myelin-oligodendrocyte-glycoprotein-(35-55) and Leukemic-Infiltration

Though several functional properties of laquinimod have been identified, our understanding of the underlying mechanisms is still incomplete. Since the compound elicits similar immunomodulatory effects to ligands of the aryl hydrocarbon receptor (AhR), we compared the efficacy of laquinimod in experimental autoimmune encephalomyelitis (EAE)-afflicted wild-type and AhR-deficient mice. Laquinimod failed to ameliorate clinical symptoms and leukocyte infiltration in AhR-deficient mice; however, treatment exerted neuroprotection by elevation of brain-derived neurotrophic factor (BDNF) independent of genetic profile. Thus, our data identify the AhR pathway in these mutant mice as crucial for the immunomodulatory, but not neuroprotective, efficacy of laquinimod in EAE.

Topics: Analysis of Variance; Animals; Axons; Brain-Derived Neurotrophic Factor; CD3 Complex; Demyelinating Autoimmune Diseases, CNS; Disease Models, Animal; Gene Expression Regulation; Immunologic Factors; Leukemic Infiltration; Mice, Inbred C57BL; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Quinolones; Rats; Receptors, Aryl Hydrocarbon; RNA, Messenger; Spinal Cord; T-Lymphocytes; White Matter

Although multiple sclerosis (MS) has traditionally been considered to be an inflammatory disease, recent evidence has brought neurodegeneration into the spotlight, suggesting that accumulated damage and loss of axons is critical to disease progression and the associated irreversible disability. Proposed mechanisms of axonal degeneration in MS posit cytosolic and subsequent mitochondrial Ca(2+) overload, accumulation of pathologic reactive oxygen species (ROS), and mitochondrial dysfunction leading to cell death. In this context, the role of the p66 isoform of ShcA protein (p66) may be significant. The ShcA isoform is uniquely targeted to the mitochondrial intermembrane space in response to elevated oxidative stress, and serves as a redox enzyme amplifying ROS generation in a positive feedforward loop that eventually mediates cell death by activation of the mitochondrial permeability transition pore. Consequently, we tested the hypothesis that genetic inactivation of p66 would reduce axonal injury in a murine model of MS, experimental autoimmune encephalomyelitis (EAE). As predicted, the p66-knockout (p66-KO) mice developed typical signs of EAE, but had less severe clinical impairment and paralysis than wild-type (WT) mice. Histologic examination of spinal cords and optic nerves showed significant axonal protection in the p66-KO tissue, despite similar levels of inflammation. Furthermore, cultured p66-KO neurons treated with agents implicated in MS neurodegenerative pathways showed greater viability than WT neurons. These results confirm the critical role of ROS-mediated mitochondrial dysfunction in the axonal loss that accompanies EAE, and identify p66 as a new pharmacologic target for MS neuroprotective therapeutics.

Topics: Animals; Axons; Cell Proliferation; Cells, Cultured; Cerebral Cortex; Cyclophilins; Cytokines; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Freund's Adjuvant; Glycoproteins; Hydrogen Peroxide; Leukemic Infiltration; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron, Transmission; Myelin-Oligodendrocyte Glycoprotein; Nerve Fibers, Myelinated; Neurons; Optic Nerve; Peptide Fragments; Peptidyl-Prolyl Isomerase F; Shc Signaling Adaptor Proteins; Spinal Cord; Src Homology 2 Domain-Containing, Transforming Protein 1; T-Lymphocytes