The
adenosine A2A receptor antagonist,
istradefylline, enhances anti-parkinsonian activity in patients with advanced Parkinson׳s disease (PD) already treated with combinations of
L-DOPA and
dopamine agonist drugs but who are still exhibiting prolonged 'OFF' periods. In contrast, the effects of
istradefylline on motor function when administered in combination with low dose
dopamine agonist therapy in early PD are unknown. We now investigate whether
istradefylline administered with a threshold dose of either the non-ergot
dopamine agonist,
ropinirole or the ergot
dopamine agonist,
pergolide enhances anti-parkinsonian activity in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP)-treated common marmoset. Both
ropinirole (0.01-0.1mg/kg p.o.) and
pergolide (0.003-0.1mg/kg p.o.) administered alone produced dose dependent increases in locomotor activity, a reduction in motor disability. Threshold doses of
ropinirole (0.025-0.075mg/kg p.o.) and
pergolide (0.01-0.075mg/kg p.o.) were then selected that in individual animals caused a small but non-significant anti-parkinsonian effect. Administration of
istradefylline (10mg/kg p.o.) alone resulted in a decrease in motor disability and increase in 'ON' time but
dyskinesia was not observed. Combined administration of
pergolide or
ropinirole with
istradefylline resulted in an increase in the reversal of motor disability and increase in 'ON' time compared to that produced by either treatment alone but
dyskinesia was still not observed. These results show that
istradefylline is effective in improving motor function when combined with low dose
dopamine agonist treatment. In early PD, this may avoid dose escalation or allow a reduction in
dopamine agonist dosage without a loss of efficacy and prevent dopaminergic side-effects from becoming treatment limiting.