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.
Skihar
Viktor
V
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Silva
Claudia
C
Chojnacki
Andrew
A
Döring
Axinia
A
Stallcup
William B
WB
Weiss
Samuel
S
Yong
V Wee
VW
D000818:Animals; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D009186:Myelin Sheath / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D010455:Peptides / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology
D017077:Culture Media, Conditioned; D016207:Cytokines; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D008244:Lysophosphatidylcholines; D009414:Nerve Growth Factors; D010455:Peptides; D000068717:Glatiramer Acetate