Endocrinology and Genomics Research Axis of the CHUQ, CHUL, Quebec City, Quebec, Canada.
J Neuroendocrinol. 2012 Nov;24(11):1375-85. doi: 10.1111/j.1365-2826.2012.02349.x.
Parkinson's disease (PD) is characterised by the loss of nigrostriatal dopamine (DA) neurones and glutamate overactivity. There is substantial evidence to suggest that oestrogens prevent or delay the disease. 17β-oestradiol has neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and modulates brain NMDA receptors. In MPTP-lesioned mice, oestrogen receptor (ER)α and ERβ are important in 17β-oestradiol-induced neuroprotection. To evaluate the role of ERs in the response of NMDA receptors to lesion, we compared wild-type (WT) with ER knockout (KO) C57Bl/6 male mice that received 7, 9 or 11 mg/kg of MPTP. These mice were also treated with MPTP (9 mg/kg) and 17β-oestradiol. [(3) H]Ro 25-6981 specific binding autoradiography was used to label NMDA receptors containing NR2B subunits. In the frontal and cingulate cortex and striatum, vehicle-treated WT mice had higher [(3) H]Ro 25-6981 specific binding compared to ERKO mice. Cortical [(3) H]Ro 25-6981 specific binding decreased with increasing doses of MPTP in WT and ERKOα but not ERKOβ mice, whereas a dose-related decrease was only observed in the striatum of WT mice remaining low in ERKOα and ERKOβ mice. No effect of 17β-oestradiol treatment in intact or MPTP-lesioned mice of all three genotypes was observed in the cortex, whereas it increased striatal specific binding of intact ERKOβ and MPTP-lesioned WT mice. Striatal [(3) H]Ro 25-6981 specific binding positively correlated with striatal DA concentrations only in WT mice. MPTP and 17β-oestradiol treatments had more limited effects in the hippocampus. Only in the CA3 and dentate gyrus did vehicle and 17β-oestradiol-treated ERKOα mice have higher [(3) H]Ro 25-6981 specific binding than WT and ERKOβ mice, whereas MPTP decreased this specific binding only in the CA1, CA2 and CA3 of ERKOα mice. Hence, brain NMDA receptors were affected by the deletion of ERs, which affect the response to MPTP and 17β-oestradiol treatments with brain region specificity.
帕金森病（PD）的特征是黑质纹状体多巴胺（DA）神经元的丧失和谷氨酸过度活跃。有大量证据表明，雌激素可以预防或延迟这种疾病。17β-雌二醇在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的 PD 小鼠模型中具有神经保护作用，并调节脑 NMDA 受体。在 MPTP 损伤的小鼠中，雌激素受体（ER）α和 ERβ在 17β-雌二醇诱导的神经保护中很重要。为了评估 ERs 在 NMDA 受体对损伤反应中的作用，我们比较了接受 7、9 或 11mg/kg MPTP 的野生型（WT）和 ER 敲除（KO）C57Bl/6 雄性小鼠。这些小鼠还接受了 MPTP（9mg/kg）和 17β-雌二醇治疗。[3H]Ro 25-6981 特异性结合放射自显影用于标记含有 NR2B 亚基的 NMDA 受体。在额皮质、扣带皮质和纹状体中，与 ERKO 小鼠相比，载体处理的 WT 小鼠具有更高的[3H]Ro 25-6981 特异性结合。在 WT 和 ERKOα 小鼠中，随着 MPTP 剂量的增加，皮质[3H]Ro 25-6981 特异性结合减少，但在 ERKOβ 小鼠中没有观察到这种情况，而在 WT 小鼠的纹状体中仅观察到剂量相关的减少，而在 ERKOα 和 ERKOβ 小鼠中仍然较低。在所有三种基因型的完整或 MPTP 损伤的小鼠中，未观察到 17β-雌二醇治疗的影响，但它增加了完整的 ERKOβ 和 MPTP 损伤 WT 小鼠的纹状体特异性结合。纹状体[3H]Ro 25-6981 特异性结合仅与 WT 小鼠的纹状体 DA 浓度呈正相关。MPTP 和 17β-雌二醇处理在海马体中仅有更有限的影响。只有在 CA3 和齿状回中，与 WT 和 ERKOβ 小鼠相比，载体和 17β-雌二醇处理的 ERKOα 小鼠具有更高的[3H]Ro 25-6981 特异性结合，而 MPTP 仅降低了 ERKOα 小鼠 CA1、CA2 和 CA3 中的这种特异性结合。因此，大脑 NMDA 受体受到 ER 缺失的影响，这影响了对 MPTP 和 17β-雌二醇治疗的反应，具有脑区特异性。
