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

Neurobiology of Disease

Saskia Fekete¹  Melissa Frank²  David Pleasure³  Jahan Ara⁴  Jeffrey A. Golden⁴  Ignacio Valencia⁵ 

[1] Corresponding author at: Department of Pediatrics, Drexel University College of Medicine and Saint Christopher's Hospital for Children, 245 N. 15th Street, New College Building, Room 7408, Philadelphia, PA 19102, USA. Fax: [phone].;Departamento de Pediatria, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, SP, Brazil;Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA;Department of Pediatrics, Drexel University College of Medicine and Saint Christopher's Hospital for Children, Philadelphia, PA 19102, USA;Institute for Pediatric Regenerative Medicine, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA;

关键词: Neuroprotection;    Hypoxic-preconditioning;    Piglet;    Newborn brain;    Hypoxia–ischemia;    VEGF;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 3 h and 24 h later were exposed to hypoxia–ischemia (HI) produced by a combination of hypoxia (5% FiO2) for a period of 30 min and ischemia induced by a period of hypotension (10 min of reduced mean arterial blood pressure; ≤70% of baseline). Neuropathologic analysis and unbiased stereology, conducted at 24 h, 3 and 7 days 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 0 h, 6 h, 24 h, 3 and 7 days 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.

【 授权许可】

Unknown