KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse

Abstract

The risk of Parkinson's disease (PD) is associated with a lower intake of caffeine, a non-selective adenosine A 2A antagonist. In agreement, genetic or pharmacological inactivation of adenosine A 2A receptors in animal models of PD has demonstrated both symptomatic and neuroprotective effects. These findings and the lack of disease modifying therapies have led to intense research on adenosine A 2A antagonists as a novel treatment for PD. In the present study the neuroprotective effect of the A 2A receptor antagonist KW-6002 was investigated using different models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice, which induced dopaminergic terminal and or dopaminergic cell loss and inflammation. Treatment with KW-6002 prevented the loss of dopaminergic striatal terminals and nigral cell bodies and inhibited the nigral microglia activation. Our results confirm previous findings that pharmacological inactivation of A 2A receptors inhibits MPTP-induced dopaminergic damage at the level of striatum. In addition, we demonstrate for the first time that, after MPTP treatment in mice, an A 2A antagonist is neuroprotective, and has anti-inflammatory effects, at the level of the substantia nigra. Thus, our data further support the use of A 2A receptor antagonists as a novel neuroprotective therapy for PD.