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 |
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Displacement of insulin-like growth factors from their binding proteins as a potential treatment for stroke
SA Loddick, XJ Liu, ZX Lu, C Liu, DP Behan, DC Chalmers, AC Foster, WW Vale, N Ling, EB de Souza |
Proceedings of the National Academy of Sciences | 1998 |
Asphyxial brain injury—the role of the IGF system
PD Gluckman, J Guan, C Williams, A Scheepens, R Zhang, L Bennet, A Gunn |
Molecular and Cellular Endocrinology | 1998 |
The role of neuronal growth factors in neurodegenerative disorders of the human brain
B Connor, M Dragunow |
Brain Research Reviews | 1998 |
Effects of Chronic Placental Insufficiency on Brain Development in Fetal Sheep
EC Mallard, S Rees, M Stringer, ML Cock, R Harding |
Pediatric Research | 1998 |
Maturational Change in the Cortical Response to Hypoperfusion Injury in the Fetal Sheep
K Reddy, C Mallard, J Guan, K Marks, L Bennet, M Gunning, A Gunn, P Gluckman, C Williams |
Pediatric Research | 1998 |
Roles of Bcl-2 and caspases in hypoxia-induced neuronal cell death: a possible neuroprotective mechanism of peptide growth factors
M Tamatani, S Ogawa, M Tohyama |
Molecular Brain Research | 1998 |
Co-ordinated and cellular specific induction of the components of the IGF/IGFBP axis in the rat brain following hypoxic–ischemic injury
EJ Beilharz, VC Russo, G Butler, NL Baker, B Connor, ES Sirimanne, M Dragunow, GA Werther, PD Gluckman, CE Williams, A Scheepens |
Molecular Brain Research | 1998 |
Les leucomalacies périventriculaires. I. Aspects histologiques et étiopathogéniques
S Marret, V Zupan, P Gressens, H Lagercrantz, P Evrard |
Archives de Pédiatrie | 1998 |
Pharmacological strategies for the prevention of perinatal brain damage
AJ Gunn, PD Gluckman |
Seminars in Neonatology | 1998 |
The insulin-like growth factor-I receptor: Implications for the aging process
D Lcroith, A Butler, VA Blakesley |
The Aging Male | 1998 |
Ischemia and Reperfusion Injury: The Ultimate Pathophysiologic Paradox
C Hammerman, M Kaplan |
Clinics in Perinatology | 1998 |
IGFs in the Nervous System
EE Müller |
1998 |