KW-6002 protects from MPTP induced dopaminergic toxicity in the mouse.
The risk of Parkinson's disease (PD) is associated with a lower intake of caffeine, a non-selective adenosine A2A antagonist. In agreement, genetic or pharmacological inactivation of adenosine A2A 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 A2A antagonists as a novel treatment for PD. In the present study the neuroprotective effect of the A2A 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 A2A 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 A2A antagonist is neuroprotective, and has anti-inflammatory effects, at the level of the substantia nigra. Thus, our data further support the use of A2A receptor antagonists as a novel neuroprotective therapy for PD.
Pierri
Mette
M
Pharmacology Target Research, H. Lundbeck A/S, Ottilliavej 7-9, DK-2500 Valby, Denmark.
Vaudano
Elisabetta
E
Sager
Thomas
T
Englund
Ulrica
U
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D011687:Purines; C111599:istradefylline; D004298:Dopamine