title: Co-ordinated and cellular specific induction of the components of the IGF/IGFBP axis in the rat brain following hypoxic-ischemic injury.
abstract: Insulin-like growth factor 1 (IGF-1) is induced after hypoxic-ischemic (HI) brain injury, and therapeutic studies suggest that IGF-1 may restrict delayed neuronal and glial cell loss. We have used a well-characterised rat model of HI injury to extend our understanding of the modes of action of the IGF system after injury. The induction of the IGF system by injury was examined by in situ hybridization, immunohistochemistry, Northern blot analysis, RNase protection assay and reverse transcriptase-polymerase chain reaction (RT-PCR). IGF-1 accumulated in blood vessels of the damaged hemisphere within 5 h after a severe injury. By 3 days, IGF-1 mRNA was expressed by reactive microglia in regions of delayed neuronal death, and immunoreactive IGF-1 was associated with these microglia and reactive astrocytes juxtaposed to surviving neurones surrounding the infarct. Total IGF-1 receptor mRNA was unchanged by the injury. IGFBP-2 mRNA was strongly induced in reactive astrocytes throughout the injured hemisphere, and IGFBP-3 and IGFBP-5 mRNA were moderately induced in reactive microglia and neurones of the injured hippocampus, respectively. IGFBP-6 mRNA was induced in the damaged hemisphere by 3 days and increased protein was seen on the choroid plexus, ependyma and reactive glia. In contrast, insulin II was not induced. These results indicate cell type-specific expression for IGF-1, IGFBP-2,3,5 and 6 after injury. Our findings suggest that the IGF-1 produced by microglia after injury is transferred to perineuronal reactive astrocytes expressing IGFBP-2. Thus, modulation of IGF-1 action by IGFBP-2 might represent a key mechanism that restricts neuronal cell loss following HI brain injury.
authors.affiliation: Research Centre for Developmental Medicine and Biology, School of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: E J
authors.initials: EJ
authors.lastname: Beilharz
authors.forename: V C
authors.initials: VC
authors.lastname: Russo
authors.forename: G
authors.initials: G
authors.lastname: Butler
authors.forename: N L
authors.initials: NL
authors.lastname: Baker
authors.forename: B
authors.initials: B
authors.lastname: Connor
authors.forename: E S
authors.initials: ES
authors.lastname: Sirimanne
authors.forename: M
authors.initials: M
authors.lastname: Dragunow
authors.forename: G A
authors.initials: GA
authors.lastname: Werther
authors.forename: P D
authors.initials: PD
authors.lastname: Gluckman
authors.forename: C E
authors.initials: CE
authors.lastname: Williams
authors.forename: A
authors.initials: A
authors.lastname: Scheepens
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D001923:Brain Chemistry / Q000502:physiology; D002545:Brain Ischemia / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000098:blood supply / Q000737:chemistry; D005786:Gene Expression Regulation / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D002534:Hypoxia, Brain / Q000503:physiopathology*; D017403:In Situ Hybridization; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics; D018976:Insulin-Like Growth Factor Binding Protein 6 / Q000235:genetics; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D009457:Neuroglia / Q000737:chemistry / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D005904:Glial Fibrillary Acidic Protein; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5; D018976:Insulin-Like Growth Factor Binding Protein 6; D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1