Insulin-like growth factor (IGF)-1 suppresses oligodendrocyte caspase-3 activation and increases glial proliferation after ischemia in near-term fetal sheep.
Insulin-like growth factor (IGF-1) markedly increases myelination and glial numbers in white matter after ischemia in near-term fetal sheep; however, it is unclear whether this is due to reduced cell loss or increased secondary proliferation. Brain injury was induced in near-term fetal sheep by 30 minutes of bilateral carotid artery occlusion. Ninety minutes after the occlusion, fetuses were given, intracerebroventricularly, either a single dose of IGF-1 (either 3 or 30 micro g), or 3 micro g followed by 3 micro g over 24 hours (3 + 3 micro g). White matter was assessed 4 days after reperfusion. Three micrograms, but not 30 micro g of IGF-1 prevented loss of oligodendrocytes and myelin basic protein density (P < 0.001) compared to the vehicle-treated ischemia controls. No additional effect was observed in the 3 + 3 micro g group. IGF-1 treatment was associated with reduced caspase-3 activation and increased glial proliferation in a similar dose-dependent manner. Caspase-3 was only expressed in oligodendrocytes that showed apoptotic morphology. Proliferating cell nuclear antigen co-localized with both oligodendrocytes and astrocytes and microglia. Thus, increased oligodendrocyte numbers after IGF-1 treatment is partly due to suppression of apoptosis, and partly to increased proliferation. In contrast, the increase in reactive glia was related only to proliferation. Speculatively, reactive glia may partly mediate IGF-1 white matter protection.
Cao
Yun
Y
The Liggins Institute, Faculty of Medicine and Health Sciences, University of Auckland, Auckland, New Zealand.
Gunn
Alistair Jan
AJ
Bennet
Laura
L
Wu
David
D
George
Sherly
S
Gluckman
Peter D
PD
Shao
Xiao-Mei
XM
Guan
Jian
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000737:chemistry / Q000166:cytology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003593:Cytoplasm / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005865:Gestational Age; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006023:Glycoproteins; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D037102:Lectins / Q000032:analysis; D004676:Myelin Basic Protein / Q000235:genetics; D009836:Oligodendroglia / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011247:Pregnancy; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D011510:Proteolipids / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012756:Sheep
D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D037102:Lectins; D004676:Myelin Basic Protein; D018809:Proliferating Cell Nuclear Antigen; D011510:Proteolipids; D012333:RNA, Messenger; C473590:isolectin B4-binding glycoprotein, mouse; D007334:Insulin-Like Growth Factor I; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases