Behavioural pharmacologyThe 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
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.
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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
References (27)
- et al.
Role of dopamine receptor agonists in the treatment of early Parkinson’s disease
Parkinsonism Relat. Disord.
(2009) - et al.
Adenosine A2A receptor antagonists KF17837 and KW-6002 potentiate rotation induced by dopaminergic drugs in hemi-parkinsonian rats
Eur. J. Pharmacol.
(2000) Motor fluctuations and dyskinesia in Parkinson’s disease
Parkinsonism Relat. Disord.
(2001)- et al.
Targeting adenosine A2A receptors in Parkinson’s disease
Trends Neurosci.
(2006) - et al.
The adenosine A2A receptor antagonist, istradefylline enhances the anti-parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets
Eur. J. Pharmacol.
(2015) - et al.
The adenosine A2A receptor antagonist, istradefylline enhances the motor response of l-DOPA without worsening dyskinesia in MPTP-treated common marmosets
J. Pharmacol. Sci.
(2014) - et al.
Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature
Mov. Disord.
(2001) - et al.
Rescue of locomotor impairment in dopamine D2 receptor deficient mice by an adenosine A2A receptor antagonist
J. Neurosci.
(2000) - et al.
Dopamine receptor agonists for Parkinson’s disease
Expert Opin. Investig. Drugs
(2014) - et al.
Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer
Proc. Natl. Acad. Sci. USA
(2015)