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Therapeutic Developments fphar-08-00661 September 22, 2017 Time: 16:27 # 1 REVIEW published: 25 September 2017 doi: 10.3389/fphar.2017.00661 Purinergic Signalling: Therapeutic Developments Geoffrey Burnstock1,2* 1 Autonomic Neuroscience Centre, University College Medical School, London, United Kingdom, 2 Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, VIC, Australia Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been Edited by: developed that are orally bioavailable and stable in vivo and are currently in clinical trials Kenneth A. Jacobson, National Institutes of Health (NIH), for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. United States Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory Reviewed by: disorders, including neurodegenerative diseases. Other investigations are in progress Stanko S. Stojilkovic, for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, National Institutes of Health (NIH), United States irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and Rennolds S. Ostrom, cancer. Chapman University, United States *Correspondence: Keywords: ATP, adenosine, CNS diseases, peripheral diseases, infection, inflammation Geoffrey Burnstock [email protected] INTRODUCTION Specialty section: This article was submitted to Purinergic signalling, i.e., nucleotides as extracellular signalling molecules, was proposed in Experimental Pharmacology and Drug 1972 (Burnstock, 1972). However, this concept was not well accepted until the 1990’s when Discovery, receptor subtypes for purines and pyrimidines were cloned and characterised, which includes a section of the journal four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors, Frontiers in Pharmacology and eight subtypes of the P2Y G protein-coupled receptor (Ralevic and Burnstock, 1998). Early Received: 07 August 2017 studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic Accepted: 05 September 2017 signalling (Burnstock, 2007). Adenosine 50-triphosphate (ATP) is a cotransmitter with classical Published: 25 September 2017 transmitters in both the peripheral and central nervous systems. In addition, purines are powerful Citation: extracellular messengers to non-neuronal cells, including secretory, exocrine and endocrine, Burnstock G (2017) Purinergic Signalling: Therapeutic endothelial, immune, musculo-skeletal and inflammatory cells (Burnstock and Knight, 2004). Developments. Purinergic signalling is rapid in neurotransmission, neuromodulation and in secretion, but is also Front. Pharmacol. 8:661. long-term in proliferation, differentiation, migration and death in development and regeneration doi: 10.3389/fphar.2017.00661 (Burnstock, 2016f). Frontiers in Pharmacology| www.frontiersin.org 1 September 2017| Volume 8| Article 661 fphar-08-00661 September 22, 2017 Time: 16:27 # 2 Burnstock Purinergic Signalling: Therapeutic Developments More recently, the focus has been on the pathophysiology and P2Y4R antagonists are potential therapeutic targets for the and therapeutic potential of both P1 (Chen et al., 2013; de Lera treatment of AD (Erb et al., 2015; Miras-Portugal et al., 2015; Ruiz et al., 2014; Layland et al., 2014; Liu and Xia, 2015; Borea Woods et al., 2016). It has been suggested that the blockade et al., 2016) and P2 (Burnstock and Kennedy, 2011; Bartlett et al., of P2Y1R may have therapeutic potential against cognitive 2014; Ford et al., 2015; Burnstock, 2016e) receptors. Reviews disturbances in AD (Guzman and Gerevich, 2016). b-Amyloid focussed on different aspects of purinergic pathophysiology are increased release of ATP, which potentiated excitatory synaptic also available, including inflammatory and immune disorders activity via P2XR, effects that were blocked by P2X antagonists (Arulkumaran et al., 2011; Junger, 2011; Hansson et al., 2016); (Sáez-Orellana et al., 2016). The glycosylphosphatidylinositol- cancer (Burnstock and Di Virgilio, 2013; Di Virgilio and Adinolfi, anchored prion protein binds to and modulates the expression 2017); gout and fibrosis (Gicquel et al., 2017); P2X7 receptors of P2X4R, which may be involved in AD (Carneiro et al., 2016). (R) as therapeutic targets (Romagnoli et al., 2008); medicinal Recently, a potential role has been proposed for ATP-sensitive chemistry of purinoceptors (Jacobson and Muller, 2016); pain potassium channel (KATP) modulation as a therapeutic strategy (Burnstock and Sawynok, 2010; Alves et al., 2013; Kuan and Shyu, against AD (Salgado-Puga et al., 2017). 2016; Sawynok, 2016) and adenosine kinase inhibitors (Kowaluk Adenosine A3R agonists suppress amyloid-b protein and Jarvis, 2000). A number of purine-related compounds precursor internalisation and amyloid-b generation (Li S. et al., have been patented. Therapeutic developments for disorders of 2015). Hippocampal adenosine A2AR up-regulation is necessary different systems in the body will now follow. Reviews concerned to trigger memory dysfunction in AD (Cunha, 2015). with the early literature will be quoted, so the focus of this review will be concerned largely with the most recent findings. Parkinson’s Disease (PD) The involvement of adenosine A2AR in PD and their interactions with dopamine receptors has attracted most attention (see Jenner, DISORDERS OF THE CENTRAL 2014). A2AR antagonists have been proposed for the treatment NERVOUS SYSTEM (CNS) of PD (Jenner, 2014; Mori, 2014; Pinna, 2014; Navarro et al., 2016). KATP (Dragicevic et al., 2015) and P2X1R (Gan et al., 2015; Investigations into purinergic signalling and its roles in Navarro et al., 2016; Yang Z. et al., 2016) in PD have also been disorders of the CNS have been reported, for instance following reported, perhaps indicating new therapeutic targets. Clinical surgery, stroke, accidents and ischemia, neurodegenerative trials istradefylline, an A2AR antagonist, have taken place and it diseases (such as Parkinson’s, Alzheimer’s and Huntington’s may have a beneficial effect in conjunction with commonly used diseases), multiple sclerosis (MS), amyotrophic lateral sclerosis anti-Parkinson’s therapies (Tao and Liang, 2015; Uchida et al., (ALS), epilepsy and neuropsychiatric disorders (including 2015; Vorovenci and Antonini, 2015), although in a later study, schizophrenia, depression and anxiety). Reviews covering this istradefylline was shown to enhance amyloid-b generation and topic are available (Burnstock, 2008b; Burnstock et al., 2011), g-secretase activity (Lu et al., 2016). Oligomerisation kinetics including the recent attention to the development of centrally of A2A and dopamine D2R have important implications for penetrant P2X7R antagonists for the treatment of CNS disorders PD (Casadó-Anguera et al., 2016; Ferré et al., 2016; Guixà- (Burnstock and Verkhratsky, 2012; Puchalowicz et al., 2014; González et al., 2016). Clinical trials for A2A antagonists for PD Sperlagh and Illes, 2014; Burnstock, 2015b; Cisneros-Mejorado are assessed in a review (Navarro et al., 2016). A2AR inhibition et al., 2015b). stopped rotenone-induced motor impairment in a rat model of PD (Fathalla et al., 2016). A1 as well as A2AR antagonists were Neurodegenerative Diseases recommended as promising candidates for treatment of PD in a Neurodegeneration in the CNS is associated with inflammation recent paper (Essawy et al., 2017). and damage to both neurons and glia (Rama Rao and Kielian, P2X7R antagonists have also been implicated in this disease 2015). Reviews are available that include coverage of early papers (Jörg et al., 2014; Wang et al., 2017). A P2X7R antagonist, concerned with neurodegenerative diseases (Puchalowicz et al., brilliant blue G, was recently shown to be protective in a 2014; Santiago et al., 2014; Fasullo and Endres, 2015; Förster and lipopolysaccharide (LPS) animal model of PD (Wang et al., 2017). Reiser, 2015; Burnstock, 2016a; Fumagalli et al., 2016). Recent attention has been directed toward the use of P2X7R antagonists Huntington’s Disease (HD) for the treatment of neurodegenerative diseases (Metzger et al., Earlier studies reported that A2AR agonists could be 2017). However, adenosine acting via A2AR has also been therapeutically useful for HD and that P2X7R antagonists claimed as a promising therapeutic agent for the prevention and inhibited neuronal apoptosis and attenuated body weight loss treatment of neurodegenerative diseases (Cunha, 2016; Harmse and motor
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