piperidines and myelin-oligodendrocyte-glycoprotein-(35-55)

Multiple sclerosis (MS) is the most popular chronic and debilitating inflammatory disease of the central nervous system (CNS) that remains incurable. Dihydroorotate dehydrogenase (DHODH) is critical to the activity of T lymphocytes and represents a potential therapeutic target for MS. Here we identify piperine, a bioactive constituent of black pepper, as a potent inhibitor of DHODH with an IC

Topics: Alkaloids; Animals; Benzodioxoles; Biological Products; Blood-Brain Barrier; Crystallography, X-Ray; Dihydroorotate Dehydrogenase; Encephalomyelitis, Autoimmune, Experimental; Enzyme Inhibitors; Female; Humans; Jurkat Cells; Mice, Inbred C57BL; Models, Molecular; Molecular Targeted Therapy; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Oxidoreductases Acting on CH-CH Group Donors; Peptide Fragments; Piperidines; Polyunsaturated Alkamides; Spleen

During immune-mediated demyelinating lesions, the endocannabinoid system is involved in the pathogenesis of both neuroinflammation and neurodegeneration through different mechanisms. Here we explored the cellular distribution of the CB1 receptor (CB1R) in the central nervous system (CNS) and detected the level of CB1R expression during experimental autoimmune encephalomyelitis (EAE) by RT-qPCR, Western blotting, and immunostaining. Expression of CB1R was observed in neurons and microglia/macrophages but was barely detected in astrocytes. During EAE, the expression of CB1R in spinal cords was reduced at days 9, 17, and 28 postimmunization (p.i.), but the level of CB1R expression in spleens did not show a significant difference compared with complete Freund's adjuvant (CFA)-immunized mice. A selective CB1R antagonist (SR141716A) increased EAE clinical score, accompanied by weight loss. Unexpectedly, SR141716A inhibited the expression of CB1R but increased the expression of CB2R in brains, spinal cords, and spleens simultaneously. The administration of SR141716A increased interferon-γ, interleukin-17 (IL-17), and inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor-α in brains and/or spinal cords. A similar increase was observed in spontaneous and specific antigen-stimulated splenic mononuclear cells compared with vehicle controls. Interestingly, the expression of CX3CL1 was increased in brains and spinal cords but declined in spleens of EAE mice treated with SR141716A. These results indicate that manipulation of the CB1R may have therapeutic value in MS, but its complexity remains to be carefully considered and studied in further clinical application.

Topics: Analysis of Variance; Animals; Cells, Cultured; Cytokines; Disease Models, Animal; Embryo, Mammalian; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Hippocampus; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Neuroglia; Neurons; Peptide Fragments; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; RNA, Messenger; Spinal Cord; Spleen