N-myc Downstream-Regulated Gene 2 (Ndrg2): A Critical Mediator of Estrogen-Induced Neuroprotection Against Cerebral Ischemic Injury
N-myc Downstream-Regulated Gene 2 (Ndrg2): A Critical Mediator of Estrogen-Induced Neuroprotection Against Cerebral Ischemic Injury
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DOI：
10.1007/s12035-022-02877-5
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发表时间：
2021-12
影响因子：
5.1
通讯作者：
Jin Wang;Min Liu;Wugang Hou;M. Hou;Lixia Zhang;Miao Sun;Siyuan Liu;Huikai Yang;Han Guo
中科院分区：
文献类型：
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作者：
Jin Wang;Min Liu;Wugang Hou;M. Hou;Lixia Zhang;Miao Sun;Siyuan Liu;Huikai Yang;Han Guo
越来越多的证据表明，雌激素在抗脑缺血的神经保护中起着关键作用，但这种保护的分子机制仍不清楚。N-myc下游调节基因2(Ndrg2)是一种雌激素靶向基因，已被证明对雄性小鼠脑缺血具有神经保护作用。然而，Ndrg2在雌激素的神经保护作用中的作用仍不清楚。在这项研究中，我们首先用蛋白质印迹分析检测了雌性和雄性小鼠大脑皮质和纹状体中NDRG2的表达水平。然后，我们通过建立Ndrg2基因敲除或条件性基因敲除雌性小鼠大脑中动脉阻塞再灌注(MCAO-R)模型来检测脑缺血损伤。我们进一步在去卵巢Ndrg2基因敲除或条件性基因敲除的雌性小鼠中实施雌激素、ERα或ERβ激动剂的替代，然后检测NDR2的表达、胶质纤维酸性蛋白的表达以及脑缺血损伤的程度。我们发现NDRG2在雌性小鼠的皮质和纹状体中的表达显著高于雄性小鼠。Ndrg2基因敲除和条件性敲除显示显著加重雌性小鼠的脑缺血损伤。雌激素和雌激素受体β替代治疗导致去卵巢小鼠皮质和纹状体NDRG2表达上调。雌激素和DPN还导致去卵巢小鼠GFAP表达上调。然而，雌激素和DPN在Ndrg2基因敲除OVX小鼠和原代培养的星形胶质细胞中失去了激活星形胶质细胞的作用，但在条件基因敲除OVX小鼠中保留了部分作用。最重要的是，我们发现E2和DPN对脑缺血损伤的神经保护作用在Ndrg2基因敲除OVX小鼠中消失，但在条件性基因敲除OVX小鼠中部分保留。这些结果表明雌激素通过ERβ上调Ndrg2的表达从而激活星形胶质细胞来减轻脑缺血损伤，提示Ndrg2是E2诱导的脑缺血损伤神经保护的关键介质。
Growing evidence indicates that estrogen plays a pivotal role in neuroprotection against cerebral ischemia, but the molecular mechanism of this protection is still elusive. N‐myc downstream‐regulated gene 2 (Ndrg2), an estrogen-targeted gene, has been shown to exert neuroprotective effects against cerebral ischemia in male mice. However, the role ofNdrg2in the neuroprotective effect of estrogen remains unknown. In this study, we first detected NDRG2 expression levels in the cortex and striatum in both female and male mice with western blot analyses. We then detected cerebral ischemic injury by constructing middle cerebral artery occlusion and reperfusion (MCAO-R) models inNdrg2knockout or conditional knockdown female mice. We further implemented estrogen, ERα, or ERβ agonist replacement in the ovariectomized (OVX)Ndrg2knockout or conditional knockdown female mice, then tested for NDRG2 expression, glial fibrillary acidic protein (GFAP) expression, and extent of cerebral ischemic injury. We found that NDRG2 expression was significantly higher in female than in male mice in both the cortex and striatum.Ndrg2knockouts and conditional knockdowns showed significantly aggravated cerebral ischemic injury in female mice. Estrogen and ERβ replacement treatment (DPN) led to NDRG2 upregulation in both the cortex and striatum of OVX mice. Estrogen and DPN also led to GFAP upregulation in OVX mice. However, the effect of estrogen and DPN in activating astrocytes was lost inNdrg2knockout OVX mice and primary cultured astrocytes, but partially retained in conditional knockdown OVX mice. Most importantly, we found that the neuroprotective effects of E2 and DPN against cerebral ischemic injury were lost inNdrg2knockout OVX mice but partially retained in conditional knockdown OVX mice. These findings demonstrate that estrogen alleviated cerebral ischemic injury via ERβ upregulation ofNdrg2, which could activate astrocytes, indicating thatNdrg2is a critical mediator of E2-induced neuroprotection against cerebral ischemic injury.