title: Preconditioning and post-treatment with cobalt chloride in rat model of perinatal hypoxic-ischemic encephalopathy.
abstract: BACKGROUND
  Hypoxia-ischemia (HI)-induced perinatal encephalopathy is a major cause of acute mortality and chronic neurologic morbidities such as cerebral palsy, mental retardation, and epilepsy. As the essential transcription factor for the activation of hypoxia-inducible genes, hypoxia-inducible factor 1 alpha (HIF-1α) plays an important role in the pathophysiological response to the stress of HI brain damage. Whether HIF-1α activation promotes neuroprotection in HI tissues is controversial.
  
  
  METHODS
  The left common carotid artery of rats aged 7days was ligated under anesthesia. The pups were then exposed to hypoxia in a normobaric chamber filled with 8% oxygen and 92% nitrogen for 2.5h. In the sham control group, the left common carotid artery was exposed but was not ligated or exposed to hypoxia. To assess the time window for effective treatment, the HIF-1α inducer cobalt chloride (CoCl2) was injected subcutaneously 1day before surgery, immediately or 1day after surgery. The brain tissues were harvested from the pups of each groups at 1, 2 and 7days after insult for HIF-1α protein ant its target genes expression and for investigating the injury. Morris water maze tests were performed at postnatal 7weeks.
  
  
  RESULTS
  HIF-1α protein levels and its target genes vascular endothelial growth factor, heme oxygenase-1, and insulin-like growth factor 1 were markedly increased after intraperitoneal injection of CoCl2 (60mg/kg). The target gene inducible nitric oxide synthase exhibited a biphasic time course. HI caused apoptosis and reduced capillary density, which were ameliorated by CoCl2. Both preconditioning with CoCl2 24h before HI and administration of CoCl2 24h after HI improved long-term reference memory compared with that in vehicle-injected littermate controls. Administration of CoCl2 immediately after HI did not improve spatial working memory.
  
  
  CONCLUSIONS
  CoCl2 activates HIF-1α and protects against brain damage in vivo. The time of administration could be used to manipulate the activity of HIF-1α pathways and promote recovery.
authors.affiliation: Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Children's Nutritional Research Center, Key Laboratory of Developmental Diseases in Childhood of Education Ministry, Key Laboratory of Pediatrics in Chongqing, CSTC2009CA5002, Chongqing International Science and Technology Cooperation Center for Child Development and Disorder, Children's Hospital of Chongqing Medical University, PR China.
authors.forename: Wendi
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Children's Nutritional Research Center, Key Laboratory of Developmental Diseases in Childhood of Education Ministry, Key Laboratory of Pediatrics in Chongqing, CSTC2009CA5002, Chongqing International Science and Technology Cooperation Center for Child Development and Disorder, Children's Hospital of Chongqing Medical University, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Children's Nutritional Research Center, Key Laboratory of Developmental Diseases in Childhood of Education Ministry, Key Laboratory of Pediatrics in Chongqing, CSTC2009CA5002, Chongqing International Science and Technology Cooperation Center for Child Development and Disorder, Children's Hospital of Chongqing Medical University, PR China.
authors.forename: Youxue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University, PR China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Primary Child Health Care, Children's Hospital of Chongqing Medical University, PR China; Children's Nutritional Research Center, Key Laboratory of Developmental Diseases in Childhood of Education Ministry, Key Laboratory of Pediatrics in Chongqing, CSTC2009CA5002, Chongqing International Science and Technology Cooperation Center for Child Development and Disorder, Children's Hospital of Chongqing Medical University, PR China. Electronic address: tyli@vip.sina.com.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D003035:Cobalt / Q000008:administration & dosage / Q000627:therapeutic use*; D015870:Gene Expression / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D003035:Cobalt; C018021:cobaltous chloride
keywords: Cobalt chloride; Hypoxia-inducible factor-1α; Hypoxic–ischemic encephalopathy; Neuroprotection; Postconditioning; Preconditioning