Protective actions of ovarian hormones in the serotonin system of macaques.
Protective actions of ovarian hormones in the serotonin system of macaques.
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DOI：
10.1016/j.yfrne.2009.04.003
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发表时间：
2009-07
影响因子：
7.4
通讯作者：
Lima FB
中科院分区：
文献类型：
--
作者：
Bethea CL;Reddy AP;Tokuyama Y;Henderson JA;Lima FB
中缝背核和中缝核的血清素神经元投射到前脑的所有区域，在情绪障碍中发挥关键作用。因此，血清素神经元的任何损失或退化都可能产生深远的影响。在激素替代且无神经损伤的绝经手术猴模型中，E 和 P 降低了中缝背核中促进细胞死亡的 c-jun N 末端激酶 (JNK1) 和犬尿素单加氧酶 (KMO) 的基因表达。同时，E 和 P 增加了超氧化物歧化酶 (SOD1)、VEGF 和 caspase 抑制蛋白的基因表达，从而促进中缝背核的细胞弹性。随后，我们发现卵巢类固醇抑制激光捕获的血清素神经元中 caspase 依赖性和 caspase 非依赖性途径的关键基因，包括凋亡激活因子 (Apaf1)、凋亡诱导因子 (AIF) 和第二种线粒体衍生的 caspase 激活剂 (Smac/Diablo)。 SOD1 在激光捕获的血清素神经元中也明显增加。对中缝背侧块中蛋白质表达的检查显示，JNK1、磷酸化 JNK1、AIF 和 AIF 从线粒体到细胞核的易位随着激素治疗而减少，而 caspase 途径中的关键执行蛋白则没有变化。此外，细胞周期蛋白A、B、D1和E被抑制，这将防止重新进入细胞周期和灾难性死亡。这些数据表明，在中脑没有受到严重损伤的情况下，卵巢类固醇会抑制血清素神经元中的半胱天冬酶独立途径和细胞周期启动。为了确定这些分子作用是否可以防止细胞脆弱性或死亡，我们使用 TUNEL 测定（末端脱氧核苷酸转移酶缺口末端标记）检查了中缝背核中的 DNA 片段化。卵巢类固醇显着减少中缝背侧 TUNEL 阳性细胞的数量。此外，TUNEL 染色与 TPH 免疫染色（血清素神经元的标记物）显着共定位。总之，卵巢类固醇可以增加血清素神经元的细胞弹性，并可能防止绝经后面临数十年寿命的女性血清素神经元死亡。血清素神经元的存活将支持认知和心理健康。
The serotonin neurons of the dorsal and medial raphe nuclei project to all areas of the forebrain and play a key role in mood disorders. Hence, any loss or degeneration of serotonin neurons could have profound ramifications. In a monkey model of surgical menopause with hormone replacement and no neural injury, E and P decreased gene expression in the dorsal raphe nucleus of c-jun n-terminal kinase (JNK1) and kynurenin mono-oxygenase (KMO) that promote cell death. In concert, E and P increased gene expression of superoxide dismutase (SOD1), VEGF, and caspase inhibitory proteins that promote cellular resilience in the dorsal raphe nucleus. Subsequently, we showed that ovarian steroids inhibit pivotal genes in the caspase-dependent and caspase-independent pathways in laser captured serotonin neurons including apoptosis activating factor (Apaf1), apoptosis inducing factor (AIF) and second mitochondria-derived activator of caspases (Smac/Diablo). SOD1 was also increased specifically in laser captured serotonin neurons. Examination of protein expression in the dorsal raphe block revealed that JNK1, phosphoJNK1, AIF and the translocation of AIF from the mitochondria to the nucleus decreased with hormone therapy, whereas pivotal execution proteins in the caspase pathway were unchanged. In addition, cyclins A, B, D1 and E were inhibited, which would prevent re-entry into the cell cycle and catastrophic death. These data indicated that in the absence of gross injury to the midbrain, ovarian steroids inhibit the caspase-independent pathway and cell cycle initiation in serotonin neurons. To determine if these molecular actions prevented cellular vulnerability or death, we examined DNA fragmentation in the dorsal raphe nucleus with the TUNEL assay (terminal deoxynucleotidyl transferase nick end labeling). Ovarian steroids significantly decreased the number of TUNEL positive cells in the dorsal raphe. Moreover, TUNEL staining prominently colocalized with TPH immunostaining, a marker for serotonin neurons. In summary, ovarian steroids increase the cellular resilience of serotonin neurons and may prevent serotonin neuron death in women facing decades of life after menopause. The survival of serotonin neurons would support cognition and mental health.
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影响因子：
3.6
作者：
Cutler, Sarah M.;VanLandingham, Jacob W.;Stein, Donald G.
通讯作者：
Stein, Donald G.
影响因子：
5.1
作者：
Bethea CL;Centeno ML;Cameron JL
通讯作者：
Cameron JL
影响因子：
4.2
作者：
Djebaili, M;Guo, QM;Stein, DG
通讯作者：
Stein, DG
影响因子：
4.7
作者：
Chiarugi, A;Meli, E;Moroni, F
通讯作者：
Moroni, F
DOI：
10.1002/ajmg.b.30084
发表时间：
2005-01-05
影响因子：
2.8
作者：
Adams, JH;Wigg, KG;Barr, CL
通讯作者：
Barr, CL