Adenosine Receptors and the Central Nervous System

Abstract

The adenosine receptors (ARs) in the nervous system act as a kind of "go-between" to regulate the release of neurotransmitters (this includes all known neurotransmitters) and the action of neuromodulators (e.g., neuropeptides, neurotrophic factors). Receptor-receptor interactions and AR-transporter interplay occur as part of the adenosine's attempt to control synaptic transmission. A(2A)ARs are more abundant in the striatum and A(1)ARs in the hippocampus, but both receptors interfere with the efficiency and plasticity-regulated synaptic transmission in most brain areas. The omnipresence of adenosine and A(2A) and A(1) ARs in all nervous system cells (neurons and glia), together with the intensive release of adenosine following insults, makes adenosine a kind of "maestro" of the tripartite synapse in the homeostatic coordination of the brain function. Under physiological conditions, both A(2A) and A(1) ARs play an important role in sleep and arousal, cognition, memory and learning, whereas under pathological conditions (e.g., Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, stroke, epilepsy, drug addiction, pain, schizophrenia, depression), ARs operate a time/circumstance window where in some circumstances A(1)AR agonists may predominate as early neuroprotectors, and in other circumstances A(2A)AR antagonists may alter the outcomes of some of the pathological deficiencies. In some circumstances, and depending on the therapeutic window, the use of A(2A)AR agonists may be initially beneficial; however, at later time points, the use of A(2A)AR antagonists proved beneficial in several pathologies. Since selective ligands for A(1) and A(2A) ARs are now entering clinical trials, the time has come to determine the role of these receptors in neurological and psychiatric diseases and identify therapies that will alter the outcomes of these diseases, therefore providing a hopeful future for the patients who suffer from these diseases.

Neuromuscular transmission modulation by adenosine upon aging

“…In rat diaphragm, the quantal content was reported to increase during the first 9 months of life and then to decline (Kelly, 1978). The reduction in A 2A receptors effects in aged rats might be one of the causes of the age-related changes in the neuromuscular transmission, because these receptors are known to influence the action of several neurotransmitters/neuromodulators/receptors/transporters at the nerve terminal (see Sebastião and Ribeiro, 2009). For instance, A 2A receptors at motor nerve terminals trigger the action of brain derived neurotrophic factor (BDNF) (Pousinha et al, 2006), which enhances transmitter release at developing end plates (Boulanger and Poo, 1999), improves neuromuscular transmission in the adult rat diaphragm (Mantilla et al, 2004) and facilitates synaptic efficacy by increasing presynaptic depolarization at the neuromuscular junction (see Huang and Reichardt, 2001).…”

“…In the central nervous system, the neuromodulatory action of adenosine and the expression of its membrane receptors change with age (see Diógenes et al, 2011;Sebastião and Ribeiro, 2009). So, it was considered of interest to investigate the role of adenosine at the neuromuscular junction, as a function of age, looking at the relative importance of adenosine A 1 receptors vis-a-vis adenosine A 2A receptors.…”

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

“…Adenosine A1 receptor (A 1 AR) activation can also activate several types of K + channels and mitogen-activated protein kinases (MAPK) via β,γ-subunits released from G i/o proteins, and also inhibits N-type Ca 2+ currents via PTX-sensitive pathways [1]. A 1 ARs are expressed in large numbers in the brain, as well as in peripheral tissues including kidney, heart and liver [2]. Because of adenosine exerting different physiological effects, a large number of A 1 AR antagonists exhibit a plethora of actions including anti-hypertensive, anti-depressive, anti-diabetic, anti-Parkinson and anti-hyperanalgesic effects [3].…”

Neurabin: a key factor in the specific neuroprotection mediated by Adenosine

“…It has always been suggested that adenosine could serve as an important neuroprotectant and anti-seizure compound [6,8] via A1Rs, but its therapeutic efficacy has always been questioned by the potential side effects of A1 agonists at different peripheric organs and systems. By showing that adenosine induced neuroprotection can be achieved by a…”

“…It has always been suggested that adenosine could serve as an important neuroprotectant and anti-seizure compound [6,8] via A1Rs, but its therapeutic efficacy has always been questioned by the potential side effects of A1 agonists at different peripheric organs and systems. By showing that adenosine induced neuroprotection can be achieved by a direct interaction with neurabin that does not require administration of adenosine A1R agonists, this article opens up the possibility to exploit the adenosinergic system to obtain molecules able to show therapeutic efficacy specifically at the level of CNS.…”