Matrine alleviates astrogliosis through sphingosine 1-phosphate signaling in experimental autoimmune encephalomyelitis

Expression of sphingosine/sphingosine 1-phosphate (SPH/S1P) in resident cells of the central nervous system plays an important role in the pathogenesis of multiple sclerosis (MS). Accumulated evidence has shown the protective effects of S1P receptor modulators on MS and its animal model, experimental autoimmune encephalomyelitis (EAE). However, effective therapies to regulate SPH/S1P molecules themselves have not been well addressed. Our previous studies showed that matrine (MAT), a natural alkaloid component extracted from the Sophora root, has beneficial effects in EAE through immunomodulation. Here we demonstrate that MAT alleviated astrogliosis in the CNS of EAE rats, and downregulated levels of SPH, S1P and S1P1 expression in CNS tissues and astrocytes. Expression of SPH kinases (SPHK) 1 and 2, which splice SPH into S1P, was also inhibited by MAT treatment. In vitro studies showed a direct inhibitory effect of MAT on S1P1 expression of activated astrocytes, suggesting that MAT could function as an S1PRs antagonist. Moreover, MAT upregulated the expression of plasma gelsolin, which combines with S1P to reduce its concentration. These findings indicate that MAT could alleviate astrogliosis in EAE through diminishing the SPH/SPHK/S1P1 pathway.