Connective tissue components such as proteoglycans are known 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 that preferentially binds heparan sulfate and related proteoglycans. We have previously reported that surfen reduces T cell proliferation in vivo and in vitro. Here we extend this work by characterizing surfen in mouse models of chronic neuroinflammation (experimental autoimmune encephalomyelitis; EAE) and demyelination (lysolecithin).
Female adult C57Bl/6 mice were immunized with myelin oligodendrocyte glycoprotein emulsified in a 1:1 ratio with complete Freund's adjuvant. Mice were scored daily and received either surfen (5mg/kg, i.p) or vehicle (DMSO, i.p.) every second day following the onset of clinical symptoms. In a separate cohort, lysolecithin was injected bilaterally into the corpus callosum of adult C57Bl/6 mice to induce demyelination.
Relative to vehicle treatment (0.1 % DMSO), stereotactic administration of surfen (100 µM) 48 hours following lysolecithin increased total lesion area seven days post-injection with concomitant increases in glial and macrophage activity. By contrast, surfen (5 mg/kg, i.p.) ameliorated EAE clinical severity compared to vehicle controls. Taken together, these results signify that while peripheral proteoglycan antagonism by surfen reduces neuroinflammation and cellular infiltration in EAE, some families of proteoglycans such as heparan sulfate proteoglycans may serve to promote remyelination centrally where general antagonism should be avoided.
Conflictsof Interest:
None.
