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.

Focusing on Adenosine Receptors as a Potential Targeted Therapy in Human Diseases

“…Conversely, the levels of glutamate and N-methyl-d-aspartate (NMDA), which are responsible for neuronal damage, may increase during hypoxia and ischemia [134]. It was assumed that prolonged activation of A 1 AR increased A 2A AR expression, which generated global damage and neurodegeneration in ischemic stroke [135]. Recently, an A 1 AR selective agonist, NNC-21-0136, was designed for neuroprotection in stroke models [123].…”

“…According to physiological factors, neuromodulation of adenosine through activation of high-affinity A 2A AR is important [163]. Indeed, A 2A AR was associated with neurodegeneration due to its excitatory effects [135]. Presynaptic A 2A AR counteracts the inhibitory effect of presynaptic A 1 AR on glutamate release from axon terminals, inducing glutamate release that would predispose to excitotoxic injury, yet A 2A AR may also exert a neuroprotective effect by promoting vasodilation and preserving cerebral blood flow autoregulation [143].…”

Special Issue: Adenosine Receptors

“…Thus, striatal extracellular adenosine would mostly reflect an increased activation of receptors positively linked to adenylyl cyclase. Stockwell et al discuss the role of CNS A 1 R and A 2A R in both normal and pathological conditions, and they outline the potential therapeutic use of these receptors in neurodegenerative diseases (i.e., Parkinson’s disease, PD) [ 18 ]. In addition, the authors highlight the cross-talk between A 1 R and A 2A R, supported by the existence A 1 R/A 2A R heteromers [ 19 ], and its role in several neurodegenerative disorders, including ischemia, stroke, epilepsy, and PD [ 18 ].…”

“…Stockwell et al discuss the role of CNS A 1 R and A 2A R in both normal and pathological conditions, and they outline the potential therapeutic use of these receptors in neurodegenerative diseases (i.e., Parkinson’s disease, PD) [ 18 ]. In addition, the authors highlight the cross-talk between A 1 R and A 2A R, supported by the existence A 1 R/A 2A R heteromers [ 19 ], and its role in several neurodegenerative disorders, including ischemia, stroke, epilepsy, and PD [ 18 ]. Finally, Ciancetta and Jacobson review the structure-based molecular modeling applied to elucidate the binding of agonists to the A 3 R. The authors discussed the challenges associated with an accurate prediction of the receptor extracellular vestibule through homology modeling from the available X-ray templates [ 20 ].…”

Papel do receptor B2 de cininas na terapia da neurodegeneração dopaminérgica em modelo animal

“…Gs/Gi protein activation, however, will work through the stimulation/inhibition of adenylate cyclase, respectively, with subsequent up-or down-regulation of cyclic AMP (cAMP) production. Final effects of purinergic receptor-promoted signaling will depend on the cell type and other intra-/intercellular conditions, as i.e., in physiological embryonic and adult neurogenesis (Oliveira et al, 2016), and in various pathological scenarios, such as inflammatory (Beamer et al, 2016;Madeira et al, 2017;Przybyła et al, 2018), oncological (Allard et al, 2016;Vijayan et al, 2017;Whiteside, 2017;Kazemi et al, 2018), neurological (Burnstock et al, 2011;Stockwell et al, 2017), metabolic (Lindberg et al, 2015;Csóka et al, 2017;Parpura et al, 2017;Tozzi and Novak, 2017;Labazi et al, 2018), psychiatric (Cunha, 2008;Lindberg et al, 2015;Ortiz et al, 2015;Krügel, 2016;Cheffer et al, 2017;Oliveros et al, 2017), cognitive (Illes and Verkhratsky, 2016), and peripheral neuromuscular and/or neuromotor diseases (Robitaille, 1995;Kalmar, 2005;Burnstock et al, 2013;Jiménez et al, 2014;Bogacheva and Balezina, 2015;Puchałowicz et al, 2015;Safarzadeh et al, 2016).…”