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Purinergic Signaling in Neuroinflammation
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Purinergic Signaling in Neuroinflammation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 55647

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Dmitry Aminin

E-Mail Website
Guest Editor
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of the Russian Academy of Sciences, 690022 Vladivostok, Russia
Interests: biochemistry; cell biology; structure and function of biological membranes; mechanism of biological activity of natural and synthetic biologically active substances; new drug discovery; molecular targets; toxicology; ecotoxicology; biomarkers; biosensors
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Peter Illes

E-Mail Website
Guest Editor
Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universitaet Leipzig, Leipzig, Germany
Interests: neuropharmacology; neurotoxicology; purinergic mechanisms; modulation of synaptic transmission; glial cells; necrosis/apoptosis; analgesia; learning and memory; epileptic state
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is clear today that the physiological effect of extracellular ATP is mediated by its interaction with specific purinergic receptors. All purinergic receptors are divided into P1-purinoreceptors (the main ligand adenosine) and P2-purinoreceptors (the main ligands ATP/ADP, UTP/UDP). Each of the subtypes is divided into a number of families. For instance, P2 receptors are divided into P2X and P2Y receptors according to the mechanism by which their effect is realized: P2Y are G-protein coupled receptors, while P2X receptors are ligand-operated ion channels (or ionotropic receptors). P2X receptors are important molecular therapeutic targets, the malfunctioning of which leads to serious complications in the physiology of humans and animals, and cause dangerous diseases. The search for compounds that can modulate the function of purinergic receptors can lead to the creation of new drugs that are effective in the treatment of diseases of the central and peripheral nervous system and immune system, including neuroinflammation, hypoxia/ischemia, epilepsy and neuropathic pain. In this Special Issue, we wish to offer a platform for high-quality publications on the latest advances on identification of P2X/Y and P1 (A1, A2A, A2B, A3) receptor blockers, functions, and regulation by them; the characterization of these receptor signaling networks and crosstalk; mechanisms underlying the role of purinoceptors in neurodegenerative illnesses as well as chronic neuronal changes following acute noxious damage; and therapeutic opportunities associated with regulation of purinergic receptor activity. This issue will be of interest to researchers working on cell signaling, neurology and immunology, and also to chemical biologists interested in drug discovery, and clinicians.

Dr. Dmitry L. Aminin
Prof. Dr. Peter Illes
Guest Editor

Manuscript Submission Information

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Keywords

  • purinergic receptors
  • P2X, P2Y and P1 family receptors
  • signaling mechanisms
  • neuroinflammation
  • neurodegeneration and neuroregeneration
  • epilepsy
  • hypoxia/ischemia
  • neuropathic and inflammatory pain
  • receptor antagonists
  • enzyme inhibitors
  • drug discovery

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Related Special Issue

Published Papers (13 papers)

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Editorial

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3 pages, 176 KiB  
Editorial
Purinergic Signaling in Neuroinflammation
by Dmitry Aminin and Peter Illes
Int. J. Mol. Sci. 2021, 22(23), 12895; https://doi.org/10.3390/ijms222312895 - 29 Nov 2021
Cited by 2 | Viewed by 1815
Abstract
ATP is stored in millimolar concentrations within the intracellular medium but may be released to extracellular sites either through the damaged plasma membrane or by means of various transporters [...] Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)

Research

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22 pages, 3205 KiB  
Article
Gallic Acid Alleviates Visceral Pain and Depression via Inhibition of P2X7 Receptor
by Lequan Wen, Lirui Tang, Mingming Zhang, Congrui Wang, Shujuan Li, Yuqing Wen, Hongcheng Tu, Haokun Tian, Jingyi Wei, Peiwen Liang, Changsen Yang, Guodong Li and Yun Gao
Int. J. Mol. Sci. 2022, 23(11), 6159; https://doi.org/10.3390/ijms23116159 - 31 May 2022
Cited by 21 | Viewed by 3551
Abstract
Chronic visceral pain can occur in many disorders, the most common of which is irritable bowel syndrome (IBS). Moreover, depression is a frequent comorbidity of chronic visceral pain. The P2X7 receptor is crucial in inflammatory processes and is closely connected to developing pain [...] Read more.
Chronic visceral pain can occur in many disorders, the most common of which is irritable bowel syndrome (IBS). Moreover, depression is a frequent comorbidity of chronic visceral pain. The P2X7 receptor is crucial in inflammatory processes and is closely connected to developing pain and depression. Gallic acid, a phenolic acid that can be extracted from traditional Chinese medicine, has been demonstrated to be anti-inflammatory and anti-depressive. In this study, we investigated whether gallic acid could alleviate comorbid visceral pain and depression by reducing the expression of the P2X7 receptor. To this end, the pain thresholds of rats with comorbid visceral pain and depression were gauged using the abdominal withdraw reflex score, whereas the depression level of each rat was quantified using the sucrose preference test, the forced swimming test, and the open field test. The expressions of the P2X7 receptor in the hippocampus, spinal cord, and dorsal root ganglion (DRG) were assessed by Western blotting and quantitative real-time PCR. Furthermore, the distributions of the P2X7 receptor and glial fibrillary acidic protein (GFAP) in the hippocampus and DRG were investigated in immunofluorescent experiments. The expressions of p-ERK1/2 and ERK1/2 were determined using Western blotting. The enzyme-linked immunosorbent assay was utilized to measure the concentrations of IL-1β, TNF-α, and IL-10 in the serum. Our results demonstrate that gallic acid was able to alleviate both pain and depression in the rats under study. Gallic acid also reduced the expressions of the P2X7 receptor and p-ERK1/2 in the hippocampi, spinal cords, and DRGs of these rats. Moreover, gallic acid treatment decreased the serum concentrations of IL-1β and TNF-α, while raising IL-10 levels in these rats. Thus, gallic acid may be an effective novel candidate for the treatment of comorbid visceral pain and depression by inhibiting the expressions of the P2X7 receptor in the hippocampus, spinal cord, and DRG. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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24 pages, 3006 KiB  
Article
Involvement of GPR17 in Neuronal Fibre Outgrowth
by Max Braune, Nico Scherf, Claudia Heine, Katja Sygnecka, Thanigaimalai Pillaiyar, Chiara Parravicini, Bernd Heimrich, Maria P. Abbracchio, Christa E. Müller and Heike Franke
Int. J. Mol. Sci. 2021, 22(21), 11683; https://doi.org/10.3390/ijms222111683 - 28 Oct 2021
Cited by 7 | Viewed by 2794
Abstract
Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established ex vivo model of organotypic slice co-cultures [...] Read more.
Characterization of new pharmacological targets is a promising approach in research of neurorepair mechanisms. The G protein-coupled receptor 17 (GPR17) has recently been proposed as an interesting pharmacological target, e.g., in neuroregenerative processes. Using the well-established ex vivo model of organotypic slice co-cultures of the mesocortical dopaminergic system (prefrontal cortex (PFC) and substantia nigra/ventral tegmental area (SN/VTA) complex), the influence of GPR17 ligands on neurite outgrowth from SN/VTA to the PFC was investigated. The growth-promoting effects of Montelukast (MTK; GPR17- and cysteinyl-leukotriene receptor antagonist), the glial cell line-derived neurotrophic factor (GDNF) and of two potent, selective GPR17 agonists (PSB-16484 and PSB-16282) were characterized. Treatment with MTK resulted in a significant increase in mean neurite density, comparable with the effects of GDNF. The combination of MTK and GPR17 agonist PSB-16484 significantly inhibited neuronal growth. qPCR studies revealed an MTK-induced elevated mRNA-expression of genes relevant for neuronal growth. Immunofluorescence labelling showed a marked expression of GPR17 on NG2-positive glia. Western blot and RT-qPCR analysis of untreated cultures suggest a time-dependent, injury-induced stimulation of GPR17. In conclusion, MTK was identified as a stimulator of neurite fibre outgrowth, mediating its effects through GPR17, highlighting GPR17 as an interesting therapeutic target in neuronal regeneration. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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22 pages, 4242 KiB  
Article
P2Y2 and P2X4 Receptors Mediate Ca2+ Mobilization in DH82 Canine Macrophage Cells
by Reece Andrew Sophocleous, Nicole Ashleigh Miles, Lezanne Ooi and Ronald Sluyter
Int. J. Mol. Sci. 2020, 21(22), 8572; https://doi.org/10.3390/ijms21228572 - 13 Nov 2020
Cited by 17 | Viewed by 3888
Abstract
Purinergic receptors of the P2 subclass are commonly found in human and rodent macrophages where they can be activated by adenosine 5′-triphosphate (ATP) or uridine 5′-triphosphate (UTP) to mediate Ca2+ mobilization, resulting in downstream signalling to promote inflammation and pain. However, little [...] Read more.
Purinergic receptors of the P2 subclass are commonly found in human and rodent macrophages where they can be activated by adenosine 5′-triphosphate (ATP) or uridine 5′-triphosphate (UTP) to mediate Ca2+ mobilization, resulting in downstream signalling to promote inflammation and pain. However, little is understood regarding these receptors in canine macrophages. To establish a macrophage model of canine P2 receptor signalling, the expression of these receptors in the DH82 canine macrophage cell line was determined by reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. P2 receptor function in DH82 cells was pharmacologically characterised using nucleotide-induced measurements of Fura-2 AM-bound intracellular Ca2+. RT-PCR revealed predominant expression of P2X4 receptors, while immunocytochemistry confirmed predominant expression of P2Y2 receptors, with low levels of P2X4 receptor expression. ATP and UTP induced robust Ca2+ responses in the absence or presence of extracellular Ca2+. ATP-induced responses were only partially inhibited by the P2X4 receptor antagonists, 2′,3′-O-(2,4,6-trinitrophenyl)-ATP (TNP-ATP), paroxetine and 5-BDBD, but were strongly potentiated by ivermectin. UTP-induced responses were near completely inhibited by the P2Y2 receptor antagonists, suramin and AR-C118925. P2Y2 receptor-mediated Ca2+ mobilization was inhibited by U-73122 and 2-aminoethoxydiphenyl borate (2-APB), indicating P2Y2 receptor coupling to the phospholipase C and inositol triphosphate signal transduction pathway. Together this data demonstrates, for the first time, the expression of functional P2 receptors in DH82 canine macrophage cells and identifies a potential cell model for studying macrophage-mediated purinergic signalling in inflammation and pain in dogs. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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Review

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18 pages, 1466 KiB  
Review
Inherent P2X7 Receptors Regulate Macrophage Functions during Inflammatory Diseases
by Wenjing Ren, Patrizia Rubini, Yong Tang, Tobias Engel and Peter Illes
Int. J. Mol. Sci. 2022, 23(1), 232; https://doi.org/10.3390/ijms23010232 - 26 Dec 2021
Cited by 47 | Viewed by 6585
Abstract
Macrophages are mononuclear phagocytes which derive either from blood-borne monocytes or reside as resident macrophages in peripheral (Kupffer cells of the liver, marginal zone macrophages of the spleen, alveolar macrophages of the lung) and central tissue (microglia). They occur as M1 (pro-inflammatory; classic) [...] Read more.
Macrophages are mononuclear phagocytes which derive either from blood-borne monocytes or reside as resident macrophages in peripheral (Kupffer cells of the liver, marginal zone macrophages of the spleen, alveolar macrophages of the lung) and central tissue (microglia). They occur as M1 (pro-inflammatory; classic) or M2 (anti-inflammatory; alternatively activated) phenotypes. Macrophages possess P2X7 receptors (Rs) which respond to high concentrations of extracellular ATP under pathological conditions by allowing the non-selective fluxes of cations (Na+, Ca2+, K+). Activation of P2X7Rs by still higher concentrations of ATP, especially after repetitive agonist application, leads to the opening of membrane pores permeable to ~900 Da molecules. For this effect an interaction of the P2X7R with a range of other membrane channels (e.g., P2X4R, transient receptor potential A1 [TRPA1], pannexin-1 hemichannel, ANO6 chloride channel) is required. Macrophage-localized P2X7Rs have to be co-activated with the lipopolysaccharide-sensitive toll-like receptor 4 (TLR4) in order to induce the formation of the inflammasome 3 (NLRP3), which then activates the pro-interleukin-1β (pro-IL-1β)-degrading caspase-1 to lead to IL-1β release. Moreover, inflammatory diseases (e.g., rheumatoid arthritis, Crohn’s disease, sepsis, etc.) are generated downstream of the P2X7R-induced upregulation of intracellular second messengers (e.g., phospholipase A2, p38 mitogen-activated kinase, and rho G proteins). In conclusion, P2X7Rs at macrophages appear to be important targets to preserve immune homeostasis with possible therapeutic consequences. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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16 pages, 1095 KiB  
Review
Astroglial and Microglial Purinergic P2X7 Receptor as a Major Contributor to Neuroinflammation during the Course of Multiple Sclerosis
by Marta Sidoryk-Węgrzynowicz and Lidia Strużyńska
Int. J. Mol. Sci. 2021, 22(16), 8404; https://doi.org/10.3390/ijms22168404 - 5 Aug 2021
Cited by 24 | Viewed by 3120
Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that leads to the progressive disability of patients. A characteristic feature of the disease is the presence of focal demyelinating lesions accompanied by an inflammatory reaction. Interactions between autoreactive immune [...] Read more.
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that leads to the progressive disability of patients. A characteristic feature of the disease is the presence of focal demyelinating lesions accompanied by an inflammatory reaction. Interactions between autoreactive immune cells and glia cells are considered as a central mechanism underlying the pathology of MS. A glia-mediated inflammatory reaction followed by overproduction of free radicals and generation of glutamate-induced excitotoxicity promotes oligodendrocyte injury, contributing to demyelination and subsequent neurodegeneration. Activation of purinergic signaling, in particular P2X7 receptor-mediated signaling, in astrocytes and microglia is an important causative factor in these pathological processes. This review discusses the role of astroglial and microglial cells, and in particular glial P2X7 receptors, in inducing MS-related neuroinflammatory events, highlighting the importance of P2X7R-mediated molecular pathways in MS pathology and identifying these receptors as a potential therapeutic target. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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26 pages, 3040 KiB  
Review
Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy
by Karol Chojnowski, Mikolaj Opielka, Wojciech Nazar, Przemyslaw Kowianski and Ryszard T. Smolenski
Int. J. Mol. Sci. 2021, 22(13), 6898; https://doi.org/10.3390/ijms22136898 - 27 Jun 2021
Cited by 14 | Viewed by 3833
Abstract
Guanosine (Guo) is a nucleotide metabolite that acts as a potent neuromodulator with neurotrophic and regenerative properties in neurological disorders. Under brain ischemia or trauma, Guo is released to the extracellular milieu and its concentration substantially raises. In vitro studies on brain tissue [...] Read more.
Guanosine (Guo) is a nucleotide metabolite that acts as a potent neuromodulator with neurotrophic and regenerative properties in neurological disorders. Under brain ischemia or trauma, Guo is released to the extracellular milieu and its concentration substantially raises. In vitro studies on brain tissue slices or cell lines subjected to ischemic conditions demonstrated that Guo counteracts destructive events that occur during ischemic conditions, e.g., glutaminergic excitotoxicity, reactive oxygen and nitrogen species production. Moreover, Guo mitigates neuroinflammation and regulates post-translational processing. Guo asserts its neuroprotective effects via interplay with adenosine receptors, potassium channels, and excitatory amino acid transporters. Subsequently, guanosine activates several prosurvival molecular pathways including PI3K/Akt (PI3K) and MEK/ERK. Due to systemic degradation, the half-life of exogenous Guo is relatively low, thus creating difficulty regarding adequate exogenous Guo distribution. Nevertheless, in vivo studies performed on ischemic stroke rodent models provide promising results presenting a sustained decrease in infarct volume, improved neurological outcome, decrease in proinflammatory events, and stimulation of neuroregeneration through the release of neurotrophic factors. In this comprehensive review, we discuss molecular signaling related to Guo protection against brain ischemia. We present recent advances, limitations, and prospects in exogenous guanosine therapy in the context of ischemic stroke. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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22 pages, 1104 KiB  
Review
Purinergic–Glycinergic Interaction in Neurodegenerative and Neuroinflammatory Disorders of the Retina
by Laszlo G. Harsing, Jr., Gábor Szénási, Tibor Zelles and László Köles
Int. J. Mol. Sci. 2021, 22(12), 6209; https://doi.org/10.3390/ijms22126209 - 8 Jun 2021
Cited by 7 | Viewed by 2932
Abstract
Neurodegenerative–neuroinflammatory disorders of the retina seriously hamper human vision. In searching for key factors that contribute to the development of these pathologies, we considered potential interactions among purinergic neuromodulation, glycinergic neurotransmission, and microglia activity in the retina. Energy deprivation at cellular levels is [...] Read more.
Neurodegenerative–neuroinflammatory disorders of the retina seriously hamper human vision. In searching for key factors that contribute to the development of these pathologies, we considered potential interactions among purinergic neuromodulation, glycinergic neurotransmission, and microglia activity in the retina. Energy deprivation at cellular levels is mainly due to impaired blood circulation leading to increased release of ATP and adenosine as well as glutamate and glycine. Interactions between these modulators and neurotransmitters are manifold. First, P2Y purinoceptor agonists facilitate reuptake of glycine by glycine transporter 1, while its inhibitors reduce reverse-mode operation; these events may lower extracellular glycine levels. The consequential changes in extracellular glycine concentration can lead to parallel changes in the activity of NR1/NR2B type NMDA receptors of which glycine is a mandatory agonist, and thereby may reduce neurodegenerative events in the retina. Second, P2Y purinoceptor agonists and glycine transporter 1 inhibitors may indirectly inhibit microglia activity by decreasing neuronal or glial glycine release in energy-compromised retina. These inhibitions may have a role in microglia activation, which is present during development and progression of neurodegenerative disorders such as glaucomatous and diabetic retinopathies and age-related macular degeneration or loss of retinal neurons caused by thromboembolic events. We have hypothesized that glycine transporter 1 inhibitors and P2Y purinoceptor agonists may have therapeutic importance in neurodegenerative–neuroinflammatory disorders of the retina by decreasing NR1/NR2B NMDA receptor activity and production and release of a series of proinflammatory cytokines from microglial cells. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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14 pages, 317 KiB  
Review
A2B Adenosine Receptors: When Outsiders May Become an Attractive Target to Treat Brain Ischemia or Demyelination
by Elisabetta Coppi, Ilaria Dettori, Federica Cherchi, Irene Bulli, Martina Venturini, Daniele Lana, Maria Grazia Giovannini, Felicita Pedata and Anna Maria Pugliese
Int. J. Mol. Sci. 2020, 21(24), 9697; https://doi.org/10.3390/ijms21249697 - 18 Dec 2020
Cited by 20 | Viewed by 3351
Abstract
Adenosine is a signaling molecule, which, by activating its receptors, acts as an important player after cerebral ischemia. Here, we review data in the literature describing A2BR-mediated effects in models of cerebral ischemia obtained in vivo by the occlusion of the [...] Read more.
Adenosine is a signaling molecule, which, by activating its receptors, acts as an important player after cerebral ischemia. Here, we review data in the literature describing A2BR-mediated effects in models of cerebral ischemia obtained in vivo by the occlusion of the middle cerebral artery (MCAo) or in vitro by oxygen-glucose deprivation (OGD) in hippocampal slices. Adenosine plays an apparently contradictory role in this receptor subtype depending on whether it is activated on neuro-glial cells or peripheral blood vessels and/or inflammatory cells after ischemia. Indeed, A2BRs participate in the early glutamate-mediated excitotoxicity responsible for neuronal and synaptic loss in the CA1 hippocampus. On the contrary, later after ischemia, the same receptors have a protective role in tissue damage and functional impairments, reducing inflammatory cell infiltration and neuroinflammation by central and/or peripheral mechanisms. Of note, demyelination following brain ischemia, or autoimmune neuroinflammatory reactions, are also profoundly affected by A2BRs since they are expressed by oligodendroglia where their activation inhibits cell maturation and expression of myelin-related proteins. In conclusion, data in the literature indicate the A2BRs as putative therapeutic targets for the still unmet treatment of stroke or demyelinating diseases. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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21 pages, 894 KiB  
Review
Targeting Adenosine Receptors: A Potential Pharmacological Avenue for Acute and Chronic Pain
by Fabrizio Vincenzi, Silvia Pasquini, Pier Andrea Borea and Katia Varani
Int. J. Mol. Sci. 2020, 21(22), 8710; https://doi.org/10.3390/ijms21228710 - 18 Nov 2020
Cited by 49 | Viewed by 5077
Abstract
Adenosine is a purine nucleoside, responsible for the regulation of multiple physiological and pathological cellular and tissue functions by activation of four G protein-coupled receptors (GPCR), namely A1, A2A, A2B, and A3 adenosine receptors (ARs). In [...] Read more.
Adenosine is a purine nucleoside, responsible for the regulation of multiple physiological and pathological cellular and tissue functions by activation of four G protein-coupled receptors (GPCR), namely A1, A2A, A2B, and A3 adenosine receptors (ARs). In recent years, extensive progress has been made to elucidate the role of adenosine in pain regulation. Most of the antinociceptive effects of adenosine are dependent upon A1AR activation located at peripheral, spinal, and supraspinal sites. The role of A2AAR and A2BAR is more controversial since their activation has both pro- and anti-nociceptive effects. A3AR agonists are emerging as promising candidates for neuropathic pain. Although their therapeutic potential has been demonstrated in diverse preclinical studies, no AR ligands have so far reached the market. To date, novel pharmacological approaches such as adenosine regulating agents and allosteric modulators have been proposed to improve efficacy and limit side effects enhancing the effect of endogenous adenosine. This review aims to provide an overview of the therapeutic potential of ligands interacting with ARs and the adenosinergic system for the treatment of acute and chronic pain. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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28 pages, 1345 KiB  
Review
Purinergic Signaling in Endometriosis-Associated Pain
by Carla Trapero and Mireia Martín-Satué
Int. J. Mol. Sci. 2020, 21(22), 8512; https://doi.org/10.3390/ijms21228512 - 12 Nov 2020
Cited by 17 | Viewed by 7250
Abstract
Endometriosis is an estrogen-dependent gynecological disease, with an associated chronic inflammatory component, characterized by the presence of endometrial tissue outside the uterine cavity. Its predominant symptom is pain, a condition notably altering the quality of life of women with the disease. This review [...] Read more.
Endometriosis is an estrogen-dependent gynecological disease, with an associated chronic inflammatory component, characterized by the presence of endometrial tissue outside the uterine cavity. Its predominant symptom is pain, a condition notably altering the quality of life of women with the disease. This review is intended to exhaustively gather current knowledge on purinergic signaling in endometriosis-associated pain. Altered extracellular ATP hydrolysis, due to changes in ectonucleotidase activity, has been reported in endometriosis; the resulting accumulation of ATP in the endometriotic microenvironment points to sustained activation of nucleotide receptors (P2 receptors) capable of generating a persistent pain message. P2X3 receptor, expressed in sensory neurons, mediates nociceptive, neuropathic, and inflammatory pain, and is enrolled in endometriosis-related pain. Pharmacological inhibition of P2X3 receptor is under evaluation as a pain relief treatment for women with endometriosis. The role of other ATP receptors is also discussed here, e.g., P2X4 and P2X7 receptors, which are involved in inflammatory cell–nerve and microglia–nerve crosstalk, and therefore in inflammatory and neuropathic pain. Adenosine receptors (P1 receptors), by contrast, mainly play antinociceptive and anti-inflammatory roles. Purinome-targeted drugs, including nucleotide receptors and metabolizing enzymes, are potential non-hormonal therapeutic tools for the pharmacological management of endometriosis-related pain. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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Graphical abstract

32 pages, 1463 KiB  
Review
Neonatal Seizures and Purinergic Signalling
by Aida Menéndez Méndez, Jonathon Smith and Tobias Engel
Int. J. Mol. Sci. 2020, 21(21), 7832; https://doi.org/10.3390/ijms21217832 - 22 Oct 2020
Cited by 7 | Viewed by 5792
Abstract
Neonatal seizures are one of the most common comorbidities of neonatal encephalopathy, with seizures aggravating acute injury and clinical outcomes. Current treatment can control early life seizures; however, a high level of pharmacoresistance remains among infants, with increasing evidence suggesting current anti-seizure medication [...] Read more.
Neonatal seizures are one of the most common comorbidities of neonatal encephalopathy, with seizures aggravating acute injury and clinical outcomes. Current treatment can control early life seizures; however, a high level of pharmacoresistance remains among infants, with increasing evidence suggesting current anti-seizure medication potentiating brain damage. This emphasises the need to develop safer therapeutic strategies with a different mechanism of action. The purinergic system, characterised by the use of adenosine triphosphate and its metabolites as signalling molecules, consists of the membrane-bound P1 and P2 purinoreceptors and proteins to modulate extracellular purine nucleotides and nucleoside levels. Targeting this system is proving successful at treating many disorders and diseases of the central nervous system, including epilepsy. Mounting evidence demonstrates that drugs targeting the purinergic system provide both convulsive and anticonvulsive effects. With components of the purinergic signalling system being widely expressed during brain development, emerging evidence suggests that purinergic signalling contributes to neonatal seizures. In this review, we first provide an overview on neonatal seizure pathology and purinergic signalling during brain development. We then describe in detail recent evidence demonstrating a role for purinergic signalling during neonatal seizures and discuss possible purine-based avenues for seizure suppression in neonates. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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15 pages, 657 KiB  
Review
Bone Marrow and Adipose Tissue Adenosine Receptors Effect on Osteogenesis and Adipogenesis
by Anna Eisenstein, Shlok V. Chitalia and Katya Ravid
Int. J. Mol. Sci. 2020, 21(20), 7470; https://doi.org/10.3390/ijms21207470 - 10 Oct 2020
Cited by 19 | Viewed by 3385
Abstract
Adenosine is an extracellular signaling molecule that is particularly relevant in times of cellular stress, inflammation and metabolic disturbances when the levels of the purine increase. Adenosine acts on two G-protein-coupled stimulatory and on two G-protein-coupled inhibitory receptors, which have varying expression profiles [...] Read more.
Adenosine is an extracellular signaling molecule that is particularly relevant in times of cellular stress, inflammation and metabolic disturbances when the levels of the purine increase. Adenosine acts on two G-protein-coupled stimulatory and on two G-protein-coupled inhibitory receptors, which have varying expression profiles in different tissues and conditions, and have different affinities for the endogenous ligand. Studies point to significant roles of adenosine and its receptors in metabolic disease and bone health, implicating the receptors as potential therapeutic targets. This review will highlight our current understanding of the dichotomous effects of adenosine and its receptors on adipogenesis versus osteogenesis within the bone marrow to maintain bone health, as well as its relationship to obesity. Therapeutic implications will also be reviewed. Full article
(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation)
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