Review
Adenosine as a Multi-Signalling Guardian Angel in Human Diseases: When, Where and How Does it Exert its Protective Effects?

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Trends

Adenosine is a ubiquitous nucleoside, an integral part of ATP that acts as a homeostatic regulator through the activation of four GPCRs, A1, A2A, A2B, and A3, and through receptor-independent mechanisms.

Adenosine levels increase in areas of inflammation and hypoxia, where it protects tissues by restoring the oxygen supply:demand ratio, as well as affecting preconditioning, exerting anti-inflammatory effects, and stimulating angiogenesis.

Adenosine favours the resolution of pathologies such as epilepsy, pain, ischaemia, inflammation, and cancer, in which it behaves like a guardian angel against cellular damage.

New adenosinergic drugs for pain, inflammatory diseases, and cancer are already in clinical development.

The importance of adenosine for human health cannot be overstated. Indeed, this ubiquitous nucleoside is an integral component of ATP, and regulates the function of every tissue and organ in the body. Acting via receptor-dependent and -independent mechanisms [the former mediated via four G-protein-coupled receptors (GPCRs), A1, A2A, A2B, and A3,], it has a significant role in protecting against cell damage in areas of increased tissue metabolism, and combating organ dysfunction in numerous pathological states. Accordingly, raised levels of adenosine have been demonstrated in epilepsy, ischaemia, pain, inflammation, and cancer, in which its behaviour can be likened to that of a guardian angel, even though there are instances in which overproduction of adenosine is pathological. In this review, we condense the current body of knowledge on the issue, highlighting when, where, and how adenosine exerts its protective effects in both the brain and the periphery.

Section snippets

Adenosine as a Protective Agent

The purine nucleoside adenosine is a ubiquitous molecule whose importance for human health cannot be overstated. Indeed, it is the backbone of ATP and regulates the functions of every tissue and organ [1], mainly, but not solely, through the activation of a family of four GPCRs, A1, A2A, A2B, and A3. Interestingly, the A1 and A3 subtypes have an inhibitory effect on adenylyl cyclase (AC) activity, while A2A and A2B stimulate it, with a consequent modulation of cyclic AMP levels [1]. Although

Adenosine and Epilepsy

There is a huge body of evidence showing that adenosine is an inhibitory modulator of brain activity, and its anticonvulsant effects, mediated by both receptor-dependent and -independent pathways, have been demonstrated in several experimental models of epilepsy [5]. The ability of adenosine to prevent or ameliorate seizures induced by pentylenetetrazole, pilocarpine, NMDA, bicuculline, organophosphate treatment, and electrical stimulation has been attributed essentially to A1 receptor

Adenosine and Ischaemia

Adenosine appears to have a role as an endogenous mediator of neuroprotection in the homeostatic response to changes occurring during ischaemia and stroke. Indeed, by activating A1 receptors, this nucleoside hinders Ca2+ influx, thereby inducing presynaptic inhibition and a reduction in the release of excitatory neurotransmitters. In addition, it increases the conductance of K+ and Cl ions, mediating a fall in neuronal excitability and having a key role in ischaemic preconditioning (IP) 17, 18

Adenosine and Pain

Adenosine has been recognised as a potent antinociceptive agent in several different preclinical models of chronic pain and, therefore, is undergoing clinical trials for chronic regional pain syndrome, as well as perioperative and neuropathic pain 53, 54. Indeed, in the spinal cord and periphery, adenosine has been shown to reduce neuronal activity and, therefore, pain, through its activation of the A1 receptor. These results are consistent across several experimental pain models, including

Adenosine and Inflammation

By activating the A2A, A2B, and A3 receptor subtypes, adenosine has a crucial role in the regulation of tissue homeostasis, affecting the immune system. It typically inhibits endothelial cell adhesion and superoxide anion production by neutrophils, and reduces proinflammatory cytokine release from macrophages, dendritic cells, and lymphocytes 80, 81, 82, 83, 84, 85. In 2001, a seminal paper by Ohta et al. reported increased inflammation, tissue damage, TNF-α/interferon (IFN)-γ levels, and

Adenosine and Cancer

Adenosine does have a protective role in cancer, but this risks partial disturbance by its concomitant effects on the immune system. Indeed, high levels of CD39 and CD73 lead to increased adenosine concentration, which, through A2A and A2B receptor-mediated effects on immune cells, creates an immune-tolerant tumour microenvironment 135, 136. This effect of adenosine may be considered a natural consequence of its attempting to avoid excessive inflammation during tissue injury, but suggests both

Concluding Remarks

Adenosine has long attracted considerable attention due to its stress-induced release and homeostatic regulation capabilities. Basic research in several pathologies has generated a huge amount of data suggesting that adenosine has an important function in protecting cells and tissues against injury. As studies have shown, adenosine is implicated in stressful conditions, such as hypoxia and ischaemia, in which levels of adenosine dramatically increase. Accordingly, adenosine signalling has a

Glossary

Chronic pain
defined as pain that lasts longer than 12 weeks.
Inflammatory pain
pain associated with tissue injury and inflammation, autoimmune disease, or exposure to irritating agents.
Ischaemic preconditioning
a process where repeated short, sublethal insults protect the tissue against subsequent ischaemic damage.
Neuropathic pain
pain induced by injury or damage that concerns the sensory system.
Nociceptive pain
pain caused by ongoing noxious stimuli, such as heat, cold, and chemicals, or acute

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