Surfen, A Proteoglycan Antagonist, Reduces Lysolecithin-Induced Demyelination with Related Effects on Macrophage Function

Proteoglycans are components of the extracellular matrix and have roles in brain development and responses to injury. Connective tissue components are known to be major inhibitors of remyelination in mouse models of demyelination and are found at the border of active demyelinating lesions in Multiple Sclerosis. Surfen (bis 2-methyl, 4- amino, 6-quinolyl amide) is a small molecule antagonist previously shown to bind preferentially to heparan sulfate and related proteoglycans.We have previously reported that surfen reduces T cell proliferation in vivo and in vitro. Here we report the effects of surfen on an in vivo model of demyelination and its effects on macrophage function in vitro. Demyelination was induced by injecting the detergent lysolecithin into the spinal cord dorsal columns of adult C57Bl/6 mice. Relative to vehicle treated mice, co-injection of surfen (100 μM) with lysolecithin reduced total lesion area seven days post-injection. Because macrophages dominate these lesions and influence remyelination, murine bone marrow derived macrophages were assessed using assays of chemotaxis and phagocytosis. Macrophages chemotaxis was increased in response to surfen (10 μM) relative to vehicle by approximately 15% (p<0.05). Phagocytosis of E. coli was not affected by surfen.These effects of surfen on experimental demyelination and macrophage function suggest that proteoglycan binding may promote aspects of myelin repair relevant to Multiple Sclerosis.