Blunting type 1 insulin-like growth factor receptor expression exacerbates neuronal apoptosis following hypoxic/ischemic injury

• Published in: BMC neuroscience Vol. 12; no. 1; p. 64
• Main Authors: Liu, Wen, D'Ercole, Joseph A, Ye, Ping
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 30.06.2011; BioMed Central; BMC
• Subjects: Animals; Apoptosis; Diagnosis; Gene Expression; Growth factor receptors; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - pathology; Mice; Mice, Knockout; Mice, Mutant Strains; Neurons - metabolism; Neurons - pathology; Physiological aspects; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Risk factors; Wounds and injuries; United States
• ISSN: 1471-2202; 1471-2202
• DOI: 10.1186/1471-2202-12-64

Abundant experimental data have implicated an important role for insulin-like growth factor (IGF) in protecting neuronal cells from injury, including hypoxia/ischemia (H/I) injury, a major cause of neuron death. While the specific interaction of IGFs with neuronal or glial type 1 IGF receptors (IGF1R) has been shown to be essential to IGF actions during development, the same has not been directly demonstrated following H/I injury. To directly examine the role of neuronal IGF1R following H/I injury, we utilized conditional mutant nes-igf1r(-/Wt) mice and determined the impact of IGF1R haplodeficiency specifically in nestin-expressing neuronal precursors and their progeny on H/I-induced neuronal damage and apoptosis in hippocampus. H/I induced significant damage to the cerebral hemisphere and hippocampus ipsilateral to the ligated right common carotid artery both in control and nes-igf1r(-/Wt) mice at postnatal day 10. Blunting IGF1R expression, however, markedly exacerbated H/I-induced damage and appeared to increase mortality. In the ipsilateral hemisphere and hippocampus, nes-igf1r(-/Wt) mice had infarct areas double the size of those in controls. The size of the ipsilateral hemisphere and hippocampus in nes-igf1r(-/Wt) mice were 15% to 17% larger than those in controls, reflecting more severe edema. Consistent with its effects on infarct area, IGF1R haplodeficiency causes a greater decrease in neurons in the ipsilateral hippocampus of nes-igf1r(-/Wt) mice. The reduction in neurons was largely due to increases in neuronal apoptosis. Judged by pyknotic nuclei, TUNEL and caspase-3 labeling, nes-igf1r(-/Wt) mice had significantly more apoptotic cells than that in controls after injury. To determine possible mechanisms of IGF1R actions, the mRNA expression of the pro-survival proteins IAP-1 and XIAP was determined. Compared to controls, the abundance of cIAP-1 and XIAP mRNA was markedly suppressed in mice with blunted IGF1R or IGF-I expression, while was increased in the brain of IGF-I overexpressing transgenic mice. IGF1R in neuronal cells is critically important for their survival following H/I injury, and IGF-upregulated expression of neuronal cIAP-1 and XIAP likely in part contributes to IGF-IGF1R protection against neuronal apoptosis following H/I injury.