Sex differences in a transgenic rat model of Huntington's disease:: decreased 17β-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males
Sex differences in a transgenic rat model of Huntington's disease:: decreased 17β-estradiol levels correlate with reduced numbers of DARPP32+ neurons in males
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DOI：
10.1093/hmg/ddn159
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发表时间：
2008-09-01
影响因子：
3.5
通讯作者：
von Hoersten, Stephan
中科院分区：
文献类型：
--
作者：
Bode, Felix J.;Stephan, Michael;von Hoersten, Stephan
最近的临床研究强调，女性性激素是潜在的神经保护介质，可以防止急性和慢性脑部疾病造成的损害。这一证据已被实验研究证实，这些研究记录了女性性激素在体外和体内的保护作用，尽管这些研究并没有特别关注亨廷顿病（HD）。因此，我们研究了不同年龄的雌性和雄性转基因（tg）HD（CAG（n51））和对照大鼠中HD的发病和病程，并重点关注三个方面：（i）行为和生理改变（能量消耗、居家活动、情绪障碍和运动功能障碍），（ii）形态学标记（纹状体DARPP 32（+）中型多棘神经元（MSN）和多巴胺受体放射自显影的数量和特征）和（iii）外周性激素水平以及纹状体雌激素受体表达。与性别无关，tgHD大鼠表现出食物摄入水平增加、笼内活动评分升高和抗焦虑样行为，而仅雄性大鼠表现出运动功能受损。与后一发现一致，DARPP 32（+）MSN的丢失和萎缩仅在雄性tgHD大鼠中明显。这一结果与14个月龄时纹状体多巴胺D1受体密度降低和17 β-雌二醇血浆水平降低有关。由于DARPP 32（+）MSN同时表达α和β-雌激素受体，并显示细胞数量与17 β-雌二醇水平之间的相关性，我们的研究结果表明HD表型中存在性别相关差异，这表明性激素具有显著的神经保护作用，并为HD治疗开辟了新的视角。
Recent clinical studies have highlighted that female sex hormones represent potential neuroprotective mediators against damage caused by acute and chronic brain diseases. This evidence has been confirmed by experimental studies documenting the protective role of female sex hormones both in vitro and in vivo, although these studies did not specifically focus on Huntington's disease (HD). We therefore investigated the onset and course of HD in female and male transgenic (tg) HD (CAG(n51)) and control rats across age and focused on three aspects: (i) behavioral and physiological alterations (energy expenditure, home-cage activity, emotional disturbance and motor dysfunction), (ii) morphological markers (numbers and characteristics of striatal DARPP32(+) medium-sized spiny neurons (MSNs) and dopamine receptor autoradiography) and (iii) peripheral sex hormone levels as well as striatal estrogen receptor expression. Independent of their sex, tgHD rats exhibited increased levels of food intake, elevated home-cage activity scores and anxiolytic-like behavior, whereas only males showed an impairment of motor function. In line with the latter finding, loss and atrophy of DARPP32(+) MSNs were apparent only in male tgHD rats. This result was associated with a decreased striatal dopamine D1 receptor density and lower plasma levels of 17 beta-estradiol at the age of 14 months. As DARPP32(+) MSNs expressed both alpha-and beta-estrogen receptors and showed a correlation between cell numbers and 17 beta-estradiol levels, our findings suggest sex-related differences in the HD phenotype pointing to a substantial neuroprotective effect of sex hormones and opening new perspectives on the therapy of HD.