title: 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.
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.
authors.affiliation: Motac Neuroscience Ltd, Manchester, United Kingdom. Electronic address: d.ko@motac.com.
authors.forename: Wai Kin D
authors.initials: WKD
authors.lastname: Ko
authors.affiliation: Motac Neuroscience Ltd, Manchester, United Kingdom.
authors.forename: Sandrine M
authors.initials: SM
authors.lastname: Camus
authors.affiliation: Motac Neuroscience Ltd, Manchester, United Kingdom.
authors.forename: Qin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Motac Neuroscience Ltd, Manchester, United Kingdom.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Motac Neuroscience Ltd, Manchester, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: McGuire
authors.affiliation: Motac Neuroscience Ltd, Manchester, United Kingdom.
authors.forename: Elsa Y
authors.initials: EY
authors.lastname: Pioli
authors.affiliation: Motac Neuroscience Ltd, Manchester, United Kingdom; Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D005260:Female; D018476:Hypokinesia / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D007980:Levodopa / Q000008:administration & dosage* / Q000633:toxicity; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D008252:Macaca fascicularis; D019957:Motor Skills Disorders / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D011687:Purines / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; C111599:istradefylline; D007980:Levodopa
keywords: Cognition; Istradefylline; KW-6002; MPTP; Parkinson's disease; l-DOPA-induced dyskinesia