An inhibitor of chondroitin sulfate proteoglycan synthesis promotes central nervous system remyelination.
Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Michael B
MB
Keough
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
James A
JA
Rogers
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
Ping
P
Zhang
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Samuel K
SK
Jensen
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Erin L
EL
Stephenson
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
Tieyu
T
Chen
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Mitchel G
MG
Hurlbert
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Lorraine W
LW
Lau
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Khalil S
KS
Rawji
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Jason R
0000-0003-1385-1464
JR
Plemel
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
Marcus
M
Koch
Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta, Canada T2N 1N4.
Chang-Chun
CC
Ling
Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
V Wee
VW
Yong
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002240:Carbohydrate Sequence; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D011508:Chondroitin Sulfate Proteoglycans / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000737:chemistry; D005260:Female; D005944:Glucosamine / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D000074586:Remyelination / Q000187:drug effects / Q000502:physiology*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D014539:Uridine Diphosphate Sugars / Q000737:chemistry / Q000494:pharmacology
C000627293:4-fluoro-N-acetylhexosamine uridine diphosphate; D011508:Chondroitin Sulfate Proteoglycans; D054852:Small Molecule Libraries; D014539:Uridine Diphosphate Sugars; D005944:Glucosamine