This study was designed to determine the potential of IGF-1 as a neuronal rescue agent after cerebral ischemia. Unanesthetized late gestation fetal sheep were subjected to 30-min cerebral ischemia by inflation of carotid artery occluder cuffs. 2 h later either 0.1 microgram rhIGF-1, 1 microgram rhIGF-1, 10 micrograms rhIGF-1, or vehicle was infused into a lateral cerebral ventricle over 1 h. Histologic outcome was assessed 5 d later. Overall neuronal loss was reduced with 0.1 microgram (P < 0.05) and 1 microgram (P < 0.002) rhIGF-1, but treatment with 10 micrograms was not effective. With 1 microgram rhIGF-1 neuronal loss scores were significantly lower in brain regions examined including cortex, hippocampus, and striatum, whereas with 0.1 microgram rhIGF-1 the parietal cortex and thalamus were not improved and the improvement seen in other regions was less than with 1 microgram rhIGF-1. Treatment with 1 microgram rhIGF-1 also delayed the onset of seizures and reduced their incidence. Moreover, the secondary phase of cytotoxic edema was reduced and delayed in onset. We conclude that low dose rhIGF-1 therapy promotes neuronal rescue after cerebral hypoxic-ischemic injury in utero, but the effect is dose dependent. Importantly, rhIGF-1 is effective and nontoxic when administered 2 h after the hypoxic ischemic insult. This distinguishes IGF-1 from most other neuroprotective therapies and suggests clinical application may be possible.
B M Johnston, E C Mallard, C E Williams, P D Gluckman
Title and authors | Publication | Year |
---|---|---|
Insulin-like growth factor-1 and post-ischemic brain injury
J Guan, L Bennet, PD Gluckman, AJ Gunn |
Progress in Neurobiology | 2003 |
Glutamate excitotoxicity attenuates insulin-like growth factor-i prosurvival signaling
E Garcia-Galloway, C Arango, S Pons, I Torres-Aleman |
Molecular and Cellular Neuroscience | 2003 |
Neuroprotective Effects of Insulin-Like Growth Factor-Binding Protein Ligand Inhibitors in Vitro and in Vivo
KB Mackay, SA Loddick, GS Naeve, AM Vana, GM Verge, AC Foster |
Journal of Cerebral Blood Flow & Metabolism | 2003 |
Insulin-like Growth Factor (IGF)-1 Suppresses Oligodendrocyte Caspase-3 Activation and Increases Glial Proliferation After Ischemia in Near-Term Fetal Sheep
Y Cao, AJ Gunn, L Bennet, D Wu, S George, PD Gluckman, XM Shao, J Guan |
Journal of Cerebral Blood Flow & Metabolism | 2003 |
Estrogen interacts with the IGF-1 system to protect nigrostriatal dopamine and maintain motoric behavior after 6-hydroxdopamine lesions
A Quesada, PE Micevych |
Journal of Neuroscience Research | 2003 |