Adenosine A2A Receptor Antagonists as Drugs for Symptomatic Control of Parkinson’s Disease in Preclinical Studies

Abstract

Parkinson's disease (PD) is primarily a neurological basal ganglia (BG)-related disorder caused by progressive degeneration of the nigrostriatal dopaminergic neurons, which results in the cardinal motor symptoms of PD, including bradykinesia (slow movement and difficulty in initiation movement), resting tremor, muscle tone rigidity, postural instability, and sensorimotor integration deficits. The gold standard of PD therapy is characterized by the dopamine precursor L-DOPA however, after several years, this therapy leads to neuropsychiatric and motor complications, including fluctuations in motor response and dyskinesias, which develop in the majority of patients. Consequently, one of the main targets of research in PD is to identify alternative therapeutic approaches to ameliorate PD symptoms without inducing motor complications. Among the non-dopaminergic strategies for PD, one of the most promising is represented by adenosine A 2A receptor antagonists, due to the colocalization of these receptors and dopamine D 2 receptors in the striatopallidal neurons of the BG, which provides the anatomical basis for the existence of a functional antagonistic interaction between these receptors. Thus, extensive preclinical studies have been performed to prove the effectiveness of adenosine A 2A receptor blockade in counteracting the cardinal motor symptoms of PD.This chapter describes the effects of A 2A antagonists alone or in combination with L-DOPA against the cardinal motor symptoms of PD, using rodent and primate models of PD, and the main mechanisms responsible for these anti-parkinsonian effects. In addition, findings suggesting the potential utilization of A 2A antagonists, as adjunctive treatments to L-DOPA to reduce the L-DOPA induced wearing-off without modifying dyskinetic movements, have been reviewed. Keywords Parkinson's disease · Rodent models · Non-human primate models · Catalepsy · Rigidity · Tremor · 6-Hydroxydopamine lesion · MPTP lesion · A 2A receptor antagonists · Adenosine