Pathophysiological roles for purines: adenosine, caffeine and urate

Abstract

The motor symptoms of Parkinson's disease (PD) are primarily due to the degeneration of the dopaminergic neurons in the nigrostriatal pathway. However, several other brain areas and neurotransmitters other than dopamine such as noradrenaline, 5-hydroxytryptamine and acetylcholine are affected in the disease. Moreover, adenosine because of the extensive interaction of its receptors with the dopaminergic system has been implicated in the pathophysiology of the disease. Based on the involvement of these non-dopaminergic neurotransmitters in PD and the sometimes severe adverse effects that limit the mainstay use of dopamine-based anti-parkinsonian treatments, recent assessments have called for a broadening of therapeutic options beyond the traditional dopaminergic drug arsenal. In this review we describe the interactions between dopamine and adenosine receptors that underpin the pre-clinical and clinical rationale for pursuing adenosine A(2A) receptor antagonists as symptomatic and potentially neuroprotective treatment of PD. The review will pay particular attention to recent results regarding specific A(2A) receptor-receptor interactions and recent findings identifying urate, the end product of purine metabolism, as a novel prognostic biomarker and candidate neuroprotectant in PD.

Fig 1

Functional interactions between dopamine D₂, adenosine A_2A, cannabinoid CB₁ and glutamate mGlu5 receptors in striatopallidal neurons. Adenosine A_2A receptors interact antagonistically with D₂ and CB₁ receptors at the intramembrane level and at the adenylyl cyclase level; Metabotropic glutamate mGlu5 and adenosine A_2A receptors act synergistically to counteract the D₂ dopamine receptor signalling in striatopallidal neurons. Synergistic interactions exist between A_2A and mGlu5 receptors at the level of c-fos expression, MAP kinases and phosphorylation of DARPP-32 protein; for further explanation see text. broken arrows – inhibitory effect; ‘+’- stimulation; ‘- ’ – inhibition; AC – adenylyl cyclase; Ca2+ - calcium ions; CaMK II/IV calcium/calmodulin –dependent protein kinase type II/IV; cAMP – cyclic AMP; CREB – cAMP response element-binding protein; K+ - potassium channel; DARPP-32 -dopamine and cAMP-regulated phosphoprotein; DARPP-32-P (Thr75) and DARPP-32-P (Thr34) – DARPP-32-phopshorylated at threonine residues 75 and 34, respectively; Gi, Go – inhibitory G-proteins, Gq, Gs, Golf – stimulatory G-proteins; MAPK – mitogen-activated protein kinase; PKA - protein kinase A; PKC - protein kinase C; PLC – phospholipase C; PP-1 – protein phosphatase-1 ; PP-2 - protein phosphatase-2.

Fig. 2

Schematic representation of possible cellular mechanisms affected by A_2A receptor blockade in a neuroprotective model of PD. In presynaptic neurons, A_2A antagonism inhibits glutamate efflux either directly or indirectly through an inhibition of GDNF receptors (see text for more details on this mechanism). A decrease in glutamate release results in reduced glial response and as a consequence release of toxic factors. In microglia, direct A_2A receptor blockade inhibits NO and COX-2 production. In astroglia, direct A_2A receptor blockade inhibits glutamate release directly or indirectly through an inhibition of GLT-1.

Fig 3

Therapeutic targets along the purine metabolic pathway. Adenosine A_2A antagonists (including caffeine) and urate have emerged as realistic candidate neuroprotectants. In humans the enzymatic metabolism of purines such as adenosine ends with urate due to multiple mutations within the urate oxidase gene during primate evolution (see text). The schematic suggests a possible homeostatic mechanism linking an adenosinergic neurodegenerative influence with an offsetting neuroprotective influence of urate.