Hypoxic-preconditioning induces neuroprotection against hypoxia-ischemia in newborn piglet brain

Jahan Ara, Saskia Fekete, Melissa Frank, Jeffrey A. Golden, David E Pleasure, Ignacio Valencia

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Preconditioning-induced ischemic tolerance has been documented in the newborn brain, however, the signaling mechanisms of this preconditioning require further elucidation. The aims of this study were to develop a hypoxic-preconditioning (PC) model of ischemic tolerance in the newborn piglet, which emulates important clinical similarities to human situation of birth asphyxia, and to characterize some of the molecular mechanisms shown to be implicated in PC-induced neuroprotection in rodent models. One day old piglets were subjected to PC (8% O2/92% N2) for 3h and 24h later were exposed to hypoxia-ischemia (HI) produced by a combination of hypoxia (5% FiO2) for a period of 30min and ischemia induced by a period of hypotension (10min of reduced mean arterial blood pressure; ≤70% of baseline). Neuropathologic analysis and unbiased stereology, conducted at 24h, 3 and 7days of recovery following HI, indicated a substantial reduction in the severity of brain damage in PC piglets compared to non-PC piglets (P<0.05). PC significantly increased the mRNA expression of hypoxia-inducible factor-1α (HIF-1α) and its target gene, vascular endothelial growth factor (VEGF) at 0h, 6h, 24h, 3 and 7days of recovery. Immunoblot analysis demonstrated that PC resulted in HIF-1α protein stabilization and accumulation in nuclear extracts of cerebral cortex of newborn piglet brain compared to normoxic controls. Protein levels of VEGF increased in a time-dependent manner in both cortex and hippocampus following PC. Double-immunolabeling indicated that VEGF is mainly expressed in neurons, endothelial cells and astroglia. Our study demonstrates for the first time the protective efficacy of PC against hypoxic-ischemic injury in newborn piglet model, which recapitulates many pathophysiological features of asphyxiated human neonates. Furthermore, as has been shown in rodent models of preconditioning, our results suggest that PC-induced protection in neonatal piglets may involve upregulation of VEGF.

Original languageEnglish (US)
Pages (from-to)473-485
Number of pages13
JournalNeurobiology of Disease
Volume43
Issue number2
DOIs
StatePublished - Aug 2011

Fingerprint

Vascular Endothelial Growth Factor A
Ischemia
Hypoxia-Inducible Factor 1
Ischemic Preconditioning
Brain
Rodentia
Arterial Pressure
Asphyxia
Astrocytes
Cerebral Cortex
Hypotension
Hippocampus
Proteins
Up-Regulation
Endothelial Cells
Parturition
Neurons
Messenger RNA
Hypoxia
Neuroprotection

Keywords

  • Hypoxia-ischemia
  • Hypoxic-preconditioning
  • Neuroprotection
  • Newborn brain
  • Piglet
  • VEGF

ASJC Scopus subject areas

  • Neurology

Cite this

Hypoxic-preconditioning induces neuroprotection against hypoxia-ischemia in newborn piglet brain. / Ara, Jahan; Fekete, Saskia; Frank, Melissa; Golden, Jeffrey A.; Pleasure, David E; Valencia, Ignacio.

In: Neurobiology of Disease, Vol. 43, No. 2, 08.2011, p. 473-485.

Research output: Contribution to journalArticle

Ara, Jahan ; Fekete, Saskia ; Frank, Melissa ; Golden, Jeffrey A. ; Pleasure, David E ; Valencia, Ignacio. / Hypoxic-preconditioning induces neuroprotection against hypoxia-ischemia in newborn piglet brain. In: Neurobiology of Disease. 2011 ; Vol. 43, No. 2. pp. 473-485.
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