COORDINATED AND CELLULAR SPECIFIC INDUCTION OF THE COMPONENTS OF THE IGF IGFBP AXIS IN THE RAT-BRAIN FOLLOWING HYPOXIC-ISCHEMIC INJURY/

Insulin-like growth factor 1 (IGF-1) is induced after hypoxic-ischemic (HI) brain injury, and therapeutic studies suggest that IGF-1 may res trict delayed neuronal and glial cell loss. We have used a well-charac terised rat model of HI injury to extend our understanding of the mode s of action of the IGF system after injury. The induction of the IGF s ystem by injury was examined by in situ hybridization, immunohistochem istry, Northern blot analysis, RNase protection assay and reverse tran scriptase-polymerase chain reaction (RT-PCR). IGF-1 accumulated in blo od 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 wit h these microglia and reactive astrocytes juxtaposed to surviving neur ones surrounding the infarct. Total IGF-1 receptor mRNA was unchanged by the injury. IGFBP-2 mRNA was strongly induced in reactive astrocyte s 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 hem isphere 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 produce d by microglia after injury is transferred to perineuronal reactive as trocytes expressing IGFBP-2. Thus, modulation of IGF-1 action by IGFBP -2 might represent a key mechanism that restricts neuronal cell loss f ollowing HI brain injury. (C) 1998 Elsevier Science B.V. All rights re served.