Insulin-like growth factor-1 is a potent neuronal rescue agent after hypoxic-ischemic injury in fetal lambs.

Abstract

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 g rhIGF-1, 1 g rhIGF-1, 10 g 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 g ( P Ͻ 0.05) and 1 g ( P Ͻ 0.002) rhIGF-1, but treatment with 10 g was not effective. With 1 g rhIGF-1 neuronal loss scores were significantly lower in brain regions examined including cortex, hippocampus, and striatum, whereas with 0.1 g rhIGF-1 the parietal cortex and thalamus were not improved and the improvement seen in other regions was less than with 1 g rhIGF-1. Treatment with 1 g 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.

Low IGF-I suppresses VEGF-survival signaling in retinal endothelial cells: Direct correlation with clinical retinopathy of prematurity

“…supply to raise IGF-I to a more normal level. Because ROP is correlated with other developmental problems, increasing IGF-I levels to the level of infants without ROP also may improve neurological development (35) and somatic growth (34).…”

Activation of Hypoxia-Inducible Factor-1 in the Rat Cerebral Cortex after Transient Global Ischemia: Potential Role of Insulin-Like Growth Factor-1

“…The expression of IGF-1 and its binding proteins are altered in response to brain ischemia (Lee et al, 1996;Schwab et al, 1997;Beilharz et al, 1998), and exogenous administration of IGF-1 significantly reduces neuronal loss in different models of cerebral ischemia (Johnston et al, 1996;Tagami et al, 1997;Guan et al, 2000;Wang et al, 2000). Furthermore, it has been shown that IGF-1 protects cultured neurons against diverse forms of injury, including hypoxia and oxidative stress (Heck et al, 1999;Yamaguchi et al, 2001).…”

Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide

“…Peptide growth factors such as IGF-1 and bFGF have been proposed to play a neuroprotective role against ischemic insult (Jhonston et al, 1996;Yamada et al, 1991), but the mechanism by which they do so remains largely unknown. To examine the neuroprotective role of these growth factors in NO-mediated neuronal death, neurons were pretreated or not treated with increasing concentrations (1, 10, 100 ng/ml) or either IGF-1 or bFGF for 6 h, and then exposed to 50 mM SNP for 24 h. Administration of IGF-1 dose-dependently increased survival of neurons exposed to SNP, where 100 ng/ml of IGF-1 rescued 65% of cells from death induced by SNP ( Figure 5A).…”

“…Previous studies revealed that these growth factors prevent neuronal death in vitro due to glutamate toxicity (Mattson et al, 1989;Freese et al, 1992 ), hypoglycemia (Cheng and Mattson, 1992) or nitric oxide toxicity (Maiese et al, 1993). Moreover, administration of these growth factors protects against neuronal death after cerebral hypoxia-ischemia in vivo (Jhonston et al, 1996;Yamada et al, 1991). Recent reports suggest that the mechanism whereby the growth factors protect neurons from ischemic damage involves stabilization of neuronal calcium homeostasis (Mattson and Cheng, 1993).…”