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. 2016-11-01; 110: 48-58
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1. Neuropharmacology. 2016 Nov;110(Pt A):48-58. doi:
10.1016/j.neuropharm.2016.07.012. Epub 2016 Jul 14.
An evaluation of istradefylline treatment on Parkinsonian motor and cognitive
deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque
Ko WKD(1), Camus SM(2), Li Q(2), Yang J(2), McGuire S(2), Pioli EY(2), Bezard
(1)Motac Neuroscience Ltd, Manchester, United Kingdom. Electronic address:
(2)Motac Neuroscience Ltd, Manchester, United Kingdom.
(3)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,
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.
PMID: 27424102 [Indexed for MEDLINE]