Adenosine A1 and A2A Receptors in the Brain: Current Research and Their Role in Neurodegeneration

Abstract

The inhibitory adenosine A1 receptor (A1R) and excitatory A2A receptor (A2AR) are predominantly expressed in the brain. Whereas the A2AR has been implicated in normal aging and enhancing neurotoxicity in multiple neurodegenerative diseases, the inhibitory A1R has traditionally been ascribed to have a neuroprotective function in various brain insults. This review provides a summary of the emerging role of prolonged A1R signaling and its potential cross-talk with A2AR in the cellular basis for increased neurotoxicity in neurodegenerative disorders. This A1R signaling enhances A2AR-mediated neurodegeneration, and provides a platform for future development of neuroprotective agents in stroke, Parkinson's disease and epilepsy.

Keywords: A1R-mediated neurotoxicity; adenosine receptor cross-talk; neurodegenerative diseases.

Figure 1

Adenosine A1R activation induces neuronal death in vivo. (A) Representative confocal microscopy images showing hippocampal slices stained with propidium iodide, a fluorescent marker for cell death. Male Sprague-Dawley rats were given intraperitoneal (i.p.) injections of CPA (5 mg/kg) or CPA (5 mg/kg) + DPCPX (3 mg/kg) and sacrificed at 48 h following initial injection. Acute coronal brain slices were taken and stained with propidium iodide. In animals treated with CPA alone, there was significantly increased propidium iodide fluorescence, indicating increased cell death in the hippocampus. DPCPX treatment prevented CPA-induced neuronal death. Scale bar 0.5 mm; (B) Confocal microscopy images of area CA1 of rat hippocampal slices with the same in vivo treatments above. DAPI, a nuclear stain is shown in blue (far left panels), single-stranded DNA (ssDNA) shown in green (second from left panels), NeuN shown in red (second from right panels), and a merge of all three channels shown in the far right panels. The marker ssDNA was used to label apoptotic cells, while NeuN (a neuronal marker) was used to label the CA1 cell layer. CPA treatment caused increased ssDNA staining in CA1 compared to control and DPCPX + CPA treated brains, indicating that CPA treatment was pro-apoptotic. Scale bar 30 µm.

Figure 2

Proposed signaling cascade induced by A1R and A2AR activation. This figure represents our proposed interaction between A1Rs and A2ARs and how they interact to modulate the surface expression of AMPA receptors and also our proposed mechanism of cross-talk through CK2 activation. Abbreviations: A1R—adenosine A1 receptor, GluA1 and GluA2—subunits of AMPA receptors, A2AR—adenosine A2A receptor, JNK—C-jun N-terminal kinase, p38—p38 mitogen-activated protein kinase (MAPK), PP2A—protein phosphatase 2A, PP1—protein phosphatase 1, PP2B—protein phosphatase 2B, PKA—protein kinase A, cAMP—cyclic adenosine monophosphate, AC—adenylyl cyclase, CK2—protein kinase CK2.