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首页> 中文期刊> 《中国神经再生研究：英文版》 >Influence of hypoxia-inducible factor 1-alpha on neuronal apoptosis in a rat model of hypoxia-or hypoxia-ischemia-induced brain injury

Influence of hypoxia-inducible factor 1-alpha on neuronal apoptosis in a rat model of hypoxia-or hypoxia-ischemia-induced brain injury

         
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BACKGROUND: In addition to neuroprotective genes, the targeted genes of hypoxia-induciblefactor 1α (HIF-1α) include pro-apoptotic genes. However, the influence of HIF-1α on neuronalapoptosis in hypoxia-ischemia remains poorly understood.OBJECTIVE: To investigate the relationship between HIF-1α expression and neuronal apoptosis inhypoxia or hypoxia-ischemia brain injury and to determine the role of HIF-1α in regulating neuronalapoptosis.DESIGN, TIME AND SETTING: A randomized, controlled animal experiment was performed at theLaboratory of Children Neurology of Sichuan University between May 2006 and May 2007.MATERIALS: In situ cell death detected kit was provided by Roche, USA; rabbit anti-mouse HIF-1αpolyclonal antibody was purchased from Santa Cruz Biotechnologies, USA; rabbit anti-mousecleaved caspase-3 polyclonal antibody was purchased from Chemicon, USA.METHODS: A total of 36 Sprague Dawley rats aged 10 days were randomly assigned to 3 groups:sham-surgery, hypoxia, and hypoxia-ischemia, with 12 rats per group. The rats were treated at 3time points: 4, 8, and 24 hours, with 4 rats per time point. In the hypoxia-ischemia group, the rightcommon carotid artery was exposed and permanently ligated through a midline cervical incision. A2.5-hour exposure to hypoxia (8% O_2/92% N_2) was used to induce hypoxia-ischemia injury. In thehypoxia group, rats were exposed to hypoxia without ligation of the common carotid artery. In thesham-surgery group, the common carotid artery was exposed without ligation or hypoxia.MAIN OUTCOME MEASURES: Histopathological changes, HIF-1α and activated caspase-3 proteinexpression, integrated optical density of positive cells, and apoptosis-positive cells.RESULTS: Hematoxylin and eosin staining showed that neuronal degeneration and edema wasmost prominent at 24 hours after hypoxia-ischemia. HIF-1α protein expression was significantlyupregulated at 4 hours, peaked at 8 hours, and decreased at 24 hours after hypoxia orhypoxia-ischemia. HIF-1α protein expression was significant greater in the hypoxia andhypoxia-ischemia groups compared with the sham-surgery group (P < 0.01). Activated caspase-3protein expression began to increase at 4 and 8 hours following hypoxia or hypoxia-ischemia andwas significantly upregulated at 24 hours. Activated caspase-3 protein expression remained at lowlevels in the sham controls compared with the hypoxia and hypoxia-ischemia groups (P< 0.01).TUNEL staining showed that the number of apoptotic cells significantly increased at 24 hours afterhypoxia or hypoxia-ischemia. In addition, HIF-1α protein expression was greater in the hypoxiagroup compared with the hypoxia-ischemia group at the same time point (P< 0.05). However,activated caspase-3 expression and the number of TUNEL-positive cells were less in the hypoxiagroup compared with the hypoxia-ischemia group at the same time point (P < 0.05).CONCLUSION: HIF-1α played a neuroprotective role following hypoxia-ischemia brain injury.

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