The translocator protein ligand XBD173 improves clinical symptoms and neuropathological markers in the SJL/J mouse model of multiple sclerosis.
Fiche publication
Date publication
décembre 2017
Journal
Biochimica et biophysica acta. Molecular basis of disease
Auteurs
Membres identifiés du Cancéropôle Est :
Pr DE SEZE Jérôme
Tous les auteurs :
Leva G, Klein C, Benyounes J, Hallé F, Bihel F, Collongues N, De Seze J, Mensah-Nyagan AG, Patte-Mensah C
Lien Pubmed
Résumé
Multiple sclerosis (MS) is a severe autoimmune disease characterized by inflammatory, demyelinating and neurodegenerative components causing motor, sensory, visual and/or cognitive symptoms. The relapsing-remitting MS affecting 85% of patients is reliably mimicked by the proteolipid-protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) SJL/J-mouse model. Significant progress was made for MS treatment but the development of effective therapies devoid of severe side-effects remains a great challenge. Here, we combine clinical, behavioral, histopathological, biochemical and molecular approaches to demonstrate that low and well tolerated doses (10-20mg/kg) of TSPO ligand XBD173 (Emapunil) efficiently ameliorate clinical signs and neuropathology of PLP-EAE mice. In addition to the conventional clinical scoring of symptoms, we applied the robust behavioral Catwalk-method to confirm that XBD173 (10mg/kg) increases the maximum contact area parameter at EAE-disease peak, indicating an improvement/recovery of motor functions. Consistently, histopathological studies coupled with microscope-cellSens quantification and RT-qPCR analyzes showed that XBD173 prevented demyelination by restoring normal protein and mRNA levels of myelin basic protein that was significantly repressed in PLP-EAE mice spinal cord and brain. Interestingly, ELISA-based measurement revealed that XBD173 increased allopregnanolone concentrations in PLP-EAE mice spinal and brain tissues. Furthermore, flow cytometry assessment demonstrated that XBD173 therapy decreased serum level of pro-inflammatory cytokines, including interleukin-17A, Interleukin-6 and tumor-necrosis-factor alpha in PLP-EAE mice. As the optimal XBD173 dosing exerting the maximal beneficial action in EAE mice is the lower 10mg/kg dose, the paper opens interesting perspectives for the development of efficient and safe therapies against MS with slight or no side-effects.
Mots clés
Animals, Biomarkers, metabolism, Brain, drug effects, Cytokines, metabolism, Demyelinating Diseases, drug therapy, Encephalomyelitis, Autoimmune, Experimental, drug therapy, Female, Ligands, Mice, Mice, Inbred Strains, Multiple Sclerosis, Relapsing-Remitting, drug therapy, Myelin Basic Protein, genetics, Neurotransmitter Agents, metabolism, Pregnanolone, metabolism, Purines, pharmacology, RNA, Messenger, genetics, Receptors, GABA, metabolism, Spinal Cord, drug effects
Référence
Biochim Biophys Acta Mol Basis Dis. 2017 12;1863(12):3016-3027