D004357:Drug Synergism; D020820:Dyskinesias / Q000503:physiopathology*; D005260:Female; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D020734:Parkinsonian Disorders / Q000503:physiopathology*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D011687:Purines; C111599:istradefylline; D007980:Levodopa