Increasing local levels of neuregulin (glial growth factor-2) by direct infusion into areas of demyelination does not alter remyelination in the rat CNS.
Glial growth factor-2 (GGF-2) is a neuronally derived isoform of neuregulin shown in vitro to promote proliferation and survival of oligodendrocytes, the myelinating cells of the CNS. Enhanced remyelination has been demonstrated in vivo following systemic delivery of human recombinant GGF-2 (rhGGF-2) in experimental autoimmune encephalomyelitis (EAE). However, it is uncertain whether this is the result of direct effects of rhGGF-2 on cells of the oligodendrocyte lineage or due to modulation of the immune or inflammatory response. If this enhanced remyelination was due to direct effects of rhGGF-2 on cells of the oligodendrocyte lineage then one would expect rhGGF-2 to induce a similar proremyelinating response in nonimmune, gliotoxin models of demyelination. Using a gliotoxin model of demyelination we were therefore able to ascertain the in vivo effect of rhGGF-2 following local CNS delivery in a model that is not confounded by the concurrent presence of an immune-mediated process. No significant alteration in the rate or character of remyelination was evident following local delivery as compared to controls, and indeed nor following systemic delivery in the gliotoxin model. The results of this study therefore indicate that both direct infusion and systemic delivery of rhGGF-2 do not alter remyelination in a nonimmune, gliotoxin model of demyelination. This suggests that the proremyelinating effects of systemically delivered rhGGF-2 in EAE are unlikely to be due to direct effects on the oligodendrocyte lineage, but may be mediated by rhGGF-2 inducing an environment more favourable to remyelination, possibly through modulation of the immune response.
Penderis
Jacques
J
Cambridge Centre for Brain Repair and Centre for Veterinary Sciences, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
Woodruff
Rachel H
RH
Lakatos
Andras
A
Li
Wen-Wu
WW
Dunning
Mark D
MD
Zhao
Chao
C
Marchionni
Mark
M
Franklin
Robin J M
RJ
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002455:Cell Division; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000473:pathology; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes / Q000662:veterinary; D004791:Enzyme Inhibitors / Q000633:toxicity; D004996:Ethidium / Q000633:toxicity; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects*; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1 / Q000008:administration & dosage*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells; D013997:Time Factors
D001973:Bromodeoxyuridine; D004791:Enzyme Inhibitors; D004996:Ethidium; D007211:Indoles; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C490580:Nrg1 protein, rat; C007293:DAPI