Cinnabarinic acid, an endogenous agonist of type-4 metabotropic glutamate receptor, suppresses experimental autoimmune encephalomyelitis in mice

Francesco Fazio, Cristina Zappulla, Serena Notartomaso, Carla Busceti, Alban Bessede, Pamela Scarselli, Carmine Vacca, Marco Gargaro, Claudia Volpi, Massimo Allegrucci, Luana Lionetto, Maurizio Simmaco, Maria Laura Belladonna, Ferdinando Nicoletti, Francesca Fallarino

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

Cinnabarinic acid (CA) is an endogenous metabolite of the kynurenine pathway which acts as an orthosteric agonist of type-4 metabotropic glutamate receptor (mGlu4). We now report that systemic administration of CA (0.1-10 mg/kg, i.p.) was highly protective against experimental autoimmune encephalomyelitis (EAE) induced by the myelin oligodendrocyte glycoprotein (MOG35-55) peptide, which models multiple sclerosis in mice. Full protection against EAE required daily injections of CA since the time of immunization, similarly to what reported for the mGlu4 enhancer N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1acarboxamide (PHCCC). CA treatment boosted an immune response dominated by regulatory T (Treg) cells at the expenses of Th17 cells. In addition, exogenous CA enhanced endogenous CA formation in lymphocytes, suggesting the occurrence of a positive feedback loop sustaining immune tolerance. To examine whether activation of mGlu4 could account for the protective activity of CA against EAE, we used mGlu4 knockout mice. As expected, these mice displayed a more severe form of EAE in response to immunization. CA was still protective against EAE in mGlu4-deficient mice, although its action was significantly reduced both at high and low CA doses. This suggests that the action of CA against neuroinflammation involves multiple mechanisms including the activation of mGlu4. These data further suggest that CA is one possible bridge between activation of the kynurenine pathway and immune tolerance aimed at restraining neuroinflammation.

Original languageEnglish (US)
Pages (from-to)237-243
Number of pages7
JournalNeuropharmacology
Volume81
DOIs
StatePublished - Jun 2014
Externally publishedYes

Keywords

  • Cinnabarinic acid
  • Experimental autoimmune encephalomyelitis
  • Metabotropic glutamate receptor 4
  • Tolerance

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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    Fazio, F., Zappulla, C., Notartomaso, S., Busceti, C., Bessede, A., Scarselli, P., Vacca, C., Gargaro, M., Volpi, C., Allegrucci, M., Lionetto, L., Simmaco, M., Belladonna, M. L., Nicoletti, F., & Fallarino, F. (2014). Cinnabarinic acid, an endogenous agonist of type-4 metabotropic glutamate receptor, suppresses experimental autoimmune encephalomyelitis in mice. Neuropharmacology, 81, 237-243. https://doi.org/10.1016/j.neuropharm.2014.02.011