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 (2.5mg/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 (10mg/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.