Therapeutic role of Poly-I:C on myelin repair (S20.004)

Objectives: Our goals were to examine the effect of polyinosinic polycytidylic acid (poly-I:C) on myelin gene synthesis in vitro and its effect on gliotoxic models of demyelination in vivo.Background: The requisite for an inflammatory signal in remyelination is well known however, the pathways which lead to myelin synthesis are unclear. Previous studies have shown that activation of TLR3 reduces the severity of autoimmune demyelination. However, the role of poly-I:C, the dsRNA analog which activates the inflammatory signaling pathway through Toll Like Receptor 3 (TLR3) on remyelination is not known.Design and Method: (1) Post-natal day 2 rat oligodendrocyte precursor cells (OPCs) were stimulated with poly-I:C for up to 14 days and analyzed for major myelin gene expression, maturation marker O4 and MBP synthesis in vitro. (2) In vivo effect of poly- I:C on lysolecithin model of demyelination was examined.Results: Treatment of poly-I:C induced the synthesis of myelin basic protein (MBP) in oligodendrocyte precursor cells (OPCs) in vitro. OPCs treated with poly-I:C in vitro displayed the increased expression of maturation marker O4 in four days and MBP in 14 days over controls. Quantitative RT-PCR analysis performed in OPCs revealed that treatment of poly-I:C induces major myelin protein genes such as MBP, myelin oligodendrocyte glycoprotein (MOG) and myelin associated glycoprotein (MAG). Pretreatment of OPCs with TLR3 inhibitor chloroquine prevented poly-I:C induced MBP synthesis. In addition, in vitro treatment of poly-I:C increased the gene expression level of MBP promoter region binding transcription elements Purα, Sox10 and Sp1. In lysolecithin mediated gliotoxic model of demyeliation, in vivo treatment with poly-I:C showed about 23[percnt] improvement in remyelination over controls (pu003c0.05).Conclusion: In vitro and in vivo treatment of poly-I:C induces myelin genes expression and promotes remyelination. We propose that poly-I:C is a potential agent to promote remyelination in human demyelinating diseases. Disclosure: Dr. Natarajan has nothing to disclose. Dr. Yao has nothing to disclose. Dr. Sriram has nothing to disclose.