title: ERα Signaling Is Required for TrkB-Mediated Hippocampal Neuroprotection in Female Neonatal Mice after Hypoxic Ischemic Encephalopathy(1,2,3).
abstract: Male neonate brains are more susceptible to the effects of perinatal asphyxia resulting in hypoxia and ischemia (HI)-related brain injury. The relative resistance of female neonatal brains to adverse consequences of HI suggests that there are sex-specific mechanisms that afford females greater neuroprotection and/or facilitates recovery post-HI. We hypothesized that HI preferentially induces estrogen receptor α (ERα) expression in female neonatal hippocampi and that ERα is coupled to Src family kinase (SFK) activation that in turn augments phosphorylation of the TrkB and thereby results in decreased apoptosis. After inducing the Vannucci's HI model on P9 (C57BL/6J) mice, female and male ERα wild-type (ERα(+/+)) or ERα null mutant (ERα(-/-)) mice received vehicle control or the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF). Hippocampi were collected for analysis of mRNA of ERα and BDNF, protein levels of ERα, p-TrkB, p-src, and cleaved caspase 3 (c-caspase-3) post-HI. Our results demonstrate that: (1) HI differentially induces ERα expression in the hippocampus of the female versus male neonate, (2) src and TrkB phosphorylation post-HI is greater in females than in males after 7,8-DHF therapy, (3) src and TrkB phosphorylation post-HI depend on the presence of ERα, and (4) TrkB agonist therapy decreases the c-caspase-3 only in ERα(+/+) female mice hippocampus. Together, these observations provide evidence that female-specific induction of ERα expression confers neuroprotection with TrkB agonist therapy via SFK activation and account for improved functional outcomes in female neonates post-HI.
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705; Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792.
authors.forename: Ulas
authors.initials: U
authors.lastname: Cikla
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705.
authors.forename: Vishal
authors.initials: V
authors.lastname: Chanana
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kintner
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705.
authors.forename: Eshwar
authors.identifier: 0000-0001-5224-7230
authors.initials: E
authors.lastname: Udho
authors.affiliation: Department of Statistics and Bioinformatics, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53792.
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705.
authors.forename: Wendy
authors.identifier: 0000-0002-9052-7273
authors.initials: W
authors.lastname: Sun
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Marquez
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705.
authors.forename: Lucia
authors.initials: L
authors.lastname: Covert
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705.
authors.forename: Arel
authors.initials: A
authors.lastname: Otles
authors.affiliation: Department of Neuroscience, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705.
authors.forename: Robert A
authors.identifier: 0000-0002-7359-0000
authors.initials: RA
authors.lastname: Shapiro
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792.
authors.forename: Peter
authors.initials: P
authors.lastname: Ferrazzano
authors.affiliation: Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53792.
authors.forename: Raghu
authors.initials: R
authors.lastname: Vemuganti
authors.affiliation: Department of Neuroscience, University of Wisconsin School of Medicine and Public Health , Madison, Wisconsin 53705.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Levine
authors.affiliation: Waisman Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792.
authors.forename: Pelin
authors.identifier: 0000-0002-5682-5664
authors.initials: P
authors.lastname: Cengiz
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000819:agonists / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D020813:Receptor, trkB; D019061:src-Family Kinases
keywords: 7,8-dihydroxyflavone; estrogen receptor alpha; hypoxia-ischemia; neonate; src; tyrosine kinase B
references.citation: Brain Res Dev Brain Res. 2003 Oct 10;145(1):117-39
references.pmid: 14519499
references.citation: Arch Dis Child Fetal Neonatal Ed. 2005 Sep;90(5):F380-7
references.pmid: 16113154
references.citation: Neuropsychopharmacology. 2012 Jan;37(2):434-44
references.pmid: 21900882
references.citation: Am J Physiol Endocrinol Metab. 2014 Jul 15;307(2):E133-40
references.pmid: 24895281
references.citation: Antioxid Redox Signal. 2011 May 15;14(10):1803-13
references.pmid: 20712402
references.citation: Annu Rev Neurosci. 2001;24:677-736
references.pmid: 11520916
references.citation: Pediatr Crit Care Med. 2006 Jan;7(1):40-4
references.pmid: 16395073
references.citation: J Biol Chem. 2010 Mar 12;285(11):8207-17
references.pmid: 20064930
references.citation: J Neurochem. 2007 Feb;100(4):1062-71
references.pmid: 17166174
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1952-7
references.pmid: 11172057
references.citation: Clin Pharmacokinet. 2001;40(12):907-46
references.pmid: 11735609
references.citation: PLoS One. 2014;9(2):e88962
references.pmid: 24551199
references.citation: Exp Neurol. 2000 Nov;166(1):99-114
references.pmid: 11031087
references.citation: Lancet Neurol. 2004 Mar;3(3):150-8
references.pmid: 14980530
references.citation: Mol Endocrinol. 2004 May;18(5):1096-108
references.pmid: 14963108
references.citation: Neurol Res Int. 2012;2012:867531
references.pmid: 22474588
references.citation: Endocrinology. 2010 Feb;151(2):731-40
references.pmid: 19966177
references.citation: Brain Res. 2013 Jun 13;1514:107-22
references.pmid: 23500634
references.citation: Neuroscience. 2003;116(2):383-91
references.pmid: 12559094
references.citation: Neuroscience. 2012 Jan 27;202:131-46
references.pmid: 22133892
references.citation: Pediatr Res. 1990 May;27(5):450-3
references.pmid: 2345670
references.citation: Nat Methods. 2012 Jul;9(7):671-5
references.pmid: 22930834
references.citation: Reprod Sci. 2013 Mar;20(3):253-61
references.pmid: 22875845
references.citation: Cytokine Growth Factor Rev. 2012 Feb-Apr;23(1-2):15-24
references.pmid: 22341689
references.citation: Science. 2012 Dec 7;338(6112):1357-60
references.pmid: 23224557
references.citation: Ann Neurol. 2009 Dec;66(6):713-4
references.pmid: 20035500
references.citation: Nat Rev Neurosci. 2009 Dec;10(12):850-60
references.pmid: 19927149
references.citation: J Neuroendocrinol. 2009 Mar;21(4):238-42
references.pmid: 19207817
references.citation: J Cereb Blood Flow Metab. 2007 Feb;27(2):270-81
references.pmid: 16736047
references.citation: Br J Pharmacol. 2011 Feb;162(4):947-60
references.pmid: 21039416
references.citation: Front Neuroendocrinol. 2009 Jul;30(2):201-11
references.pmid: 19401209
references.citation: Stroke. 2012 Jul;43(7):1918-24
references.pmid: 22535263
references.citation: Horm Behav. 2011 Mar;59(3):353-7
references.pmid: 20713055
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):14077-82
references.pmid: 9391155
references.citation: Trends Neurosci. 2005 Feb;28(2):79-85
references.pmid: 15667930
references.citation: Brain Res Mol Brain Res. 1996 Mar;36(2):280-6
references.pmid: 8965648
references.citation: Pediatr Res. 2013 Jan;73(1):12-7
references.pmid: 23085817
references.citation: Horm Behav. 1994 Dec;28(4):367-75
references.pmid: 7729805
references.citation: Neuroscience. 2008 Apr 9;152(4):982-9
references.pmid: 18353557
references.citation: Nat Rev Drug Discov. 2013 Jul;12(7):507-25
references.pmid: 23977697
references.citation: Ann N Y Acad Sci. 1997 Dec 19;835:234-49
references.pmid: 9616778
references.citation: CNS Neurol Disord Drug Targets. 2013 May 1;12(3):360-70
references.pmid: 23469848
references.citation: J Neurochem. 2004 Sep;90(5):1068-75
references.pmid: 15312162
references.citation: Clin Cancer Res. 2012 Jan 1;18(1):6-8
references.pmid: 22215901
references.citation: Endocrinology. 2013 Feb;154(2):842-52
references.pmid: 23264616
references.citation: J Child Psychol Psychiatry. 2003 Nov;44(8):1092-115
references.pmid: 14626453
references.citation: CNS Neurol Disord Drug Targets. 2013 Nov;12(7):1066-77
references.pmid: 23844685
references.citation: Biomed Rep. 2013 Mar;1(2):167-176
references.pmid: 24648914
references.citation: J Neurosci. 2002 Apr 1;22(7):2650-9
references.pmid: 11923430
references.citation: J Neurosci. 2012 Oct 10;32(41):14318-30
references.pmid: 23055503
references.citation: N Engl J Med. 2004 Nov 4;351(19):1985-95
references.pmid: 15525724
references.citation: Endocr Rev. 2008 Apr;29(2):217-33
references.pmid: 18216219
references.citation: J Transl Med. 2008;6:33
references.pmid: 18573200
references.citation: Cereb Cortex. 2005 Mar;15(3):250-61
references.pmid: 15269108
references.citation: Handb Exp Pharmacol. 2014;220:3-15
references.pmid: 24668467
references.citation: Mol Cell Endocrinol. 2008 Aug 13;290(1-2):24-30
references.pmid: 18534740
references.citation: Neuropsychology. 2002 Oct;16(4):491-9
references.pmid: 12382988
references.citation: Neurobiol Dis. 2000 Feb;7(1):38-53
references.pmid: 10671321
references.citation: J Neurosci. 2008 Feb 27;28(9):2033-42
references.pmid: 18305238
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2687-92
references.pmid: 20133810