Abstract：
:Hypoxia-inducible transcription factors (HIFs) are crucially involved in brain development and cellular adaptation to hypoxia and ischemia. Degradation of HIF is regulated under normoxia by oxygen-dependent hydroxylation of specific prolyl residues on the labile alpha-subunit by HIF prolyl hydroxylases (PHD). Prolyl-4-hydroxylase inhibitors (PHI) have shown protective effects in vitro and in vivo in adult kidney and brain. The aim of the present study was to investigate in vivo short-term effects of a novel low molecular weight PHI, FG-4497, on HIF-regulated cytotrophic and vasoactive factors in developing mouse brain. Neonatal (P7, n=26) C57/BL6 mice were treated with PHI FG-4497 (30-100 mg/kg, i.p., duration 6 h). Gene expression was analyzed by TaqMan RT-PCR in kidney and developing brain in comparison to controls (NaCl 0.9% and non-treated animals). HIF-1alpha protein was quantified by Western blot analysis. Dose-response studies revealed prominent effects of FG-4497 at a dose of 100 mg/kg as assessed by significant up-regulation of mRNA in both kidney and brain of the following HIF-dependent genes: vascular endothelial growth factor, adrenomedullin and erythropoietin. Organ-specific transcriptional regulation was evident from analysis of hexokinase 2, inducible NO synthase and PHD3 mRNA concentrations. In the brain, HIF-1alpha and HIF-2alpha protein markedly accumulated in response to FG-4497. Besides vasoactive factors, PHI significantly increased cerebral chemokine receptor CXCR-4 mRNA levels. In conclusion, the novel PHI FG-4497 activates HIFs at an early stage of brain maturation and modulates neurotrophic processes known to be crucially involved in brain development and hypoxia-induced brain pathology.
journal_name
Brain Resjournal_title
Brain researchauthors
Schneider C,Krischke G,Keller S,Walkinshaw G,Arend M,Rascher W,Gassmann M,Trollmann Rdoi
10.1016/j.brainres.2009.05.023subject
Has Abstractpub_date
2009-07-14 00:00:00pages
43-51eissn
0006-8993issn
1872-6240pii
S0006-8993(09)00953-6journal_volume
1280pub_type
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