Chronic A2A antagonist treatment alleviates parkinsonian locomotor deficiency in MitoPark mice

Adenosine A2A receptor (A2AR) antagonists are being investigated as promising treatment strategy for Parkinson's disease (PD). To test whether A2AR antagonists are beneficial in early PD stages we used MitoPark mice, a genetic model with gradual degeneration of DA cells. Daily treatment of young MitoPark mice for eight weeks with the A2AR antagonist MSX-3 prevented the reduction of spontaneous locomotor activity observed in saline or L-DOPA treated animals. Chronic A2AR antagonist treatment neither induced desensitization of receptors nor accumulation of the drug in brain tissue. Despite beneficial effects on behavior, which are not improved upon addition of a low dose of L-DOPA, the characteristic decline of dopamine levels was not changed. Our results indicate that effective dosing with A2AR antagonists should be tested as monotherapy in early PD, and serves to remind us that positive behavioral effects of such treatment need not be reflected in rescue of striatal dopamine levels.

Research Highlights
► –A2A receptor antagonist MSX-3 is effective in MitoPark mice, a genetic Parkinson model
► –Daily treatment with MSX-3 improves spontaneous locomotion in MitoPark mice
► –8 weeks of daily MSX-3 treatment does not induce desensitization of the receptor
► –Chronic MSX-3 treatment did not prevent the striatal dopamine depletion