Abstract

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 developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

Highlights

  • Purinergic signalling, i.e., nucleotides as extracellular signalling molecules, was proposed in 1972 (Burnstock, 1972)

  • Treatment with P2XR antagonists prolongs cardiac transplant survival. Hypertension It has been proposed in a recent review (Burnstock, 2017) that there are five different ways that purinergic signalling can contribute to the development of hypertension: (1) Adenosine -triphosphate (ATP) released as a cotransmitter from sympathetic nerves together with noradrenaline (NA) contributes, via P2X1R, to the vasoconstriction that results from increased sympathetic vasomotor activity in hypertension

  • P2X3R antagonists are in clinical trials for use against visceral pain, chronic cough and hypertension

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Summary

INTRODUCTION

Purinergic signalling, i.e., nucleotides as extracellular signalling molecules, was proposed in 1972 (Burnstock, 1972). Investigations into purinergic signalling and its roles in disorders of the CNS have been reported, for instance following surgery, stroke, accidents and ischemia, neurodegenerative diseases (such as Parkinson’s, Alzheimer’s and Huntington’s diseases), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), epilepsy and neuropsychiatric disorders (including schizophrenia, depression and anxiety) Reviews covering this topic are available (Burnstock, 2008b; Burnstock et al, 2011), including the recent attention to the development of centrally penetrant P2X7R antagonists for the treatment of CNS disorders (Burnstock and Verkhratsky, 2012; Puchalowicz et al, 2014; Sperlagh and Illes, 2014; Burnstock, 2015b; Cisneros-Mejorado et al, 2015b)

Neurodegenerative Diseases
Neuroprotection and Neuroregeneration
Psychiatric Disorders
Neuropathic Pain
Brain Tumours
Sleep Disorders
CARDIOVASCULAR DISEASES
Heart Diseases
Vascular Diseases
Blood Cell Diseases
DISEASES OF THE AIRWAYS
Airway Infections
Lung Injury
Lung Cancer
Chronic Cough
Lung Allograft
DISEASES OF THE SPECIAL SENSES
Olfactory Organs
IMMUNE SYSTEM AND INFLAMMATION
ENDOCRINE DISEASES
GUT DISORDERS
Motility Disorders
Colorectal Cancer
DISEASES OF THE KIDNEY
Renal Injury and Failure
Diabetic Nephropathy
Nephrotoxicant Injury
Urinary Bladder
DISEASES OF THE LIVER
Liver Cancer
Liver Transplantation
DISEASES OF THE REPRODUCTIVE SYSTEM
Disorders of the Male Reproductive Tract
Disorders of the Female Reproductive Tract
Malignant Cancer of Reproductive Organs
Cervical Cancer
Ovarian Cancer
SKIN DISEASES
Skin Inflammation
Wound Healing
Barrier Function
Skin Cancer
MUSCULOSKELETAL DISEASES
Muscular Dystrophy
Tooth Pain
Bone Cancer Pain
Severe Combined Immunodeficiency
Ossification of the Posterior Longitudinal Ligament of the Spine
Findings
CONCLUDING COMMENTS
Full Text
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