ReviewThe therapeutic potential of purinergic signalling
Graphical abstract
Introduction
Mike Williams was a pioneer for considering the therapeutic potential of purinergic signalling and he may be surprised to learn about the massive current developments by scientists, clinicians and drug companies on this topic. I will give an overview of these developments in this article.
The receptor subtypes for purines and pyrimidines are diverse, currently consisting of 4 subtypes of the P1 (adenosine) receptor (A1, A2A, A2B and A3), 7 subtypes of P2X ion channel receptors (P2X1-P2X7) and 8 subtypes of P2Y G protein-coupled receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13 and P2Y14) (see [1]) and they are expressed on nearly all cell types (see [2] for detailed coverage of the expression and roles of P2 receptors, and [3] as well as the Special Issue published in Neuropharmacology (Volume 104, Pages 1–282, 2016) which contains considerable coverage of the therapeutic roles of P1 receptors).
Several purinergic compounds are already on the market, including clopidogrel and ticagrelor, widely used P2Y12 receptor antagonists of platelet aggregation for the treatment of thrombosis and stroke (see [4] and Fig. 1a); a long acting P2Y2 receptor agonist for the treatment of dry eye; and A1 receptor agonists for the treatment of supraventricular tachycardia. There are currently clinical trials taking place with P2X3 antagonists that are orally bioavailable and stable in vivo for the treatment of chronic cough, visceral pain (see Fig. 1b), bladder diseases and hypertension. I will now summarise, mostly with recent review articles, the studies done on diseases of nearly all the bodily systems (see reviews [5], [6], [7]).
Section snippets
Diseases of the central nervous system
P2X7 receptor antagonists are promising targets for the treatment of neurodegenerative diseases (see [8], [9]), including Brilliant Blue G (BBG) for Alzheimer’s [10] and Parkinson’s [11] diseases, multiple sclerosis [12], amyotrophic lateral sclerosis [13] and also epilepsy [14], and for neuroprotection against brain injury [15]. A2A receptor antagonists, such as istradefylline, are close to being used to treat Parkinson’s disease [16] and Huntington’s disease [17].
Purinergic compounds are
Cardiovascular diseases
Purinergic signalling is being explored for the treatment of heart diseases, including infarction, arrhythmias, tachycardia, cardiomyopathies and angina (see [26]). The roles of A1, A2A, A2B and A3 receptors, as well as P2Y4, P2Y6, P2Y12, P2Y11, P2X3, P2X4 and P2X7 receptors have all been explored for heart diseases, but apart from the use of adenosine (Adenocard) via A1 receptors for the treatment of supraventricular tachycardia, their therapeutic potential is not resolved yet.
The therapeutic
Diseases of the airways
Purinergic signalling is being actively explored for the treatment of diseases of the airways (see [36], [37]), including asthma, where both A2A receptors [38] and P2X7 in particular [39] were shown to be involved in human studies, but the potential of A1, P2Y1, P2Y6 and P2X1 receptors are also being explored, as well as novel xanthine derivatives as potent and selective A2B receptor antagonists for the treatment of asthma [40]. For the treatment of chronic obstructive pulmonary disease, P2Y2
Diseases of the special senses
The early literature about purinergic signalling in the special senses was reviewed [52].
Immune system and inflammation
P2X7, P2Y1 and P2Y2 receptors expressed by inflammatory and immune cells play a pivotal role in immunomodulation and inflammation. The purinergic contribution to these events has been discussed in recent reviews [63], [64]. A2AR and P2Y12 receptors are also involved [65], [66]. In particular, P2X7 receptor antagonists, such as oxidized ATP, have been investigated in preclinical models of autoimmune diseases and tissue transplantation [67].
Infection
Multiple P1 and P2 receptors are expressed on immune cells and ATP has different actions depending on the receptors activated. For instance ATP has cytotoxic actions on macrophages via P2X7R, is bacteriocidal together with UTP via P2Y2R. P2X7 receptors are also involved in infectious, inflammatory and autoimmune diseases [68], [69] and in both bacterial (Escherichia coli) [70] and viral (Dengue virus-2) [71] infections. P2X7 receptors also play a key role in control of parasites such as
Diabetes
P2Y receptor agonists, including adenosine-5′-O-(2-thiodiphosphate), have been developed for the treatment of type 2 diabetes following studies in rats [74] as well as A2A receptor agonists [75], [76] and uridine adenosine tetraphosphate (Up4A) [77]. P2X7 receptor antagonists are gaining attention as potential therapeutic agents for both type 1 and 2 diabetes [58], [78]. P2X3 receptor antagonists are proposed for the treatment of diabetic neuropathic pain, when in a study of diabetic rats
Obesity
A2A receptor antagonists reduce high fat diet-induced obesity in mice and show promise for therapeutic treatment of obesity [81]. UDP, acting via P2Y6 receptors in the hypothalamus, increases obesity, so P2Y6 receptor antagonists, such as MRS2578, are promising anti-obesity agents [82]. Following a study of cultured human visceral adipose tissue where inhibition of P2X7 receptors decreased levels of inflammatory cytokines, suggesting a therapeutic strategy to target inflammatory conditions in
Gut disorders
Purinergic signalling plays a major role in both the physiology and pathophysiology of the gut (see [84]). Investigations of purinergic compounds as therapeutic targets for gut disorders are in progress [85], [86], including ulcerative colitis, where P2X7 receptor antagonists such as A-438079 [87] and down-regulation of A3 receptor expression [88] was effective; Crohn’s disease, where P2X7 receptor antagonists, such as AZD-9056, are therapeutic in a mouse model of Crohn’s disease [89], but not
Diseases of the kidney
A recent review about purinergic signalling in kidney diseases is available [94]. The P2X7 receptor antagonist A438079 was effective against renal injury and failure in a mouse model [95]; polycystic kidney disease, where the P2X7 receptor antagonist oxidized ATP reduced cyst formation in a zebrafish model [96]; ischaemia, where the role of adenosine in protection from renal ischaemia-reperfusion injury has been discussed [97]; nephritis, where again P2X7 receptor antagonists have therapeutic
Diseases of the lower urinary tract
The early literature has been thoroughly reviewed [103]. Diseases include: overactive bladder, where P2X3 receptor antagonists, such as AF-742, are being considered for the treatment of both overactive bladder and bladder pain (see [104]); interstitial cystitis, both A1 receptor antagonists, for example DPCPX [105], and P2X7 receptor antagonists have been considered for the treatment of interstitial cystitis; outflow obstruction; bladder pain, P2X3 receptor antagonists are effective in reducing
Diseases of the liver
There are reviews concerned with purinergic signalling in liver diseases [108], [109], [110]. These include: fibrosis, where blockade of the P2X7 receptor/NLRP3 inflammasome axis in cultured hepatic stellate cells with A438079 was considered a novel therapeutic target for liver fibrosis [111]; cirrhosis, both A1 and A2A receptor agonists have been claimed to reduce cirrhosis; cancer, P2X3 and P2Y11 receptor antagonists and A3 receptor agonists have each been claimed to inhibit liver metastasis;
Diseases of the reproductive system
There is a review concerned with purinergic signalling in the reproductive tract in health and disease [112]. These include: erectile dysfunction, P2Y1 and P2Y4 receptor agonists have been suggested for treatment of erectile dysfunction following both animal and human studies [113], [114]. It has also been suggested that P2X3 receptor antagonists may improve recovery of erectile function, when suramin proved to be efficacious in a rat model of erectile dysfunction [115]; prostatic hyperplasia;
Skin diseases
Reviews concerned with purinergic signalling in the skin have been published [120], [121]. Psoriasis, the use of A3 receptor agonists, such as CF101 that is undergoing clinical trials, for the treatment of psoriasis has been explored [122], [123] and A2A receptor antagonists, including SCH-442416 [124] and A2B receptor agonists, such as BAY60e6583 [125] are also being considered, as well as the involvement of P2Y1, P2Y2, P2Y11 and P2X7 receptors. Scleroderma, A2A receptors have been suggested
Musculoskeletal diseases
Reviews have been published that include the roles of purinergic signalling in musculoskeletal diseases [135], [136], [137]. Muscular dystrophy, it was suggested that P2Y2 receptor antagonists may ameliorate cardiomyopathy in Duchenne muscular dystrophy, since suramin reduced cardiomyopathy in a mouse model [138]. P2X4 and P2X7 receptors are expressed on dystrophic myoblasts and following a study of the dystrophic mdx mouse it was suggested that P2X7 receptor antagonists (in particular
Concluding comments
The development of purinergic compounds for the treatment of a wide variety of diseases is still in its infancy, although P2Y12 receptor antagonists for the treatment of thrombosis and stroke, long lasting P2Y2 receptor agonists for the treatment of dry eye and A1 receptor agonists for supraventricular tachycardia are already well established. P2X3 receptor antagonists for chronic cough, visceral pain and hypertension are currently in clinical trials and further possible uses of purinergic
Conflict of interest and funding statements
The author declares that there is no conflict of interest. GB had no funding for the writing of this article.
References (158)
- et al.
Cellular distribution and functions of P2 receptor subtypes in different systems
Int. Rev. Cytol.
(2004) - et al.
Adenosine as a multi-signalling guardian angel in human diseases: when, where and how does it exert its protective effects?
Trends Pharmacol. Sci.
(2016) - et al.
Purinergic receptors as potential therapeutic targets in Alzheimer's disease
Neuropharmacology
(2016) - et al.
Role of the purinergic signaling in epilepsy
Pharmacol. Rep.
(2017) An introduction to the roles of purinergic signalling in neurodegeneration, neuroprotection and neuroregeneration
Neuropharmacology
(2016)An overview of adenosine A2A receptor antagonists in Parkinson's disease
Int. Rev. Neurobiol.
(2014)- et al.
Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington's disease models
Neurobiol. Dis.
(2015) - et al.
P2X7 receptor: an emerging target in central nervous system diseases
Trends Pharmacol. Sci.
(2014) - et al.
Involvement of adenosine A2A receptors in depression and anxiety
Int. Rev. Neurobiol.
(2014) - et al.
Purinergic signaling in atherosclerosis
Trends Mol. Med.
(2015)
Drug-drug interactions when switching between intravenous and oral P2Y12 receptor inhibitors: how real is it?
JACC Cardiovasc. Interv.
Expressions of adenosine A2A receptors in coronary arteries and peripheral blood mononuclear cells are correlated in coronary artery disease patients
Int. J. Cardiol.
Neural regulation of inflammation in the airways and lungs
Auton. Neurosci.
Design and synthesis of novel xanthine derivatives as potent and selective A2B adenosine receptor antagonists for the treatment of chronic inflammatory airway diseases
Eur. J. Med. Chem.
Extracellular adenosine 5'-triphosphate in obstructive airway diseases
Chest
Genetic polymorphisms of the P2X7 gene associated with susceptibility to and prognosis of pulmonary tuberculosis
Infect. Genet. Evol.
Purinoceptor signaling in malaria-infected erythrocytes
Microbes Infect.
The role of the adenosinergic system in lung fibrosis
Pharmacol. Res.
Altered purinergic signaling in the tumor associated immunologic microenvironment in metastasized non-small-cell lung cancer
Lung Cancer
P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study
Lancet
Purinergic signaling in retinal degeneration and regeneration
Neuropharmacology
P2X7 receptor knockout prevents streptozotocin-induced type 1 diabetes in mice
Mol. Cell. Endocrinol.
P2X7-pannexin-1 and amyloid β-induced oxysterol input in human retinal cell: role in age-related macular degeneration?
Biochimie
Nucleotide modulates odor response through activation of purinergic receptor in olfactory sensory neuron
Biochem. Biophys. Res. Commun.
Purinergic mechanisms in neuroinflammation: An update from molecules to behavior
Neuropharmacology
Purinergic signaling in the immune system
Auton. Neurosci.
Purinergic signaling in infection and autoimmune disease
Biomed. J.
The purinergic receptor P2X7 role in control of Dengue virus-2 infection and cytokine/chemokine production in infected human monocytes
Immunobiology
Trichomoniasis immunity and the involvement of the purinergic signaling
Biomed. J.
P2Y purinergic receptor-regulated insulin secretion is mediated by a cAMP/Epac/Kv channel pathway
Biochem. Biophys. Res. Commun.
Critical role for adenosine receptor A2a in β-cell proliferation
Mol. Metab.
LncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats mediated by P2X7 receptor in SCG
Auton. Neurosci.
Role of A1 and A2A adenosine receptor agonists in adipose tissue inflammation induced by obesity in mice
Eur. J. Pharmacol.
Hypothalamic UDP increases in obesity and promotes feeding via P2Y6-dependent activation of AgRP neurons
Cell
P2X7 receptor promotes intestinal inflammation in chemically induced colitis and triggers death of mucosal regulatory T cells
Biochim. Biophys. Acta
Purinergic signaling in kidney disease
Kidney Int.
Receptors for purines and pyrimidines
Pharmacol. Rev.
International union of basic and clinical pharmacology. LXXXI. Nomenclature and classification of adenosine receptors—an update
Pharmacol. Rev.
Effects of P2Y12 receptor antagonists beyond platelet inhibition - comparison of ticagrelor with thienopyridines
Br. J. Pharmacol.
Purinergic signalling: pathophysiology and therapeutic potential
J. Drug Res. Dev.
P2X receptors as drug targets
Mol. Pharmacol.
Purinergic signalling and disorders of the central nervous system
Nat. Rev. Drug Discov.
Purinergic signalling and neurological diseases: an update
CNS Neurol. Disord. Drug Targets
Inhibiting purinergic P2X7 receptors with the antagonist brilliant blue G is neuroprotective in an intranigral lipopolysaccharide animal model of Parkinson's disease
Mol. Med. Rep.
A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis
Hum. Mol. Genet.
Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis
Dis. Model. Mech.
The roles of purinergic signaling in psychiatric disorders
Acta Biochim. Pol.
Purinergic Signalling and the Nervous System
Adenosine hypothesis of antipsychotic drugs revisited: pharmacogenomics variation in nonacute schizophrenia
OMICS
Role of P2X7 receptor in an animal model of mania induced by D-amphetamine
Mol. Neurobiol.
Cited by (103)
Electrochemical detection of ATP release in-vitro and in-vivo
2023, Current Opinion in ElectrochemistryThe potential role of CpG oligodeoxynucleotides on diabetic cardiac autonomic neuropathy mediated by P2Y12 receptor in rat stellate ganglia
2023, International ImmunopharmacologyATP-mediated signalling in the central synapses
2023, NeuropharmacologyeATP and autoimmune diabetes
2023, Pharmacological ResearchTreatment of chronic cough: P2X3 receptor antagonists and beyond
2022, Pharmacology and Therapeutics