Enhancement of autophagic flux after neonatal cerebral hypoxia-ischemia and its region-specific relationship to apoptotic mechanisms

Am J Pathol. 2009 Nov;175(5):1962-74. doi: 10.2353/ajpath.2009.090463. Epub 2009 Oct 8.

Abstract

The multiplicity of cell death mechanisms induced by neonatal hypoxia-ischemia makes neuroprotective treatment against neonatal asphyxia more difficult to achieve. Whereas the roles of apoptosis and necrosis in such conditions have been studied intensively, the implication of autophagic cell death has only recently been considered. Here, we used the most clinically relevant rodent model of perinatal asphyxia to investigate the involvement of autophagy in hypoxic-ischemic brain injury. Seven-day-old rats underwent permanent ligation of the right common carotid artery, followed by 2 hours of hypoxia. This condition not only increased autophagosomal abundance (increase in microtubule-associated protein 1 light chain 3-11 level and punctuate labeling) but also lysosomal activities (cathepsin D, acid phosphatase, and beta-N-acetylhexosaminidase) in cortical and hippocampal CA3-damaged neurons at 6 and 24 hours, demonstrating an increase in the autophagic flux. In the cortex, this enhanced autophagy may be related to apoptosis since some neurons presenting a high level of autophagy also expressed apoptotic features, including cleaved caspase-3. On the other hand, enhanced autophagy in CA3 was associated with a more purely autophagic cell death phenotype. In striking contrast to CA3 neurons, those in CA1 presented only a minimal increase in autophagy but strong apoptotic characteristics. These results suggest a role of enhanced autophagy in delayed neuronal death after severe hypoxia-ischemia that is differentially linked to apoptosis according to the cerebral region.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / physiology*
  • Autophagy / physiology*
  • Biomarkers / metabolism
  • Brain* / anatomy & histology
  • Brain* / physiology
  • Caspase 3 / metabolism
  • Humans
  • Hypoxia-Ischemia, Brain* / metabolism
  • Hypoxia-Ischemia, Brain* / physiopathology
  • Infant, Newborn
  • Lysosome-Associated Membrane Glycoproteins / metabolism
  • Lysosomes / metabolism
  • Male
  • Phagosomes / metabolism
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Biomarkers
  • Lamp1 protein, rat
  • Lysosome-Associated Membrane Glycoproteins
  • Caspase 3