Elsevier

European Journal of Pharmacology

Volume 766, 5 November 2015, Pages 25-30
European Journal of Pharmacology

Behavioural pharmacology
The adenosine A2A receptor antagonist, istradefylline enhances anti-parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets

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Abstract

The adenosine A2A receptor antagonist, istradefylline improves motor function in patients with advanced Parkinson's disease (PD) optimally treated with a combination of l-DOPA and a dopamine agonist without increasing the risk of troublesome dyskinesia. However, the effects of istradefylline on motor function when administered in combination with low dose of l-DOPA and dopamine agonists as occurs in early PD are unknown. We investigated whether istradefylline enhances the combined anti-parkinsonian effects of a suboptimal dose of l-DOPA and a threshold dose of either the non-ergot dopamine agonist, ropinirole or the ergot dopamine agonist, pergolide in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset.

Threshold doses of ropinirole (0.025–0.075 mg/kg p.o.) and pergolide (0.01 mg/kg p.o.) produced a weak anti-parkinsonian effect. Co-administration of a suboptimal dose of l-DOPA (2.5 mg/kg p.o.) with threshold doses of the dopamine agonists enhanced their anti-parkinsonian effect that led to increased ‘ON’ time without dyskinesia appearing. Administering istradefylline (10 mg/kg p.o.) with the threshold doses of dopamine agonists and the suboptimal dose of l-DOPA in a triple combination caused a further enhancement of the anti-parkinsonian response but dyskinesia was still absent.

In early PD, dopamine agonists are often used as first-line monotherapy, but efficacy is usually lost within a few years, at which time l-DOPA is added but with the risk of dyskinesia appearance. These results show that istradefylline is effective in improving motor function in combination with low dose dopaminergic drug treatment without provoking dyskinesia.

Introduction

Dopamine agonists are often used as first-line monotherapy for Parkinson’s disease (PD), particularly in younger early stage patients (Bonuccelli et al., 2009) but within 2–5 years, their efficacy declines and additional dopamine replacement therapy is required. Higher dosage levels of dopamine agonists can be used but these are often associated with the onset of impulse control disorders (ICDs), vascular change, hallucinations and psychosis (Perez-Lloret and Rascol, 2010, Raja and Bentivoglio, 2012). In the majority of individuals, effective control of motor function is achieved by the addition L-3,4-dihydroxyphenylalanine (l-DOPA) to dopamine agonist therapy (Blandini and Armentero, 2014). However, adding l-DOPA carries the risk of the development of motor response fluctuations and complications such as ‘wearing-off’ and dyskinesia notably as its dose is increased (Ahlskog and Muenter, 2001, Nutt, 2001). This was emphasized recently, in the results of STRIDE-PD study showing the relationship between l-DOPA dose and age and the risk of developing ‘wearing-off’ or dyskinesia in early PD (Warren Olanow et al., 2013). These results suggest that when l-DOPA is added on to treatment with a low dose of dopamine agonists in early PD, the lowest l-DOPA dose required to achieve efficacy should be used. This strategy will initially provide adequate clinical effect but inevitably with time, the l-DOPA dose will need to be increased with disease progression so raising the risk of ‘wearing off’ and dyskinesia appearance.

Istradefylline (KW-6002) is a selective adenosine A2A receptor antagonist approved for use in PD in Japan. In Phase IIB/III clinical trial, istradefylline reduced ‘OFF’ time in late stage PD patients receiving optimized dopaminergic therapy but who were exhibiting ‘wearing off’ and long ‘OFF’ periods and importantly, it did not worsen established dyskinesia (Hauser et al., 2008, LeWitt et al., 2008, Mizuno et al., 2013). However, these studies did not show the relationship between the dose of dopaminergic medication used and the effect of istradefylline as all patients were already receiving high levels of dopamine replacement therapy and they do not reflect events in early stage PD where lower doses of l-DOPA and dopamine agonists are used. This is important because in both rodent and primate models of PD, adenosine A2A antagonists produce the most marked improvement in motor function when administered in conjunction with a sub-optimal dose of l-DOPA (Koga et al., 2000, Uchida et al., 2014). Similarly, adenosine A2A antagonists enhance the anti-parkinsonian activity of a threshold dose of dopamine agonists in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets (Uchida et al., 2015). However, there has not been any investigation whether adding istradefylline to low dose dopamine agonists and l-DOPA treatment in a triple combination therapy further improves motor function and avoids dyskinesia induction.

In this study, we have investigated whether istradefylline enhances the reversal of motor disability when administered in combination with low doses of l-DOPA and two clinically used dopamine agonist drugs, namely the ergot derivative, pergolide and the non-ergot compound, ropinirole in MPTP-treated common marmosets that show dyskinesia when challenged with high doses of l-DOPA.

Section snippets

Animals

All experiments on animals were performed in accordance with Standards for Proper Conduct of Animal Experiments at Kyowa Hakko Kirin Co., Ltd. under the approval of the company’s Institutional Animal Care and Use Committee. Fuji Research Park of Kyowa Hakko Kirin co., Ltd. is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care, International. Common marmosets (Callithrix jacchus) obtained from CLEA Japan, Inc. (Tokyo, Japan) and were of either sex

Anti-parkinsonian activity of l-DOPA, ropinirole and istradefylline in MPTP-treated common marmosets

A suboptimal dose of l-DOPA (P=0.2869), a threshold dose of ropinirole (P=0.9347) and istradefylline (P=0.1897) produced a slight but non-significant increase in locomotor activity compared with vehicle control in MPTP-treated common marmosets (Fig. 1A). Co-administration of the suboptimal dose of l-DOPA with the threshold dose of ropinirole slightly enhanced the increase in locomotor activity compared with the threshold dose of ropinirole alone (P=0.6833, Fig. 1A). Further enhancement of the

Discussion

Monotherapy with dopamine agonists is commonly used to control motor symptoms in the early stages of PD as their use can avoid or delay the onset of motor fluctuations (‘wearing off’) and motor complications (dyskinesia) (Bonuccelli et al., 2009). However, as dosage is increased the incidence of psychiatric side-effects such as ICDs and hallucinations also increases (Raja and Bentivoglio, 2012, Weintraub and Nirenberg, 2013) and this has led a more restricted use. In addition, within 2–5 years

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