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Preconditioning and post-treatment with cobalt chloride in rat model of perinatal hypoxic-ischemic encephalopathy.

Authors: Dai, Ying  Li, Wendi  Zhong, Min  Chen, Jie  Liu, Youxue  Cheng, Qian  Li, Tingyu 
Citation: Dai Y, etal., Brain Dev. 2014 Mar;36(3):228-40. doi: 10.1016/j.braindev.2013.04.007. Epub 2013 May 18.
Pubmed: (View Article at PubMed) PMID:23694759
DOI: Full-text: DOI:10.1016/j.braindev.2013.04.007

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.


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RGD ID: 12904932
Created: 2017-05-26
Species: All species
Last Modified: 2017-05-26
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.