The translocator protein ligand XBD173 improves clinical symptoms and neuropathological markers in the SJL/J mouse model of multiple sclerosis

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1863

Article

Leva, Geraldine¹  Klein, Christian¹  Benyounes, Jeremie¹  Halle, Francois²  Bihel, Frederic²  Collongues, Nicolas¹  De Seze, Jerome¹  Mensah-Nyagan, Ayikoe-Guy¹  Patte-Mensah, Christine¹ 

[1] Univ Strasbourg, FMTS, INSERM U1119,Fac Med, Biopathol Myelin Neuroprotect & Strategies Therap, Bettiment 3,11 Rue Humann, F-67000 Strasbourg, France

[2] CNRS UMR 7200, Fac Pharm Strasbourg, LIT, 74 Route Rhin,CS 60024, F-67401 Illkirch Graffenstaden, France

关键词: Multiple sclerosis;    Experimental autoimmune encephalomyelitis;    XBD173;    TSPO;    Neurodegeneration;    Neuroinflammation;   

DOI  :  10.1016/j.bbadis.2017.09.007

来源: Elsevier

【 摘 要 】

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 (10-20 mg/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 (10 mg/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 10 mg/kg dose, the paper opens interesting perspectives for the development of efficient and safe therapies against MS with slight or no side-effects.

【 授权许可】

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