PMID- 24361177 OWN - NLM STAT- MEDLINE DCOM- 20140925 LR - 20211021 IS - 1873-7544 (Electronic) IS - 0306-4522 (Print) IS - 0306-4522 (Linking) VI - 260 DP - 2014 Feb 28 TI - Sexual dimorphism in BDNF signaling after neonatal hypoxia-ischemia and treatment with necrostatin-1. PG - 106-19 LID - S0306-4522(13)01039-7 [pii] LID - 10.1016/j.neuroscience.2013.12.023 [doi] AB - Brain injury due to neonatal hypoxia-ischemia (HI) is more homogenously severe in male than in female mice. Because, necrostatin-1 (nec-1) prevents injury progression only in male mice, we hypothesized that changes in brain-derived neurotrophic factor (BDNF) signaling after HI and nec-1 are also sex-specific providing differential conditions to promote recovery of those more severely injured. The increased aromatization of testosterone in male mice during early development and the link between 17-beta-estradiol (E2) levels and BDNF transcription substantiate this hypothesis. Hence, we aimed to investigate if sexual differences in BDNF signaling existed in forebrain and diencephalon after HI and HI/nec-1 and their correlation with estrogen receptors (ER). C57B6 mice (p7) received nec-1 (0.1mul [8muM]) or vehicle (veh) intracerebroventricularly after HI. At 24h after HI, BDNF levels increased in both sexes in forebrain without evidence of tropomyosin-receptor-kinase B (TrkB) activation. At 96h after HI, BDNF levels in forebrain decreased below those seen in control mice of both sexes. Additionally, only in female mice, truncated TrkB (Tc.TrkB) and p75 neurotrophic receptor (p75ntr) levels increased in forebrain and diencephalon. In both, forebrain and diencephalon, nec-1 treatment increased BDNF levels and TrkB activation in male mice while, nec-1 prevented Tc.TrkB and p75ntr increases in female mice. While E2 levels were unchanged by HI or HI/nec-1 in either sex or treatment, ERalpha:ERbeta ratios were increased in diencephalon of nec-1-treated male mice and directly correlated with BDNF levels. Neonatal HI produces sex-specific signaling changes in the BDNF system, that are differentially modulated by nec-1. The regional differences in BDNF levels may be a consequence of injury severity after HI, but sexual differences in response to nec-1 after HI may represent a differential thalamo-cortical preservation or alternatively off-target regional effect of nec-1. The biological significance of ERalpha predominance and its correlation with BDNF levels is still unclear. CI - Copyright (c) 2013 IBRO. Published by Elsevier Ltd. All rights reserved. FAU - Chavez-Valdez, R AU - Chavez-Valdez R AD - Department of Pediatrics, Neonatal Research Laboratory, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 6-104, Baltimore, MD 21287, USA. Electronic address: rchavez2@jhmi.edu. FAU - Martin, L J AU - Martin LJ AD - Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 558, Baltimore, MD 21205, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross Research Building, Room 558, Baltimore, MD 21205, USA. FAU - Razdan, S AU - Razdan S AD - Department of Pediatrics, Neonatal Research Laboratory, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 6-104, Baltimore, MD 21287, USA. FAU - Gauda, E B AU - Gauda EB AD - Department of Pediatrics, Neonatal Research Laboratory, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 6-104, Baltimore, MD 21287, USA. FAU - Northington, F J AU - Northington FJ AD - Department of Pediatrics, Neonatal Research Laboratory, Johns Hopkins University School of Medicine, 600 North Wolfe Street, CMSC 6-104, Baltimore, MD 21287, USA. LA - eng GR - R01 HD070996/HD/NICHD NIH HHS/United States GR - R01HD070996/HD/NICHD NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20131217 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Imidazoles) RN - 0 (Indoles) RN - 0 (Neuroprotective Agents) RN - 0 (Parvalbumins) RN - 0 (Receptors, Estrogen) RN - 0 (necrostatin-1) RN - 4TI98Z838E (Estradiol) SB - IM MH - Animals MH - Animals, Newborn MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Diencephalon/drug effects/*metabolism MH - Estradiol/analysis MH - Female MH - Hypoxia-Ischemia, Brain/*drug therapy/*metabolism MH - Imidazoles/*therapeutic use MH - Indoles/*therapeutic use MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neuroprotective Agents/*therapeutic use MH - Parvalbumins/metabolism MH - Prosencephalon/drug effects/*metabolism MH - Receptors, Estrogen/metabolism MH - Sex Factors PMC - PMC3950408 MID - NIHMS555990 OTO - NOTNLM OT - ANOVA OT - BDNF OT - E2 OT - ELISA OT - ER OT - ERE OT - FL.TrkB OT - HI OT - OD OT - Tc.TrkB OT - TrkB OT - analysis of variance OT - brain-derived neurotrophic factor OT - cortex OT - enzyme-linked immunosorbent assay OT - estradiol OT - estrogen receptor OT - estrogen response element OT - full-length TrkB OT - hypoxia-ischemia OT - nec-1 OT - necrostatin-1 OT - optical density OT - p OT - p75 neurotrophic receptor OT - p75ntr OT - pTrkB OT - phosphorylated TrkB OT - plasticity OT - post-natal day OT - qRT-PCR OT - quantitative reverse transcriptase polymerase chain reaction OT - thalamus OT - tropomyosin-receptor-kinase B OT - truncated TrkB OT - truncated TrkB receptor OT - veh OT - vehicle COIS- The authors declare no conflict of interest related to the data presented in the manuscript. 8. DISCLOSURE/CONFLICT OF INTEREST: None EDAT- 2013/12/24 06:00 MHDA- 2014/09/26 06:00 PMCR- 2015/02/28 CRDT- 2013/12/24 06:00 PHST- 2013/08/23 00:00 [received] PHST- 2013/11/17 00:00 [revised] PHST- 2013/12/10 00:00 [accepted] PHST- 2013/12/24 06:00 [entrez] PHST- 2013/12/24 06:00 [pubmed] PHST- 2014/09/26 06:00 [medline] PHST- 2015/02/28 00:00 [pmc-release] AID - S0306-4522(13)01039-7 [pii] AID - 10.1016/j.neuroscience.2013.12.023 [doi] PST - ppublish SO - Neuroscience. 2014 Feb 28;260:106-19. doi: 10.1016/j.neuroscience.2013.12.023. Epub 2013 Dec 17.