title: 2-Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF-1α response after traumatic brain injury in mice.
abstract: HIF-1α is pivotal for cellular homeostasis in response to cerebral ischemia. Pharmacological inhibition of HIF-1α may reduce secondary brain damage by targeting post-translational mechanisms associated with its proteasomal degradation and nuclear translocation. This study examined the neuroprotective effects of 2-methoxyestradiol (2ME2), the involved HIF-1α-dependent response, and alternative splicing in exon 14 of HIF-1α (HIF-1α∆Ex14) after traumatic brain injury (TBI) in mice. Intraperitoneal 2ME2 administration 30 min after TBI caused a dose-dependent reduction in secondary brain damage after 24 h. 2ME2 was physiologically tolerated, showed no effects on immune cell brain migration, and mitigated trauma-induced brain expression of neuropathologically relevant HIF-1α target genes encoding for Plasminogen activator inhibitor 1 and tumor necrosis factor alpha. Moreover, TBI-induced expression of pro-apoptotic BNIP3 was attenuated by 2ME2 treatment. Alternatively, spliced HIF-1α∆Ex14 was substantially up-regulated from 6 to 48 h after TBI. In vitro, nuclear location and gene transcription activity of HIF-1α∆Ex14 were impaired compared to full-length HIF-1α, but no effects on nuclear translocation of the transcriptional complex partner HIF-1β were observed. This study demonstrates that 2ME2 confers neuroprotection after TBI. While the role of alternatively spliced HIF-1α∆Ex14 remains elusive, the in vivo data provide evidence that inhibition of a maladaptive HIF-1α-dependent response contributes to the neuroprotective effects of 2ME2. We examined neuroprotective effects of 2-methoxyestradiol (2ME2) and the hypoxia-inducible factor 1-α (HIF-1α) response following traumatic brain injury in mice. Early 2ME2 administration reduced the secondary brain damage and neuronal HIF-1α probably involving ubiquitin proteasome system-mediated degradation. The up-regulation of neuropathological HIF-1α target genes and pro-apoptotic BNIP3 protein was attenuated. We propose that the inhibition of a maladaptive HIF-1α response may contribute to 2ME2-mediated neuroprotection.
authors.affiliation: Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Eva-Verena
authors.initials: EV
authors.lastname: Schaible
authors.forename: Julia
authors.initials: J
authors.lastname: Windschügl
authors.forename: Wiesia
authors.initials: W
authors.lastname: Bobkiewicz
authors.forename: Yordan
authors.initials: Y
authors.lastname: Kaburov
authors.forename: Larissa
authors.initials: L
authors.lastname: Dangel
authors.forename: Tobias
authors.initials: T
authors.lastname: Krämer
authors.forename: Changsheng
authors.initials: C
authors.lastname: Huang
authors.forename: Anne
authors.initials: A
authors.lastname: Sebastiani
authors.forename: Clara
authors.initials: C
authors.lastname: Luh
authors.forename: Christian
authors.initials: C
authors.lastname: Werner
authors.forename: Kristin
authors.initials: K
authors.lastname: Engelhard
authors.forename: Serge C
authors.initials: SC
authors.lastname: Thal
authors.forename: Michael K E
authors.initials: MK
authors.lastname: Schäfer
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000096:biosynthesis; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D021381:Protein Transport; D013347:Subcellular Fractions / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: C508686:BNip3 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D017395:Plasminogen Activator Inhibitor 1; D014409:Tumor Necrosis Factor-alpha; C037233:2-methylestradiol; D004958:Estradiol
keywords: 2-methoxyestradiol; HIF-1; alternative splicing; cerebral ischemia; neuroprotection; traumatic brain injury