Neuropediatrics 2011; 42 - P086
DOI: 10.1055/s-0031-1274058

Activation of neuronal migration factor CXCR4 by pharmacological HIF stabilization in developing mouse brain

C Schneider 1, G Walkinshaw 2, M Gassmann 3, R Trollmann 1
  • 1Universitätsklinikum Erlangen, Klinik für Kinder und Jugendliche, Erlangen, Germany
  • 2FibroGen Inc., South San Francisco, United States
  • 3Universität Zürich, Institut für Veterinärphysiologie und Zentrum für Integrative Humanphysiologie (ZIHP), Zürich, Switzerland

Introduction: Perinatal hypoxia is an important cause of dysregulation of neuronal migration and cortical layering. Chemokine receptor CXCR4 and its physiological ligand SDF-1 are hypoxia-regulated migration factors that play an important role during early brain development. In adult stroke models modulation of regeneration processes such as directed migration of neuronal stem has been shown. Significance of CXCR4 during early regeneration period upon global hypoxia of the developing brain remains to be established. The aim of the present study was to examine effects of pharmacological and hypoxic stimulation of transcription factor HIF on cerebral activity of neuronal migration factors (CXCR4, SDF-1) in developing mouse brain.

Methods: Neonatal mice (P7) were treated with prolyl-hydroxylase inhibitor (PHI) FG-4497 (60–100mg/kg, ip). 6h after injection mice were exposed to acute systemic hypoxia (8% O2, 6h). Controls were kept under room air. Gene expression of VEGF, CXCR4 and SDF-1 was examined by RT PCR, proteins were determined by western blot analysis (HIFα) and immunofluorescence (CXCR4).

Results: Treatment with PHI FG-4497 led to cerebral accumulation of HIF-1α and -2α. Functional activation of the HIF system could be confirmed by significant induction of VEGF mRNA levels (p<0.01) compared to controls. Systemic hypoxia did not significantly alter CXCR4 and SDF-1 mRNA levels (p>0.05). However, CXCR4 mRNA concentrations significantly increased in response to PHI (60mg/kg, p<0.05; 100mg/kg, p<0.01) with additive effects under hypoxic conditions (60mg/kg, p<0.001). This activation could be confirmed at the cellular level by immunofluorescence.

Conclusion: Pharmacological stabilisation of HIF modulates neuronal migratory factors crucially involved in early brain maturation and hypoxia-induced cerebral adaptive mechanisms. Present data may implicate regenerative properties of FG-4497 as a novel therapeutic option in neonatal hypoxic brain injury.