Intraventricular injection of insulin-like growth factor 1 (IGF-1) 2 h after hypoxic–ischemic injury reduces neuronal loss. To clarify the mode of action, we compared histological outcome between treatment groups in the following three studies: 0, 0.5, 5, and 50 μg IGF-1 given 2 h after injury; 0 and 20 μg IGF-1 given 1 h before; and 20 μg IGF-1 and insulin or vehicle alone given 2 h after. Unilateral hypoxic-ischemic injury was induced in adult rats by ligation of the right carotid and exposure to 6% O2 for 10 min. Histological outcome was evaluated in the cortex, striatum, and hippocampus 5 days later. Five to 50 μg IGF-1 reduced the incidence of infarction and neuronal loss in a dose-dependent manner in all regions (p < 0.05), and 50 μg reduced the infarction rate from 87 to 26% (p < 0.01). Pretreatment did not alter outcome. IGF-1 improved outcome compared with equimolar doses of insulin (p < 0.05) and did not affect systemic glucose concentrations or cortical temperature. The results indicate that the neuronal protective effects of IGF-1 are specific and are not mediated via insulin receptors, hypothermia, or hypoglycemic mechanisms. Centrally administered IGF-1 appears to provide worthwhile trophic support to cells within most cerebral structures after transient hypoxic-ischemic injury.
AndersonKJDamDLeeSCotmanCW, (1988) Basic fibroblast growth factor prevents death of lesioned cholinergic neurons in vivo. Nature332:360–361
2.
AuerRNKalimoHOlssonYSiesjöBK, (1985) The temporal evolution of hypoglycaemic brain damage. I. Light- and electron-microscopic findings in the rat cerebral cortex. Acta Neuropathol (Berl)67:13–24
3.
BarresBAHartIKColesHSRBurneJFVoyvodicJTRichardsonWDRaffMC, (1992) Cell death in the oligodendrocyte lineage. J Neurobiol23:1221–1230
4.
BeilharzEJKlemptNDKlemptMSirimanneEDragunowMGluckmanPD, (1993) Differential expression of insulin-like growth factor binding proteins (IGFBP) 4 and 5 mRNA in the rat brain after transient hypoxic-ischemic injury. Mol Brain Res (in press)
5.
BohannonNJCorpESWilcoxBJFiglewiczDPDorsaDMBaskinDG, (1988) Localization of binding sites for insulin-like growth factor-1 (IGF-1) in the rat brain by quantitative autoradiography. Brain Res444:205–213
6.
BondyCAWernerHRobertsCTLeRoithD, (1992) Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: Comparison with insulin-like growth factors I and II. Neuroscience46:909–923
7.
BrennemanDESchultzbergMBartfalTGozesI, (1992) Cytokine regulation of neuronal survival. J Neurochem58:454–460
8.
BrownALBrierleyJB, (1972) Anoxic-ischaemic cell change in rat brain: Light microscopic and fine structural observations. J Neurol Sci16:59–84
9.
ChengBMattsonMP, (1992) IGF-1 and IGF-II protect cultured hippocampal and septal neurons against calcium-mediated hypoglycaemic damage. J Neurosci12:1558–1566
10.
ConoverWJImanRL, (1976) On some alternative procedures using ranks for analysis of experimental designs. Commun Statist Theor Methods5:1349–1368
11.
DalePSDucsayCAGilbertRDKoosBJLongoLDPowerGG, (1989) A microcomputer program for real time data acquisition in the perinatal physiology laboratory. J Dev Physiol11:185–188
12.
DeshpandeJBergstedtKLindenTKalimoHWielochT, (1992) Ultrastructural changes in the hippocampal CA1-region following transient cerebral ischemia—evidence against programmed cell death. Exp Brain Res88:91–105
13.
DragoJMurphyMCarrollSMHarveyRPBartlettPF, (1991) Fibroblast growth factor-mediated proliferation of central nervous system precursors depends on endogenous production of insulin-like growth factor I. Proc Natl Acad Sci USA88:2199–2203
14.
GilmourRSProsserCGFleetIRCoccoLSaundersJCBrownKDCorpsAN, (1988) From animal to molecule: Aspects of the biology of insulin-like growth factors. Br J Cancer58:23–30
15.
GluckmanPDKlemptNDGuanJMallardECSirimanneEDragunowMKlemptMSinghKWilliamsCENikolicsK, (1992) A role for IGF-1 in the rescue of CNS neurons following hypoxic-ischemic injury. Biochem Biophys Res Commun182:593–599
16.
HillJMLesniakMAPertCBRothJ, (1986) Autoradiographic localization of insulin receptors in rat brain: Prominence in olfactory and limbic areas. Neuroscience17:1127–1138
17.
KanjeMSkottnerASjobergJLundborgG, (1989) Insulin-like growth factor 1 (IGF-1) stimulates regeneration of the rat sciatic nerve. Brain Res486:396–398
18.
KlemptNDSirimanneEGunnAJKlemptMSinghKWilliamsCEGluckmanPD, (1992a) Hypoxia-ischemia induces transforming growth factor B mRNA in the infant rat brain. Mol Brain Res13:93–101
19.
KlemptNDKlemptMGunnAJSinghKGluckmanPD, (1992b) Expression of insulin-like growth factor-binding protein-2 (IGF-BP-2) following transient hypoxia-ischemia in the infant rat brain. Mol Brain Res15:55–61
20.
KnuselBMichelPPSchwaberJSHeftiFF, (1990) Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor insulin and the insulin-like growth factors 1 and 2. J Neurosci10:558–570
21.
KoikeTMartinDJohnsonE, (1989) Role of Ca channels in the ability of membrane depolarization to prevent neuronal death induced by trophic factor deprivation: Evidence that levels of internal Ca determine NGF dependence of sympathetic ganglion cells. Proc Natl Acad Sci USA86:6421–6425
22.
LesniakMAHillJMKiessWRojeskiMPertCBRothJ, (1988) Receptors for insulin-like growth factors I and II: Autoradiographic localization in rat brain and comparison to receptors for insulin. Endocrinology123:2089–2099
23.
LevineS, (1960) Anoxic encephalopathy in rats. Am J Pathol36:1–17
24.
MallardECWilliamsCEGunnAJGunningMGluckman (1993) Frequent episodes of brief ischemia sensitize the fetal sheep brain to neuronal loss and induce striatal injury. Pediatr Res33:61–65
25.
MartinDSchmidtRDistefanoPSLowryOHCarterJJohnsonE, (1988) Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation. J Cell Biol106:829–844
26.
PardridgeWM, (1991) Transnasal and intraventricular delivery of drugs. In: Peptide Drug Delivery to the Brain. New York, Raven Press, pp 99–122
27.
PaxinosGWatsonC, (1982) The Rat Brain in Stereotaxic Coordinates. New York, Academic Press
28.
ShigenoTYamasakiYKatoGKusakaKMimaTTakakuraKGrahamDIFurukawaS, (1990) Reduction of delayed neuronal death by inhibition of protein synthesis. Neurosci Lett120:117–119
29.
ShigenoTMimaTTakakuraKGrahamDIKatoGHashimotoYFurukawaS, (1991) Amelioration of delayed neuronal death in the hippocampus by nerve growth factor. J Neurosci11:2914–2919
VollCAuerRN, (1991) Insulin attenuates ischemic brain damage independent of its hypoglycaemic effect. J Cereb Blood Flow Metab11:1006–1014
32.
WertherGAAbateMHoggACheesmanHOldfieldBHardsDHudsonPPowerBFreedKHeringtonAC, (1990) Localization of insulin-like growth factor-I mRNA in rat brain by in situ hybridization—relationship to IGF-I receptors. Mol Endocrinol4:773–778
33.
WilliamsCEGunnAJMallardECGluckmanPD, (1992) Outcome after ischemia in the developing sheep brain: An electroencephalographic and histological study. Ann Neurol31:14–21
YamaguchiFItanoTMiyamotoOJanjuaNAOhmotoTHosokawaKHataseO, (1991) Increase of extracellular insulin-like growth factor 1 (IGF-1) concentration following electrolytical lesion in rat hippocampus. Neurosci Lett128:273–276
