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

Neuropharmacology. 2014 Jun:81:237-43. doi: 10.1016/j.neuropharm.2014.02.011. Epub 2014 Feb 21.


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.

Keywords: Cinnabarinic acid; Experimental autoimmune encephalomyelitis; Metabotropic glutamate receptor 4; Tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzopyrans / therapeutic use
  • Central Nervous System / pathology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Excitatory Amino Acid Agonists / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myelin Basic Protein / metabolism
  • Myelin-Oligodendrocyte Glycoprotein / toxicity
  • Myosin Type II / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Oxazines / therapeutic use*
  • Peptide Fragments / toxicity
  • Receptors, Metabotropic Glutamate / metabolism*
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • Th17 Cells / drug effects
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Benzopyrans
  • Cytokines
  • Excitatory Amino Acid Agonists
  • Myelin Basic Protein
  • Myelin-Oligodendrocyte Glycoprotein
  • N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Oxazines
  • Peptide Fragments
  • Receptors, Metabotropic Glutamate
  • Rorc protein, mouse
  • T-Box Domain Protein 2
  • T-Box Domain Proteins
  • Transcription Factors
  • myelin oligodendrocyte glycoprotein (35-55)
  • cinnabarinic acid
  • Myosin Type II
  • metabotropic glutamate receptor 4