ERα Signaling Is Required for TrkB-Mediated Hippocampal Neuroprotection in Female Neonatal Mice after Hypoxic Ischemic Encephalopathy
ERα Signaling Is Required for TrkB-Mediated Hippocampal Neuroprotection in Female Neonatal Mice after Hypoxic Ischemic Encephalopathy
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DOI：
10.1523/eneuro.0025-15.2015
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发表时间：
2016-01-01
期刊：
影响因子：
3.4
通讯作者：
Cengiz, Pelin
中科院分区：
文献类型：
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作者：
Cikla, Ulas;Chanana, Vishal;Cengiz, Pelin
男性新生儿的大脑更容易受到围产期窒息的影响，导致缺氧和缺血(HI)相关的脑损伤。女性新生儿大脑对HI不良后果的相对抵抗力表明，存在性别特有的机制，为女性提供更大的神经保护和/或促进HI后的恢复。我们推测，缺氧缺血优先诱导雌性新生大鼠海马区雌激素受体α(ERα)的表达，ERα与Src家族激酶(SFK)的激活偶联，进而增加TrkB的磷酸化，从而导致细胞凋亡减少。在P9(C57BL/6J)小鼠上建立Vannucci‘s HI模型后，雌雄ERα野生型(ERα(+/+))或ERα缺失突变(ERα(-/-))小鼠接受空白对照或选择性TrkB激动剂7，8-二羟基黄酮组(7，8-DHF)。观察缺氧缺血后大鼠海马区ERα、BDNFmRNA、ERα、p-TrkB、p-src、c-caspase-3蛋白表达的变化。我们的结果表明：(1)低氧诱导雌性与雄性新生小鼠海马区ERα的表达存在差异；(2)7，8-DHF治疗后，雌性新生小鼠海马区src和TrkB的磷酸化程度高于雄性；(3)缺氧缺血后src和TrkB的磷酸化程度取决于ERα的存在；(4)TrkB激动剂治疗仅降低雌性ERα(+/+)小鼠海马区c-caspase-3的表达。总之，这些观察结果提供了证据，表明女性特异性诱导ERα表达通过激活SFK而获得TrkB激动剂治疗的神经保护，并解释了HI后女性新生儿功能结局的改善。
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 alpha (ER alpha) expression in female neonatal hippocampi and that ER alpha 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 ER alpha wild-type (ER alpha(+/+)) or ER alpha null mutant (ER alpha(-/-)) mice received vehicle control or the selective TrkB agonist 7,8-dihydroxyflavone (7,8-DHF). Hippocampi were collected for analysis of mRNA of ER alpha and BDNF, protein levels of ER alpha, p-TrkB, p-src, and cleaved caspase 3 (c-caspase-3) post-HI. Our results demonstrate that: (1) HI differentially induces ER alpha 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 ER alpha, and (4) TrkB agonist therapy decreases the c-caspase-3 only in ER alpha(+/+) female mice hippocampus. Together, these observations provide evidence that female-specific induction of ER alpha expression confers neuroprotection with TrkB agonist therapy via SFK activation and account for improved functional outcomes in female neonates post-HI.