Identifying Lanthionine Ketimine Derivatives for Maturation and Proliferative Effects in Oligodendrocyte Progenitor Cells.

Abstract

Previous studies have shown that lanthionine ketimine ethyl ester (LKE) reduces clinical scores in the experimental autoimmune encephalomyelitis (EAE) mouse model of Multiple Sclerosis, induces differentiation of oligodendrocyte progenitor cells (OPCs) in vitro, and accelerates remyelination following cuprizone induced demyelination. In a search for derivatives with greater efficacy to induce OPC maturation or proliferation, we screened a panel of 2-alkyl and 3-phosphonate substituted LK derivatives. Incubation of Oli-neu oligodendrocyte cells with 2-n-butyl- or 2-n-hexyl-LKE-phosphonate reduced spontaneous cell death, increased proliferation, and increased maturation. These were associated with changes in corresponding mRNA levels of Olig2, PLP, and O4. These derivatives also reduced cell death and increased proliferation and maturation in primary mouse OPCs. The increased hydrophobicity of these derivatives suggests these will be better candidates for testing effects in animal models of Multiple Sclerosis and other demyelinating diseases.