Restoration of FcRgamma/Fyn signaling repairs central nervous system demyelination.
Disruption of myelin causes severe neurological diseases. An understanding of the mechanisms that control myelination and remyelination is needed to develop therapeutic strategies for demyelinating diseases such as multiple sclerosis (MS). Our previous finding indicating the critical involvement of the gamma chain of immunogloblin Fc receptors (FcRgamma) and Fyn signaling in oligodendrocyte differentiaion and myelination demands a fundamental revision of the strategies used for MS therapy, because antigen-antibody complexes in MS patients may induce the direct dysregulation of myelination process as well as the inflammatory destruction of myelin sheath. Here we show that the FcRgamma/Fyn signaling cascade is critically involved in cuprizone-induced demyelination/remyelination, with no lymphocytic response. The levels of phosphorylated myelin basic proteins (p-MBPs), especially the 21.5-kDa isoform, but not the levels of total MBPs, decreased markedly during demyelination induced by aging, cuprizone treatment, and double knockout of FcRgamma/Fyn genes. We also showed that the recovery from demyelination in cuprizone-treated and aged mice is achieved after administration of the herbal medicine Ninjin'yoeito, an effective therapy targeting the FcRgamma/Fyn-Rho (Rac1)-MAPK (P38 MAPK)-p-MBPs signaling cascade. These results suggest that the restoration of FcRgamma/Fyn signaling represents a new approach for the treatment of demyelinating diseases.
Seiwa
Chika
C
Department of Neuro-Glia Cell Biology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Yamamoto
Masahiro
M
Tanaka
Kayoko
K
Fukutake
Masato
M
Ueki
Toshiyuki
T
Takeda
Shuichi
S
Sakai
Risa
R
Ishige
Atsushi
A
Watanabe
Kenji
K
Akita
Masumi
M
Yagi
Takeshi
T
Tanaka
Kotaro
K
Asou
Hiroaki
H
D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008996:Monoamine Oxidase Inhibitors; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism*; D009416:Nerve Regeneration / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009498:Neurotoxins; D051076:Proto-Oncogene Proteins c-fyn / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D004365:Drugs, Chinese Herbal; D008996:Monoamine Oxidase Inhibitors; D004676:Myelin Basic Protein; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017452:Receptors, IgG; C072867:ren-shen-yang-rong-tang; D003471:Cuprizone; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn