title: Hypoxia-inducible factor 1 is essential for spontaneous recovery from traumatic brain injury and is a key mediator of heat acclimation induced neuroprotection.
abstract: Heat acclimation (HA), a well-established preconditioning model, confers neuroprotection in rodent models of traumatic brain injury (TBI). It increases neuroprotective factors, among them is hypoxia-inducible factor 1α (HIF-1α), which is important in the response to postinjury ischemia. However, little is known about the role of HIF-1α in TBI and its contribution to the establishment of the HA protecting phenotype. Therefore, we aimed to explore HIF-1α role in TBI defense mechanisms as well as in HA-induced neuroprotection. Acriflavine was used to inhibit HIF-1 in injured normothermic (NT) or HA mice. After TBI, we evaluated motor function recovery, lesion volume, edema formation, and body temperature as well as HIF-1 downstream transcription targets, such as glucose transporter 1 (GLUT1), vascular endothelial growth factor, and aquaporin 4. We found that HIF-1 inhibition resulted in deterioration of motor function, increased lesion volume, hypothermia, and reduced edema formation. All these parameters were significantly different in the HA mice. Western blot analysis and enzyme-linked immunosorbent assay showed reduced levels of all HIF-1 downstream targets in HA mice, however, only GLUT1 was downregulated in NT mice. We conclude that HIF-1 is a key mediator in both spontaneous recovery and HA-induced neuroprotection after TBI.
authors.affiliation: Department of Pharmacology, The Hebrew University, Jerusalem, Israel.
authors.forename: Gali
authors.initials: G
authors.lastname: Umschweif
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Alexandrovich
authors.forename: Victoria
authors.initials: V
authors.lastname: Trembovler
authors.forename: Michal
authors.initials: M
authors.lastname: Horowitz
authors.forename: Esther
authors.initials: E
authors.lastname: Shohami
mesh_terms: D000064:Acclimatization; D000167:Acriflavine / Q000494:pharmacology; D000818:Animals; D000891:Anti-Infective Agents, Local / Q000494:pharmacology; D051401:Aquaporin 4 / Q000096:biosynthesis; D001929:Brain Edema / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D006358:Hot Temperature; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D012075:Remission, Spontaneous
chemical_list: D000891:Anti-Infective Agents, Local; C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D051272:Glucose Transporter Type 1; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009419:Nerve Tissue Proteins; C495678:Slc2a1 protein, mouse; D000167:Acriflavine