Oral administration of 4-methylumbelliferone reduces glial scar and promotes anatomical plasticity

Abstract

Following a spinal cord injury (SCI), chondroitin sulfate proteoglycans (CSPGs) are up-regulated at the glial scar inhibiting neuroregeneration. Under normal physiological condition, CSPGs interact with hyaluronan (HA) and other extracellular matrix on neuronal surface forming a macromolecular structure called perineuronal nets (PNNs) which regulate neuroplasticity. 4-methylumbelliferone (4-MU) has been used previously to down-regulate HA synthesis but not been tested in SCI. In this study, we have evaluated the effect of 4-MU, an inhibitor of HA, in a chronic contusion model of SCI in rats. At a dose of 1.2 g/kg/day of 4-MU, we observed not only the reduction of HA in the uninjured spinal cords after 60 days of 4-MU administration, but also a down-regulation of CS glycosaminoglycans (CS-GAGs). In order to assess the effect of 4-MU in chronic SCI, rats with T8 spinal contusion injury were fed with 4-MU or placebo for 8 weeks in combination with daily treadmill rehabilitation for 16 weeks to promote neuroplasticity. 4-MU treatment promoted significant sprouting of 5-hydroxytryptamine (5-HT) positive fibres into ventral horns and reduced the HA synthesis by astrocytes around the lesion site. While 4-MU reduced astrogliosis in chronic stage of SCI, the current dose was not sufficient to down-regulate the increased production of CS-GAGs or behavioural performance. Together, these data suggest that oral treatment with 4-MU is able to induce anatomical plasticity but further adjustment on the dosage will be required to benefit functional recovery after SCI.