The effects of insulin-like growth factor (IGF)-1, IGF-2, and des-IGF-1 on neuronal loss after hypoxic-ischemic brain injury in adult rats: evidence for a role for IGF binding proteins.
Insulin-like growth factor (IGF)-1, IGF binding protein (IGFBP)-2, and IGFBP-3 are expressed in the rat brain in regions of neuronal loss by 3 days after hypoxic- ischemic (HI) brain injury and IGF-2 somewhat later. Central administration of rh-IGF-1 after HI injury reduces neuronal loss in vivo. To clarify the mode of action of IGF-1 and the potential role of IGFBPs, the effects of IGF-1, IGF-2, des(1-3)-N-IGF-1 (des-IGF-1), an analogue of IGF-1 with low affinity for IGFBPs, and IGF-1 combined with IGF-2 were compared 2 h after administration into the lateral cerebral ventricle after an HI injury. Unilateral HI was induced in adult rats by right carotid artery ligation followed by 10- min exposure to 6%O2. The extent of neuronal loss was determined in the cortex, striatum, hippocampus, dentate gyrus, and thalamus 5 days later. Central administration of 20 micrograms IGF-1 (n = 17) reduced neuronal loss in all regions (P < 0.01). Neither 20 micrograms IGF-2 (n = 17), 2 micrograms des-IGF-1 (n = 10), nor 20 micrograms des-IGF-1 (n = 17) reduced neuronal loss. There was a trend towards a reduction in neuronal loss after 150 micrograms des-IGF-1 (n = 20). IGF-2 alone increased neuronal loss in the hippocampus and dentate gyrus compared with the same regions in vehicle-treated animals (P < 0.05). Coadministration of 30 micrograms IGF-2 blocked the neuroprotective effects of 20 micrograms IGF-1 (n = 18, P < 0.05) and reduced the accumulation of [3H]IGF-1 in the injured hemisphere (n = 4) (P < 0.05). These observations suggest a role for IGFBPs in targeting the neuroprotective actions of IGF-1. IGF-2 may antagonize the protective effect of IGF-1 by displacing it from IGFBPs.
Guan
J
J
Research Centre for Developmental Medicine and Biology, University of Auckland, New Zealand.
Williams
C E
CE
Skinner
S J
SJ
Mallard
E C
EC
Gluckman
P D
PD
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D018969:Insulin-Like Growth Factor Binding Proteins; D010446:Peptide Fragments; C058957:insulin-like growth factor 1, des-(1-3)-; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II