title: Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor.
abstract: Multiple sclerosis (MS) is a T cell autoimmune, inflammatory, and demyelinating disease of the central nervous system (CNS). Currently available therapies have partially effective actions and numerous side reactions. Inosine, an endogenous purine nucleoside, has immunomodulatory, neuroprotective, and analgesic properties. Herein, we evaluated the effect of inosine on the development and progression of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Inosine (1 or 10 mg/kg, i.p.) was administrated twice a day for 40 days. Immunological and inflammatory responses were evaluated by behavioral, histological, immunohistochemical, ELISA, RT-PCR, and Western blotting analysis. The administration of inosine exerted neuroprotective effects against EAE by diminishing clinical signs, including thermal and mechanical hyperalgesia, as well as weight loss typical of the disease. These beneficial effects of inosine seem to be associated with the blockade of inflammatory cell entry into the CNS, especially lymphocytes, thus delaying the demyelinating process and astrocytes activation. In particular, up-regulation of IL-17 levels in the secondary lymphoid tissues, a result of EAE, was prevented by inosine treatment in EAE mice. Additionally, inosine consistently prevented A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. Altogether, these results allow us to propose that this endogenous purine might be a putative novel and helpful tool for the prevention of autoimmune and neurodegenerative diseases, such as MS. Thus, inosine could have considerable implications for future therapies of MS, and this study may represent the starting point for further investigation into the role of inosine and adenosinergic receptors in neuroinflammation processes. Graphical Abstract Preventive treatment with inosine inhibits the development and progression of EAE in C57Bl/6 mice. Furthermore, neuroinflammation and demyelinating processes were blocked by inosine treatment. Additionally, inosine consistently inhibited IL-17 levels in peripheral lymphoid tissue, as well as IL-4 levels and A2AR up-regulation in the spinal cord, likely, through an ERK1-independent pathway. EAE: experimental autoimmune encephalomyelitis; MS: multiple sclerosis; A2AR: adenosine A2A receptor; IL-17: interleukin-17; IL-4: interleukin-4.
authors.affiliation: Laboratório de Autoimunidade e Imunofarmacologia, Campus Araranguá, Universidade Federal de Santa Catarina, CEP 88906-072, Araranguá, SC, Brazil.|Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Stella Célio
authors.initials: SC
authors.lastname: Junqueira
authors.affiliation: Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.|Laboratório de Neurobiologia da Dor e Inflamação, Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Igor
authors.initials: I
authors.lastname: Dos Santos Coelho
authors.affiliation: Laboratório de Autoimunidade e Imunofarmacologia, Campus Araranguá, Universidade Federal de Santa Catarina, CEP 88906-072, Araranguá, SC, Brazil.|Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Vicente
authors.initials: V
authors.lastname: Lieberknecht
authors.affiliation: Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.|Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Mauricio Peña
authors.initials: MP
authors.lastname: Cunha
authors.affiliation: Centro de Inovação e Ensaios Pré-clínicos, Cachoeira do Bom Jesus, Florianópolis, SC, Brazil.
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
authors.affiliation: Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.|Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Ana Lúcia S
authors.initials: ALS
authors.lastname: Rodrigues
authors.affiliation: Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.|Laboratório de Neurobiologia da Dor e Inflamação, Departamento de Ciências Fisiológicas, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Adair Roberto Soares
authors.initials: ARS
authors.lastname: Santos
authors.affiliation: Laboratório de Autoimunidade e Imunofarmacologia, Campus Araranguá, Universidade Federal de Santa Catarina, CEP 88906-072, Araranguá, SC, Brazil. rafaelcdutra@gmail.com.|Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil. rafaelcdutra@gmail.com.
authors.forename: Rafael Cypriano
authors.initials: RC
authors.lastname: Dutra
mesh_terms: D000818:Animals; D001007:Anxiety / Q000150:complications / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006930:Hyperalgesia / Q000150:complications / Q000473:pathology; D007114:Immunization; D056747:Immunomodulation; D007249:Inflammation / Q000150:complications / Q000473:pathology; D007288:Inosine / Q000494:pharmacology / Q000627:therapeutic use*; D020381:Interleukin-17 / Q000096:biosynthesis; D008221:Lymphoid Tissue / Q000473:pathology; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009186:Myelin Sheath / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology
chemical_list: D020381:Interleukin-17; D043705:Receptor, Adenosine A2A; D007288:Inosine; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: A2A receptor; Autoimmunity; Experimental autoimmune encephalomyelitis; Inosine; Multiple sclerosis