Growth inhibitory factor prevents neurite extension and the death of cortical neurons caused by high oxygen exposure through hydroxyl radical scavenging

Growth inhibitory factor (GIF), a brain-specific member of the metallothionein family (MT-III), has been characterized as a inhibitory substance for neurotrophic factors in Alzheimer's disease brains. However, the function of GIF, other than the inhibition of neurotrophic factors, remains unknown. We demonstrate here that exogenous GIF prevents neurite extension of cortical neurons in the early period of differentiation and the death of differentiated neurons caused by high oxygen exposure. Down-regulation of GIF in cortical neurons with antisense S-oligonucleotides promoted neuronal death under high oxygen conditions. ESR spin-trapping studies demonstrated that GIF at 2-6 mum scavenged hydroxyl radicals generated by a Fenton-type reaction or the photolysis of hydrogen peroxide much more effectively than the same concentration of metallothionein I+II. GIF did not scavenge either superoxide produced by the xanthine/xanthine oxidase reaction or NO generated from 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene. Moreover, GIF at 40-80 muM inhibited tyrosine nitration by peroxynitrite as efficiently as metallothionein I+II at the same concentration. These results indicate that GIF prevents neurite extension of neurons in the early period of differentiation and supports the survival of differentiated neurons by scavenging hydroxyl radicals.