6-cyano-7-nitroquinoxaline-2-3-dione and Multiple-Sclerosis

Stabilizing the survival of oligodendrocytes and oligodendrocyte precursors within and near lesions in patients suffering from multiple sclerosis (MS) and other demyelinating diseases is an important therapeutic goal. Previous studies have identified a human-derived monoclonal IgM antibody designated rHIgM22 that induces remyelination in a mouse model of MS. We provide evidence that this antibody, directed against myelin, induces antiapoptotic signaling in premyelinating oligodendrocytes and reduces caspase-3 activation and caspase gene expression in mice undergoing antibody-induced remyelination. This effect was dependent on calcium entry via CNQX-sensitive channels and on lipid raft integrity, and was correlated with suppression of JNK signaling. We conclude that rHIgM22 may induce remyelination via rescue of oligodendrocytes, and suggest that such autoantibody-mediated signaling may have important therapeutic implications for a variety of neurological diseases, including stroke and Alzheimer's disease.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Antibodies; Apoptosis; Calcium Channels; Cardiovirus Infections; Caspase 3; Caspases; Cell Line, Tumor; Cell Survival; Humans; Hydrogen Peroxide; JNK Mitogen-Activated Protein Kinases; Membrane Microdomains; Mice; Mitogen-Activated Protein Kinases; Multiple Sclerosis; Myelin Proteins; Myelin Sheath; Nerve Degeneration; Oligodendroglia; Rats; Signal Transduction; Stem Cells; Tumor Necrosis Factor-alpha

Macroglial cells express ionotropic glutamate receptors. In the adult optic nerve, reverse transcription-PCR showed that the native receptors are formed by subunits belonging to the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate classes. Because activation of AMPA and kainate receptors can be toxic to oligodendrocytes in vitro, I examined the nature of the damage caused by kainate, an agonist of both receptor classes, applied directly onto the optic nerve. Acute infusion or chronic slow delivery of the agonist caused massive nerve damage that was more extensive in the latter. Interestingly, chronic delivery also produced inflammation and demyelination in well circumscribed areas of the nerve, together with other pathological features that closely resemble those observed in multiple sclerosis patients. Acute and chronic kainate lesions were both prevented by the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. However, GYKI53655, a specific AMPA receptor antagonist, did not significantly reduce the size of the lesion, suggesting that the kainate toxicity was mainly mediated through activation of kainate-preferring glutamate receptors. These observations suggest that alterations in glutamate signaling may be detrimental to oligodendrocytes and may be involved in the pathogenesis of multiple sclerosis and other demyelinating diseases.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Cell Death; Demyelinating Diseases; Disease Models, Animal; Excitatory Amino Acid Agonists; Humans; Kainic Acid; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; Optic Nerve; Optic Nerve Injuries; Polymerase Chain Reaction; Rats; Receptors, AMPA; Receptors, Kainic Acid