Effects of isoxazolo-pyridinone 7e, a potent activator of the Nurr1 signaling pathway, on experimental autoimmune encephalomyelitis in mice

Francesca Montarolo; Chiara Raffaele; Simona Perga; Serena Martire; Annamaria Finardi; Roberto Furlan; Samuel Hintermann; Antonio Bertolotto

doi:10.1371/journal.pone.0108791

Effects of isoxazolo-pyridinone 7e, a potent activator of the Nurr1 signaling pathway, on experimental autoimmune encephalomyelitis in mice

PLoS One. 2014 Sep 29;9(9):e108791. doi: 10.1371/journal.pone.0108791. eCollection 2014.

Authors

Francesca Montarolo¹, Chiara Raffaele², Simona Perga¹, Serena Martire¹, Annamaria Finardi², Roberto Furlan², Samuel Hintermann³, Antonio Bertolotto¹

Affiliations

¹ Neurobiology Unit, Neurologia 2 - CRESM (Regional Referring Center of Multiple Sclerosis), Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin and AOU San Luigi, Orbassano, Torino, Italy.
² Division of Neuroscience, Experimental Neurology Institute (INSPE), San Raffaele Scientific Institute, Milan, Italy.
³ Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Basel, Switzerland.

Abstract

Multiple sclerosis (MS) is an autoimmune chronic disease of the central nervous system (CNS) characterized by immune-mediated inflammation, demyelination and subsequent axonal damage. Gene expression profiling showed that Nurr1, an orphan nuclear receptor, is down-regulated in peripheral blood mononuclear cells of MS patients. Nurr1 exerts an anti-inflammatory role repressing the activity of the pro-inflammatory transcription factor NF-kB. Here, we report that the preventive treatment with isoxazolo-pyridinone 7e, an activator of Nurr1 signaling pathway, reduces the incidence and the severity of a MS murine model, i.e. experimental autoimmune encephalomyelitis (EAE). The compound is able to attenuate inflammation and neurodegeneration in spinal cords of EAE mice by an NF-kB pathway-dependent process.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Axons / drug effects
Axons / metabolism
Axons / pathology
Cell Count
Demyelinating Diseases / complications
Demyelinating Diseases / drug therapy
Demyelinating Diseases / pathology
Down-Regulation / drug effects
Encephalomyelitis, Autoimmune, Experimental / complications
Encephalomyelitis, Autoimmune, Experimental / drug therapy*
Encephalomyelitis, Autoimmune, Experimental / metabolism*
Encephalomyelitis, Autoimmune, Experimental / pathology
Female
Isoxazoles / administration & dosage
Isoxazoles / pharmacology
Isoxazoles / therapeutic use*
Macrophages / drug effects
Mice, Inbred C57BL
Myelin-Oligodendrocyte Glycoprotein
NF-kappa B / metabolism
Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism*
Oxazoles / administration & dosage
Oxazoles / pharmacology
Oxazoles / therapeutic use*
Peptide Fragments
Pyrimidinones / administration & dosage
Pyrimidinones / pharmacology
Pyrimidinones / therapeutic use*
Signal Transduction* / drug effects
Spinal Cord / drug effects
Spinal Cord / metabolism
Spinal Cord / pathology
T-Lymphocytes / drug effects

Substances

6-(4-((2-methoxyethoxy)methyl)phenyl)-5-methyl-3-phenylisoxazolo(4,5-c)pyridin-4(5H)-one
Isoxazoles
Myelin-Oligodendrocyte Glycoprotein
NF-kappa B
Nr4a2 protein, mouse
Nuclear Receptor Subfamily 4, Group A, Member 2
Oxazoles
Peptide Fragments
Pyrimidinones
myelin oligodendrocyte glycoprotein (35-55)

Grants and funding

The funder Novartis S.p.a. provided support in the form of salaries for authors S.H. who was involved in the study design and the preparation of the manuscript, but did not have any role in the data collection and analysis, and decision to publish. The specific roles of these authors are articulated in the ‘author contributions’ section.