Activation of inflammatory response by a combination of growth factors in cuprizone-induced demyelinated brain leads to myelin repair.
In vivo remyelination promoted by a combination of four oligodendrocyte specific growth factors (GFs) in cuprizone-induced demyelinated mice brains was described recently by our group. Here we report activation of inflammatory response in mice brain following cuprizone-induced demyelination and its further enhancement immediately after injection of growth factors in vivo, while no significant inflammatory response was evident in GFs-injected normal brains. Cuprizone-induced demyelination was accompanied by increased expression of inflammatory cytokines, TNFalpha and IL-1beta, anti-inflammatory cytokines TGFbeta, IL-10 and increased levels of chemokines, CCL2, CCL5, and CXCL10, produced by resident microglia and astrocytes. During demyelination, involvement of oxidative stress was evident by disruption of mitochondrial structure and temporal decline in reduced glutathione levels, later returning to normal. Increase in the cytokines and chemokines was further enhanced within 2 days post injection (dpi) of GFs, coinciding with signal for repair via activation of pAkt and NFkappaB transcription factor reported earlier. Upregulation of mRNA and protein level of antioxidant genes, metallothionein (MT) I/II and activity of a cytosolic oxidoreductase enzyme, glycerolphosphate-3 dehydrogenase (cGPDH) occurred, resulting in a metabolic shuttle with an increase in glycerol in mice brains during period of demyelination and early GF-mediated repair.
Biancotti
Juan Carlos
JC
Mental Retardation Research Center, Semel Institute for Neuroscience, David Geffen School of Medicine, University of California, 635 Charles E. Young Drive South, Room 379, Los Angeles, CA 90095, USA.
Kumar
Shalini
S
de Vellis
Jean
J
D000818:Animals; D001483:Base Sequence; D001927:Brain Diseases / Q000139:chemically induced* / Q000378:metabolism; D003471:Cuprizone / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000378:metabolism; D005260:Female; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D009186:Myelin Sheath / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D017931:DNA Primers; D006133:Growth Substances; D018836:Inflammation Mediators; D003471:Cuprizone