ARYL HYDROCARBON RECEPTOR-MEDIATED APOPTOSIS OF NEURONAL CELLS: A POSSIBLE INTERACTION WITH ESTROGEN RECEPTOR SIGNALING
ARYL HYDROCARBON RECEPTOR-MEDIATED APOPTOSIS OF NEURONAL CELLS: A POSSIBLE INTERACTION WITH ESTROGEN RECEPTOR SIGNALING
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DOI：
10.1016/j.neuroscience.2008.10.045
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发表时间：
2009-01-23
期刊：
影响因子：
3.3
通讯作者：
Lason, W.
中科院分区：
文献类型：
--
作者：
Kajta, M.;Wojtowicz, A. K.;Lason, W.
芳香烃受体（AhR）的激活诱导神经元损伤，但其发生的机制在很大程度上是未知的。本研究评估了AhR激动剂β-萘酮对小鼠原代神经元细胞培养物中凋亡途径的影响。β-萘酚酮（0.1-100 μ M）增强了新皮层和海马细胞中的半胱天冬酶-3活性和乳酸脱氢酶（LDH）释放。Hoechst 33342和钙黄绿素AM染色在细胞水平支持这些数据。α-萘酚酮抑制β-萘酚酮的作用，从而证实了AhR的特异性活化。高亲和力雌激素受体（ER）拮抗剂ICI 182，780和选择性雌激素受体调节剂（SERM）他莫昔芬可增强β-萘啶酮介导的细胞凋亡。另一种SERM，雷洛昔芬，和ER α拮抗剂，甲基-哌啶基-吡唑，不影响β-萘醌诱导的caspase-3活性。然而，他们抑制β-萘醌诱导的LDH释放在治疗的最后一个小时，从而表明延迟控制AhR介导的神经元细胞死亡。β-萘酚酮的凋亡作用伴随着AhR水平的增加，这些受体与ER β共定位，如共聚焦显微镜所示。这些数据强烈支持AhR激活在新皮层和海马组织中的凋亡效应。此外，这项研究提供了证据，AhR介导的凋亡途径与雌激素受体信号传导的直接相互作用，这为治疗或预防AhR介导的神经毒性提供了新的策略。(c)2009年IBRO。由爱思唯尔有限公司出版。保留所有权利。
Activation of aryl hydrocarbon receptors (AhRs) induces neuronal damage, but the mechanism by which this occurs is largely unknown. This study evaluated the effects of an AhR agonist, beta-naphthoflavone, on apoptotic pathways in mouse primary neuronal cell cultures. beta-Naphthoflavone (0.1-100 mu M) enhanced caspase-3 activity and lactate dehydrogenase (LDH) release in neocortical and hippocampal cells. These data were supported at the cellular level with Hoechst 33342 and calcein AM staining. a-Naphthoflavone inhibited the action of beta-naphthoflavone, thus confirming specific activation of AhRs. A high-affinity estrogen receptor (ER) antagonist, ICI 182,780, and a selective estrogen receptor modulator (SERM), tamoxifen, enhanced P-naphthoflavone-mediated apoptosis. Another SERM, raloxifene, and an ER alpha antagonist, methyl-piperidino-pyrazole, did not affect beta-naphthoflavone-induced caspase-3 activity. However, they inhibited beta-naphthoflavone-induced LDH release at a late hour of treatment, thus suggesting delayed control of AhR-mediated neuronal cell death. The apoptotic effects of beta-naphthoflavone were accompanied by increased levels of AhRs, and these receptors colocalized with ER beta as demonstrated by confocal microscopy. These data strongly support apoptotic effects of AhR activation in neocortical and hippocampal tissues. Moreover, this study provides evidence for direct interaction of the AhR-mediated apoptotic pathway with estrogen receptor signaling, which provides insight into new strategies to treat or prevent AhR-mediated neurotoxicity. (c) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.