1. 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.
- Author
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Ko WKD, Camus SM, Li Q, Yang J, McGuire S, Pioli EY, and Bezard E
- Subjects
- Adenosine A2 Receptor Antagonists administration & dosage, Animals, Cognition Disorders physiopathology, Cognition Disorders psychology, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical methods, Drug Therapy, Combination, Dyskinesia, Drug-Induced physiopathology, Dyskinesia, Drug-Induced psychology, Female, Hypokinesia drug therapy, Hypokinesia physiopathology, Hypokinesia psychology, Levodopa toxicity, MPTP Poisoning physiopathology, MPTP Poisoning psychology, Macaca fascicularis, Motor Skills Disorders drug therapy, Motor Skills Disorders physiopathology, Motor Skills Disorders psychology, Treatment Outcome, Cognition Disorders drug therapy, Dyskinesia, Drug-Induced drug therapy, Levodopa administration & dosage, MPTP Poisoning drug therapy, Purines administration & dosage
- Abstract
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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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