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Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor

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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.

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

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Acknowledgments

We thank Gabriela Segat, Thaís Barbosa Alberti, Rodrigo Marcon and Allisson Freire Bento for technical assistance. Grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC), and Programa de Pós-Graduação em Neurociências (PGN), all from Brazil, supported this work. S.C.J., I.S.C and V.L. are PhD students in neuroscience receiving grants from CAPES and FAPESC. M.P.C. holds a postdoctoral fellowship from CAPES.

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  1. Laboratório de Autoimunidade e Imunofarmacologia, Campus Araranguá, Universidade Federal de Santa Catarina, CEP 88906-072, Araranguá, SC, Brazil

    Stella Célio Junqueira, Vicente Lieberknecht & Rafael Cypriano Dutra

  2. Programa de Pós-Graduação em Neurociências, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil

    Stella Célio Junqueira, Igor dos Santos Coelho, Vicente Lieberknecht, Mauricio Peña Cunha, Ana Lúcia S. Rodrigues, Adair Roberto Soares Santos & Rafael Cypriano Dutra

  3. 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

    Igor dos Santos Coelho & Adair Roberto Soares Santos

  4. Departamento de Bioquímica, Centro de Ciências Biológicas, Campus Universitário, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil

    Mauricio Peña Cunha & Ana Lúcia S. Rodrigues

  5. Centro de Inovação e Ensaios Pré-clínicos, Cachoeira do Bom Jesus, Florianópolis, SC, Brazil

    João B. Calixto

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  1. Stella Célio Junqueira
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Highlights

• Inosine displays pronounced anti-inflammatory and antinociceptive properties.

• Inosine inhibits demyelinating process and astroglial activation.

• Inosine modulates adenosinergic receptors, especially A2AR.

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Junqueira, S.C., dos Santos Coelho, I., Lieberknecht, V. et al. Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor. Mol Neurobiol 54, 3271–3285 (2017). https://doi.org/10.1007/s12035-016-9893-3

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