Promoting oligodendrogenesis and myelin repair using the multiple sclerosis medication glatiramer acetate.

The formation of oligodendrocytes (oligodendrogenesis) and myelin is regulated by several neurotrophic factors. Strategies to increase the level of these trophic molecules may facilitate repair in demyelinating conditions, such as multiple sclerosis (MS). Because leukocytes are a source of neurotrophic factors, and as glatiramer acetate (GA) generates T helper 2 (Th2) lymphocytes that are not known to be harmful, we tested the hypothesis that GA regulates oligodendrogenesis and myelin formation. First, we generated GA-reactive Th2 cells and determined that they produced transcripts for neurotrophic factors, including insulin-like growth factor-1 (IGF-1). The conditioned medium from GA-reactive T cells elevated IGF-1 protein and promoted the formation of oligodendrocyte precursor cells (OPCs) from embryonic brain-derived forebrain cells in culture. We next subjected mice to lysolecithin-induced demyelination of the spinal cord. At 7 days after the insult, the number of OPCs in the demyelinated dorsal column was higher than that in uninjured controls, and was further increased by the daily s.c. injection with GA. Increased OPC generation by GA was associated temporally with the elevation of IGF-1 and brain-derived neurotrophic factor (BDNF) in the spinal cord. Finally, the resultant remyelination at 28 days was higher in mice treated with GA during the first 7 days of injury compared with vehicle controls. These results indicate that GA promotes oligodendrogenesis and remyelination through mechanisms that involve the elevation of growth factors conducive for repair.

Multiexponential T2 and magnetization transfer MRI of demyelination and remyelination in murine spinal cord.

Identification of remyelination is important in the evaluation of potential treatments of demyelinating diseases such as multiple sclerosis. Local injection of lysolecithin into the brain or spinal cord provides a murine model of demyelination with spontaneous remyelination. The aim of this study was to determine if quantitative, multicomponent T(2) (qT(2)) analysis and magnetization transfer ratio (MTR), both indicative of myelin content, could detect changes in myelination, particularly remyelination, of the cervical spinal cord in mice treated with lysolecithin. We found that the myelin water fraction and geometric mean T(2) value of the intra/extracellular water significantly decreased at 14 days then returned to control levels by 28 days after injury, corresponding to clearance of myelin debris and remyelination which was shown by eriochrome cyanine and oil red O staining of histological sections. The MTR was significantly decreased 14 days after lysolecithin injection, and remained low over the time course studied. Evidence of demyelination shown by both qT(2) and MTR lagged behind the histological evidence of demyelination. Myelin water fraction increased with remyelination, however MTR remained lower after 28 days. The difference between qT(2) and MTR may identify early remyelination.