title: Oxygen-sensitive regulation and neuroprotective effects of growth hormone-dependent growth factors during early postnatal development.
abstract: Perinatal hypoxia severely disrupts metabolic and somatotrophic development, as well as cerebral maturational programs. Hypoxia-inducible transcription factors (HIFs) represent the most important endogenous adaptive mechanisms to hypoxia, activating a broad spectrum of growth factors that contribute to cell survival and energy homeostasis. To analyze effects of systemic hypoxia and growth hormone (GH) therapy (rhGH) on HIF-dependent growth factors during early postnatal development, we compared protein (using ELISA) and mRNA (using quantitative RT PCR) levels of growth factors in plasma and brain between normoxic and hypoxic mice (8% O2, 6 h; postnatalday 7, P7) at P14. Exposure to hypoxia led to reduced body weight (P< 0.001) and length (P< 0.04) compared with controls and was associated with significantly reduced plasma levels of mouse GH (P< 0.01) and IGF-1 (P< 0.01). RhGH abrogated these hypoxia-induced changes of the GH/IGF-1 axis associated with normalization of weight and length gain until P14 compared with controls. In addition, rhGH treatment increased cerebral IGF-1, IGF-2, IGFBP-2, and erythropoietin mRNA levels, resulting in significantly reduced apoptotic cell death in the hypoxic, developing mouse brain. These data indicate that rhGH may functionally restore hypoxia-induced systemic dysregulation of the GH/IGF-1 axis and induce upregulation of neuroprotective, HIF-dependent growth factors in the hypoxic developing brain.
authors.affiliation: Division of Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany; and.
authors.forename: Susan
authors.initials: S
authors.lastname: Jung
authors.affiliation: Division of Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany; and.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Boie
authors.affiliation: Division of Pediatric Endocrinology, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Helmuth-Guenther
authors.initials: HG
authors.lastname: Doerr
authors.affiliation: Division of Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany; and regina.trollmann@uk-erlangen.de.
authors.forename: Regina
authors.initials: R
authors.lastname: Trollmann
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D005260:Female; D013006:Growth Hormone / Q000008:administration & dosage* / Q000378:metabolism; D019382:Human Growth Hormone / Q000008:administration & dosage; D000860:Hypoxia; D002534:Hypoxia, Brain / Q000188:drug therapy* / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D019382:Human Growth Hormone; D013006:Growth Hormone; D010100:Oxygen
keywords: IGF-1; IGF-2; cerebral apoptosis; erythropoietin; hypoxia-inducible transcription factors; insulin-like growth factors; neuroprotection; perinatal hypoxia; somatotrophic axis