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Hypoxia-inducible factor in brain.

F R Sharp1, M Bergeron, M Bernaudin

  • 1Department of Neurology, University of Cincinnati, OH, USA.

Advances in Experimental Medicine and Biology
|April 13, 2002
PubMed
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Hypoxia-inducible factor 1 (HIF-1) activation increases survival in hypoxic tissues. Studies show HIF-1 activation protects the brain from stroke and injury, suggesting its role in neuroprotection.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Hypoxia-inducible factor 1 (HIF-1), composed of HIF-1alpha and HIF-1beta subunits, is induced by hypoxia.
  • HIF-1 activation stimulates transcription of hypoxia-inducible genes, potentially promoting cell survival in hypoxic tissues.

Purpose of the Study:

  • To investigate the effect of stroke on HIF-1alpha, HIF-1beta, and target gene expression in adult rat brains.
  • To examine the role of hypoxic preconditioning and HIF-1 inducers in protecting neonatal rat brains against hypoxic-ischemic injury.

Main Methods:

  • Focal cerebral ischemia was induced in adult rats.
  • Systemic hypoxia, hypoxic preconditioning, cobalt chloride (CoCl2), and desferrioxamine (DFX) were used in neonatal rat models.
  • Expression of HIF-1alpha, HIF-1beta, and target genes (glucose transporter-1, lactate dehydrogenase) was analyzed via mRNA and protein levels.

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Main Results:

  • Focal cerebral ischemia upregulated HIF-1alpha, glucose transporter-1, and lactate dehydrogenase mRNAs in adult rat brains around the infarction area.
  • HIF-1 and its target genes were induced within 7.5 hours post-ischemia, with further increases at 19 and 24 hours.
  • Hypoxic preconditioning, CoCl2, and DFX markedly increased HIF-1alpha and HIF-1beta expression in neonatal rat brains, significantly reducing infarction size.

Conclusions:

  • Decreased blood flow during stroke likely induces HIF-1 and its target genes in the penumbra region.
  • HIF-1 activation contributes to the neuroprotective effects of hypoxic preconditioning in neonatal rat brains.
  • Pharmacological induction of HIF-1 with CoCl2 or DFX demonstrates significant neuroprotection against stroke in neonatal rats.