title: Activin A regulation under global hypoxia in developing mouse brain.
abstract: Activin A is a multifunctional growth and differentiation factor with pronounced neuroprotective properties that is strongly up-regulated in various forms of acute brain disorders and injuries including epilepsy, stroke and trauma. In a pediatric context, activin A has been advanced as a potential marker for the severity of perinatal hypoxic-ischemic brain injury. Here we investigated the regulation of activin A under global hypoxia without ischemia in primary cultures of cortical neurons and in neonatal and adult mice of two strains (C57BL/6 and CD-1). From birth to adulthood, activin βA subunit, activin receptors, and functional activin antagonists were all expressed at roughly similar mRNA levels in the brain of C57BL/6 mice. Independent of mouse line and age, we found both moderate (11% O2, 2h) and severe hypoxia (8%, 6h) to be consistently associated with normal or even reduced levels of activin βA (Inhba) mRNA. The surprising unresponsiveness of Inhba expression to hypoxia was confirmed at the protein level. In situ hybridization did not indicate regional, hypoxia-related differences in Inhba expression. Pharmacologic stabilization of hypoxia inducible factors with the prolyl hydroxylase inhibitor FG-4497 did not influence Inhba mRNA levels in neonatal mice. Our data indicate that pure hypoxia differs from other, more complex types of brain damage in that it appears not to recruit activin A as an endogenous neuroprotective agent.
authors.affiliation: Department of Pediatrics, Friedrich-Alexander Universität Erlangen-Nürnberg, Loschgestrasse 15, 91054 Erlangen, Germany. florian.brackmann@uk-erlangen.de
authors.forename: Florian A
authors.initials: FA
authors.lastname: Brackmann
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Link
authors.forename: Susan
authors.initials: S
authors.lastname: Jung
authors.forename: Mandy
authors.initials: M
authors.lastname: Richter
authors.forename: Daniel
authors.initials: D
authors.lastname: Zoglauer
authors.forename: Gail
authors.initials: G
authors.lastname: Walkinshaw
authors.forename: Christian
authors.initials: C
authors.lastname: Alzheimer
authors.forename: Regina
authors.initials: R
authors.lastname: Trollmann
mesh_terms: D028341:Activins / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000473:pathology; D017403:In Situ Hybridization; D028322:Inhibin-beta Subunits / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000378:metabolism*; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000096:biosynthesis; D012720:Severity of Illness Index
chemical_list: D018696:Neuroprotective Agents; D012333:RNA, Messenger; C422405:activin A; C103008:inhibin beta A subunit; D028341:Activins; D028322:Inhibin-beta Subunits
keywords: Activin; HIF; Hypoxia; Neonatal brain injury; Strain difference