INSULIN-LIKE GROWTH-FACTOR-I IS A POTENT NEURONAL RESCUE AGENT AFTER HYPOXIC-ISCHEMIC INJURY IN FETAL LAMBS

This study was designed to determine the potential of IGF-1 as a neuro nal rescue agent after cerebral ischemia. Unanesthetized late gestatio n fetal sheep were subjected to 30-min cerebral ischemia by inflation of carotid artery occluder cuffs. 2 h later either 0.1 mu g rhIGF-1, 1 mu g rhIGF-1, 10 mu 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 mu g (P < 0.05) and 1 mu g (P < 0.002) rhIGF-1, but treatment with 10 mu g was not effective. W ith 1 mu g rhIGF-1 neuronal loss scores were significantly lower in br ain regions examined including cortex, hippocampus, and striatum, wher eas with 0.1 mu g rhIGF-1 the parietal cortex and thalamus were not im proved and the improvement seen in other regions was less than with 1 mu g rhIGF-1. Treatment with 1 mu 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 lo w dose rhIGF-1 therapy promotes neuronal rescue after cerebral hypoxic -ischemic injury in utero, but the effect is dose dependent, Important ly, rhIGF-1 is effective and nontoxic when administered 2 h after the hypoxic ischemic insult. This distinguishes IGF-1 from most other neur oprotective therapies and suggests clinical application may be possibl e.