Trends in Pharmacological Sciences
ReviewAdenosine as a Multi-Signalling Guardian Angel in Human Diseases: When, Where and How Does it Exert its Protective Effects?
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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