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Sexual dimorphism in BDNF signaling after neonatal hypoxia-ischemia and treatment with necrostatin-1.

ABSTRACT: 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-?-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 (0.1?l [8?M]) 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, ER?:ER? 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 ER? predominance and its correlation with BDNF levels is still unclear.

SUBMITTER: Chavez-Valdez R

PROVIDER: S-EPMC3950408 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Sexual dimorphism in BDNF signaling after neonatal hypoxia-ischemia and treatment with necrostatin-1.

Chavez-Valdez R R Martin L J LJ Razdan S S Gauda E B EB Northington F J FJ

Neuroscience 20131217

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 1 ...[more]

PMID: 24361177

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Project description:Background and purposeNeonatal encephalopathy caused by hypoxia-ischemia (HI) is a major cause of death and disability in newborns. Clinical and experimental studies suggest a sexual dimorphism in HI-induced brain injury and therapy responses. A major hallmark of HI pathophysiology is the infiltration of peripheral immune cells into the injured brain. However, the specific role of regulatory T cells (Tregs) in neonatal HI is still unknown.MethodsNine-day-old mice were exposed to HI by ligation of the right common carotid artery followed by 1 hour hypoxia (10% oxygen). Using immunohistochemistry, flow cytometry, and microarray analyses, Tregs were investigated in the brain, spleen, and blood 24 hours post HI. The functional role of Tregs was evaluated by acute Treg depletion in depletion of regulatory T cells transgenic mice. Brain injury, neuroinflammatory responses, and vascular injury were analyzed via immunohistochemistry and Western blot 48 hours and 7 days after HI. Functional outcome was assessed 3 days and 5 weeks after HI.ResultsFemale mice revealed an increased cerebral Treg infiltration, coinciding with elevated chemokine receptor expression. Treg depletion in females aggravated HI-induced brain tissue injury, short-term motor deficits, and long-term deficits in exploratory activity, paralleled by an increased microglia and endothelial activation and leukocyte infiltration. Treg depletion in male mice reduced HI-induced brain injury, short-term motor, and long-term cognitive deficits, associated with reduced vascular injury. Ex vivo isolated female Tregs displayed an increased immunosuppressive activity on effector T cell proliferation and an increased gene enrichment in pathways related to enhanced Treg activity.ConclusionsTregs from neonatal female mice provide endogenous neuroprotection, whereas Tregs from male mice increase secondary neurodegeneration. As potential mechanisms, we identified intrinsic transcriptional differences associated with enhanced anti-inflammatory activity of female Tregs. Our study emphasizes the urgent need for sex-stratified clinical and preclinical analyses.

Dataset Information

Sexual dimorphism in BDNF signaling after neonatal hypoxia-ischemia and treatment with necrostatin-1.

Publications

Sexual dimorphism in BDNF signaling after neonatal hypoxia-ischemia and treatment with necrostatin-1.

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