Insulin-like growth factors in the response to cerebral ischemia

Abstract

Insulin-like growth factors-I and -II (IGF-I and -II) and their receptors are present in the central nervous system but their role in brain function is unknown. To elucidate this issue, we investigated the cellular pattern of expression for IGF-I and -II, their receptors, and binding proteins using in situ hybridization and immunocytochemistry in the setting of experimental focal cortical ischemia. There was a striking increase in both IGF-I and IGF-II gene expression in the ischemic cerebral cortex, but the two mRNAs were found in different cell populations. IGF-I mRNA was localized in reactive astrocytes that also stained intensely for glial fibrillary acidic protein (GFAP). IGF-II mRNA and immunoreactivity were contained in activated macrophages, which were highly abundant in the infarct zone and also in the meninges, blood vessels, and choroid plexus of the ischemic brain. High levels of IGF binding protein 2 mRNA were colocalized with IGF-II in these activated macrophages. Type-I IGF receptor mRNA was widely distributed in the affected area and type-II IGF receptor mRNA was also widely expressed but was particularly concentrated in macrophages. These findings suggest that the IGFs are involved in the brain's inflammatory response to injury, with IGF-I expressed by reactive astrocytes and IGF-II by activated macrophages. Their function in this setting is still unknown, but appears likely to be linked to the increased metabolic requirements associated with active phagocytosis.