Adenosine A(2A) receptors in Parkinson's disease treatment

Abstract

Latest results on the action of adenosine A(2A) receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinson's disease. Basal ganglia possess high levels of adenosine A(2A) receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinson's disease indicate that adenosine A(2A) receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A(2A) and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinson's disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A(2A) receptors. In animal models of Parkinson's disease, the use of selective antagonists of adenosine A(2A) receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A(2A) receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A(2A) receptor antagonists might be used in both moderate and advanced stages of Parkinson's disease. The long-lasting administration of adenosine A(2A) receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A(2A) receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A(2A) receptors, as an anti-Parkinson drug.