Adenosine, adenosine A_2A antagonists, and Parkinson's disease

Abstract

Adenosine derived from the degradation of ATP/AMP functions as a signalling molecule in the nervous system through the occupation of A1, A2, and A3 adenosine receptors. Adenosine A_2A receptors have a selective localization to the basal ganglia and specifically to the indirect output pathway, and as a consequence offer a unique opportunity to modulate the output from the striatum that is believed critical to the occurrence of motor components of PD. Indeed, the ability of A_2A antagonists to modulate basal ganglia neurotransmission has been shown to be associated with improved motor function in experimental models of PD. This suggests that A_2A antagonists would be effective as a symptomatic treatment in humans without provoking marked dyskinesia. Indeed, the A_2A antagonist istradefylline reduces OFF time in moderate- to late-stage patients with PD already receiving dopaminergic therapy, with an increase in non-troublesome dyskinesia. Adenosine and adenosine receptors also exert actions relevant to pathogenesis in PD, raising the possibility of their use as neuroprotective agents. Both epidemiologic evidence and the current preclinical data strongly support a role for A_2A antagonists in protecting dopaminergic neurons and influencing the onset and progression of PD.

Introduction

The number of individuals afflicted by Parkinson's disease (PD) is expected to double by 2030 in line with the aging population and increase in life expectancy [1]. Therefore, if quality of life is to be maintained and the socio-economic burden is to be reduced, more effective antiparkinsonian therapies need to be developed for use over a longer portion of the illness. This requires new pharmacologic approaches to PD management. Current therapy is as dependent on dopamine replacement strategies as it was 40 years ago, with levodopa and dopamine agonists forming the primary means of controlling motor symptoms and no truly novel drug class has been introduced into therapy for decades.

As a consequence, the problems associated with the treatment of PD remain largely unchanged. For example, the onset of motor complications (wearing-off, ON–OFF, dyskinesia) is almost inevitable [2], although the incidence of severe dyskinesia has been reduced by early use of dopamine agonists, more judicious use of levodopa [3], and the introduction of surgical approaches such as deep brain stimulation [4]. Dopaminergic side effects, including psychosis and dopamine dysregulation syndromes (e.g., compulsive gambling, hypersexuality), can become treatment limiting, and all of these phenomena are difficult to manage with currently available therapies [5]. The recognition of non-motor symptoms of PD (e.g., cognitive dysfunction, fatigue, sleep disturbance, autonomic dysfunction) as a key component of the illness has brought another area of unmet therapeutic need to the fore [6]. Non-motor features of PD invariably do not respond to dopaminergic medication and probably form the major challenge faced in the clinical management of PD [6]. Disease progression also remains untreated, with no drugs currently approved for use as neuroprotective agents or for disease modification.

Dopamine replacement therapy has provided the backbone of treatment and is based on the importance of nigral dopaminergic cell loss, the ensuing striatal dopamine depletion, and onset of motor symptoms [7]. However, the role of other neurotransmitters and neuromodulators is increasingly recognized in the appearance of motor and non-motor symptoms both as a result of pathology in a range of brainstem and forebrain regions and as adaptive changes to the alterations in basal ganglia function that occur following striatal dopamine depletion [8]. This resurgence of interest had led to extensive investigation of non-dopaminergic drugs as potential symptomatic treatments for PD. Such strategies offer the opportunity to treat PD without the involvement of the side effects common to dopaminergic therapy and to treat the non-motor symptoms of the illness. Despite some impressive effects in preclinical models of PD, to date, none has been introduced into general clinical practice, and some have failed during clinical evaluation [9].

A logical approach to a non-dopaminergic therapy for PD is to reverse the disruption to basal ganglia function by moving beyond the damaged dopaminergic input to striatum and focusing on the activity of striatal output pathways, which is known to be important in the expression of motor symptoms and the onset and/or expression of dyskinesia [8]. There are varying views on whether changes in the direct D₁-mediated GABAergic output to the internal segment of the globus pallidus (GPi) or in the indirect D₂-mediated GABAergic pathway to the external globus pallidus (GPe) are responsible for the development of dyskinesia. The indirect output pathway forms an important target not only because of alterations in its activity in PD but also because of the selective loss of spines on the medium spiny neurons comprising its cell bodies that does not occur in the direct output pathway, leading to a loss of cortical command through the glutamatergic corticostriatal pathway [10].

For these reasons, the selective localization of adenosine A_2A receptors to the cell bodies and terminals of the GABAergic neurons of the indirect pathway [11], [12] has attracted attention to the use of adenosine antagonists for controlling the motor symptoms of PD. How adenosine acts to modulate basal ganglia function is a new concept to this area, and it is necessary to understand the function of adenosine and the receptor subtypes with which it interacts under normal physiological conditions and in the abnormal basal ganglia in PD. This, and the potential of adenosine A_2A antagonists to affect striatal output and to form a novel target for the treatment of PD, is the basis of this review. The preclinical and clinical evidence for efficacy in PD are presented, and the potential for A_2A antagonists to exert neuroprotective activity in PD is considered.