Adenosine A2A antagonists in Parkinson's disease: what's next?

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, affecting up to 10 million people worldwide. Current treatment primarily involves symptom management with dopaminergic replacement therapy. Levodopa remains the most effective oral treatment, although long-term use is associated with complications such as wearing off, dyskinesias, and on-off fluctuations. Non-dopaminergic medications that improve PD symptoms and motor fluctuations are in demand. Adenosine A2A receptors are abundantly expressed within the basal ganglia and offer a unique target to modify abnormal striatal signaling associated with PD. Preclinical animal models have shown the ability of adenosine A2A receptor antagonists to improve PD motor symptoms, reduce motor fluctuations and dyskinesia, as well as protect against toxin-induced neuronal degeneration. Both istradefylline and preladenant have demonstrated moderate efficacy in reducing off time in PD patients with motor fluctuations. The safety and efficacy of this class of compounds continues to be defined and future studies should focus on non-motor symptoms, dyskinesias, and neuroprotection.