title: Hypoxia-inducible factor-1α upregulation in microglia following hypoxia protects against ischemia-induced cerebral infarction.
abstract: Activated microglia were considered to be the toxic inflammatory mediators that induce neuron degeneration after brain ischemia. Hypoxia can enhance the expression of hypoxia-inducible factor-1α (HIF-1α) in microglia and cause microglial activation. However, intermittent hypoxia has been reported recently to be capable of protecting the body from myocardial ischemia. We established a high-altitude environment as the hypoxic condition in this study. The hypoxic condition displayed a neuroprotective effect after brain ischemia, and mice exposed to this condition presented better neurological performance and smaller infarct size. At the same time, a high level of HIF-1α, low level of isoform of nitric oxide synthase, and a reduction in microglial activation were also seen in ischemic focus of hypoxic mice. However, this neuroprotective effect could be blocked by 2-methoxyestradiol, the HIF-1α inhibitor. Our finding suggested that HIF-1α expression was involved in microglial activation in vitro and was regulated by oxygen supply. The microglia were inactivated by re-exposure to hypoxia, which might be due to overexpression of HIF-1α. These results indicated that hypoxic conditions can be exploited to achieve maximum neuroprotection after brain ischemia. This mechanism possibly lies in microglial inactivation through regulation of the expression of HIF-1α.
authors.affiliation: aDepartment of Neurosurgery, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine (Guangdong Provincial Hospital of Chinese Medicine) bThe National Key Clinic Specialty, The Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University cKey Laboratory of Construction and Detection of Guangdong Province, Department of Anatomy, Southern Medical University, Guangdong, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Huang
authors.forename: Weiyi
authors.initials: W
authors.lastname: Huang
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Caijun
authors.initials: C
authors.lastname: Xie
authors.forename: Dongan
authors.initials: D
authors.lastname: Zhu
authors.forename: Zizhuang
authors.initials: Z
authors.lastname: Peng
authors.forename: Jiehan
authors.initials: J
authors.lastname: Chen
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002460:Cell Line; D002491:Central Nervous System Agents / Q000494:pharmacology; D002544:Cerebral Infarction / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D000860:Hypoxia / Q000473:pathology / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D011897:Random Allocation; D015854:Up-Regulation
chemical_list: D002491:Central Nervous System Agents; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D004958:Estradiol; D000077584:2-Methoxyestradiol