雌激素对老龄和去卵巢大鼠脑及垂体ER、NGF和ChAT表达的影响
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摘要
为了探讨雌激素对脑内ER、NGF和ChAT表达的影响及雌激素的作用形式，运用超敏感的免疫组织化学SP法，以SD大鼠为研究对象，建立老年和去卵巢大鼠模型，通过补充17β－雌二醇对ER、NGF和ChAT在小脑、间脑、端脑及垂体中的表达和分布变化进行研究，探讨雌激素对脑中三种物质的影响及其相互作用机制。另外，还通过在原代培养的神经细胞生长过程中添加17β－雌二醇来研究雌激素对体外培养神经元的生长及神经分泌功能的影响。主要实验结果如下：
1. ER、NGF和ChAT免疫阳性反应物分布于小脑的蒲肯野氏细胞层、小脑齿状核、小脑间位核和小脑室顶核，ER阳性产物主要定位于细胞胞浆、胞膜和突起中，也存在于胞核中，表明ER、NGF和ChAT在小脑中发挥了作用，雌激素在小脑发挥作用可能既通过基因组机制，也通过非基因组机制途径。老年大鼠和去卵巢大鼠小脑皮质及小脑核中ER、NGF和ChAT的表达强度及阳性细胞数量总趋势是显著降低，而补充17β－雌二醇后三种阳性产物的强度和阳性细胞数目显著回升，蒲肯野氏细胞的阳性突起长度和数量也呈此变化趋势，表明雌激素可促进NGF和ChAT的表达，在维持和保护小脑神经元的结构和功能中发挥了重要作用；另外ER、NGF和ChAT表达变化的相似性提示三者在雌激素对小脑的作用中是相互调节和影响的。
2. ER、NGF和ChAT广泛分布于间脑中，主要分布于缰核、外侧膝状体核、丘脑内侧核、外侧核、丘脑室旁核、带旁核、菱形核、下丘脑室周灰质、室周核、下丘脑腹内侧核、下丘脑前区外侧部和下丘脑后区。另外，还观察到在下丘脑前区和后区有阳性细胞成簇状密集分布的现象。ER阳性产物在细胞中呈多种形式分布，定位于胞浆、胞膜、胞核及突起中，NGF和ChAT主要定位于胞浆和突起中，表明雌激素、NGF和ChAT在间脑中发挥了作用，雌激素对间脑的作用途径是复杂的，有基因组形式，也有非基因组形式。老年大鼠和去卵巢大鼠间脑内ER、NGF和ChAT的表达强度和阳性细胞数目总趋势是显著降低，而补充外源性雌激素可以阻止其下降，表明雌激素可通过ER促进间脑中NGF和ChAT的表达，雌激素对间脑中神经元结构和功能维持是必须的，而且雌激素对间脑神经元的作用与NGF和ChAT的表达是协同和一致的。
3. ER、NGF和ChAT在大脑皮质扣带回、顶叶、额叶、梨状皮质和皮质杏仁核，海马齿状回、下托、CA2和CA3区，隔－斜角带区内侧隔核、外侧隔核、斜角带垂直部等均有分布，另外，ER阳性产物在细胞上定位于胞浆、胞核、胞膜和突起中，表明雌激素、NGF和ChAT在端脑中发挥了作用，雌激素可能既通过基因组形式，也通过非基因组形式作用于端脑。老年大鼠和去卵巢大鼠端脑大部分区域内ER、NGF和ChAT的
表达活性及阳性细胞数目均显著下降，而补充17β－雌二醇后得到回升，并基本恢复到正常水平，表明雌激素通过ER对端脑内NGF和ChAT的表达有促进作用，这种作用可能部分地与雌激素对NGF的上调而作用于胆碱能神经元有关，也可能是雌激素通过ER直接调控了ChAT的表达，增强神经信息的传递。
4. 垂体中广泛分布着ER、NGF和ChAT三种免疫阳性产物，即分布于垂体前叶、中间叶和后叶。细胞定位形式为ER主要分布于细胞浆和细胞膜，有少部分位于细胞核；NGF主要位于细胞浆和细胞膜；ChAT免疫阳性纤维终末包绕于腺细胞周围。揭示ER、NGF和ChAT参与了垂体生理功能发挥的过程。老龄化大鼠和去卵巢大鼠垂体中ER、NGF和ChAT免疫阳性细胞数目和表达强度均显著下降，而补充17β－雌二醇后其数目和强度均恢复到正常水平，且三者分布和强度的变化趋势一致，表明雌激素在垂体结构和功能维持上发挥了重要作用，通过ER促进NGF和ChAT表达而共同调节垂体的生殖内分泌活动。
5. 雌激素对体外培养神经元的生长、发育影响显著，可促进胞体生长、突起伸长，但对发出的突起数量影响不大。另外，可延长培养神经元的存活时间，阻止神经元退化、萎缩和死亡。雌激素对体外培养神经元的神经分泌功能影响显著，可显著提高ER、NGF和ChAT阳性神经元的数量并呈现出培养时间依赖性的变化。另外，雌激素还可促进培养神经元ER、NGF和ChAT的表达，也随着培养时间而呈现变化。总的来说，雌激素通过ER可直接或间接的作用于培养神经元，发挥神经营养和调控神经信息传递的作用。
The effects of estrogen on the expression of ER, NGF and ChAT in rats brain was studied by using technique of immunohistochemical ultrasensitive SP in Sprague-Dawley rat. The model of aging and ovariectomized female rat were established to study the expression and distribution of ER, NGF and ChAT in the cerebellum, diencephalons, telencephalon and pituitary after 17β-estradiol treatment, and the mechanism of its effects were discussed. In addition, the modulation of 17β-estradiol on growth and neuroendocrine in primary cultural neurons in vitro were researched. The main results as follows:
1. The immunoreactive productions were distributed in stratum Purkinje cell, nucleus golbosus, nucleus interpositus and nucleus fastigii of cerebellum, and the ER positive production mainly located in plasma, cytoplasmic membrane and neurite, also exited in nucleus. It showed that ER, NGF and ChAT played a key role in cerebellum, and the action of estrogen in cerebellum could via genomic and nongenomic mechanism. The general tendency of the expression of ER, NGF and ChAT positive production in cerebellum cortex and nuclei of the aging and ovariectomized rat is significantly decreased, while the intensity and quantity of the immunoreactive production ascended predominantly after 17β-estradiol treatment, simultaneously, the positive neurite of Purkinje cell showed the same tendency. The above results suggested that the estrogen upregulated the expression of NGF and ChAT, and played a vital role in sustaining and protecting the structure and function of cerebellum neurons. Furthermore, the similarity of their changing tendency implied that they were correlated and cooperated during the course of effect of estrogen on cerebellum.
2. ER, NGF and ChAT immunoreactive productions were widely presented in diencephalons, mainly in nucleus habenula, nucleus corpus geniculatum lateral, nucleus medialis thalami, nucleus lateral thalami, nucleus paraventricularis, nucleus paratenialis, nucleus rhomboidens, grisea periventricularis hypothalami, nucleus periventricularis hypothalami, nucleus paraventricularis hypoythalami, nucleus ventromedialis hypothalami, anterior region and posterior region hypothalami. ER immunoreactive production existed in several formation, located in plasma, cytoplasmic membrane, nucleus and neurite, while the positive production of NGF and ChAT mainly existed in plasma and neurite, which suggested that ER, NGF and ChAT played a critical role in diencephalons, and the action of estrogen was complicated and via both genomic and non- genomic mechanism. The ER, NGF and ChAT immunoreactive production in diencephalons rat is significantly reduced in aging and ovariectomized rat, and treating with estrogen could greatly improve the immunoreactive intensity and positive cell number. The results illustrated that estrogen could upregulate the expression of NGF and ChAT by conjunction with ER. Estrogen is essential in sustaining the structure and function of neurons of diencephalons. Moreover, the effects of estrogen in diencephalons are correlated with NGF and ChAT.
3. The positive production of ER, NGF and ChAT were detected in cirguli cortex, parieta lobe, frontal lobe, piriformis cortex and nucleus amydgaloideus corticalis, hippocampus gyrus fasciolaris, subiculum, CA2 and CA3, and mainly presented in nucleus medial septal, nucleus lateral septal and nucleus of diagonal band vertical division in septal-diagonal band area. In addition, the ER immunoreactive production located in plasma, nucleus, cytomembrane and neurite. The above results suggested that ER, NGF and ChAT played a key role in telencephalon, and the mechanism of its effect could be via genomic and /or nongenomic way. In the mostly part of telencephalon, the intensity and number of ER, NGF and ChAT positive production were significantly decreased in both aging and ovariectomized rat, which could be inhibited by treating with 17β-estradiol, even back to the normal level, which suggested that estrogen could upregulate NGF and ChAT, which could be partly re
1. ER、NGF和ChAT免疫阳性反应物分布于小脑的蒲肯野氏细胞层、小脑齿状核、小脑间位核和小脑室顶核，ER阳性产物主要定位于细胞胞浆、胞膜和突起中，也存在于胞核中，表明ER、NGF和ChAT在小脑中发挥了作用，雌激素在小脑发挥作用可能既通过基因组机制，也通过非基因组机制途径。老年大鼠和去卵巢大鼠小脑皮质及小脑核中ER、NGF和ChAT的表达强度及阳性细胞数量总趋势是显著降低，而补充17β－雌二醇后三种阳性产物的强度和阳性细胞数目显著回升，蒲肯野氏细胞的阳性突起长度和数量也呈此变化趋势，表明雌激素可促进NGF和ChAT的表达，在维持和保护小脑神经元的结构和功能中发挥了重要作用；另外ER、NGF和ChAT表达变化的相似性提示三者在雌激素对小脑的作用中是相互调节和影响的。
2. ER、NGF和ChAT广泛分布于间脑中，主要分布于缰核、外侧膝状体核、丘脑内侧核、外侧核、丘脑室旁核、带旁核、菱形核、下丘脑室周灰质、室周核、下丘脑腹内侧核、下丘脑前区外侧部和下丘脑后区。另外，还观察到在下丘脑前区和后区有阳性细胞成簇状密集分布的现象。ER阳性产物在细胞中呈多种形式分布，定位于胞浆、胞膜、胞核及突起中，NGF和ChAT主要定位于胞浆和突起中，表明雌激素、NGF和ChAT在间脑中发挥了作用，雌激素对间脑的作用途径是复杂的，有基因组形式，也有非基因组形式。老年大鼠和去卵巢大鼠间脑内ER、NGF和ChAT的表达强度和阳性细胞数目总趋势是显著降低，而补充外源性雌激素可以阻止其下降，表明雌激素可通过ER促进间脑中NGF和ChAT的表达，雌激素对间脑中神经元结构和功能维持是必须的，而且雌激素对间脑神经元的作用与NGF和ChAT的表达是协同和一致的。
3. ER、NGF和ChAT在大脑皮质扣带回、顶叶、额叶、梨状皮质和皮质杏仁核，海马齿状回、下托、CA2和CA3区，隔－斜角带区内侧隔核、外侧隔核、斜角带垂直部等均有分布，另外，ER阳性产物在细胞上定位于胞浆、胞核、胞膜和突起中，表明雌激素、NGF和ChAT在端脑中发挥了作用，雌激素可能既通过基因组形式，也通过非基因组形式作用于端脑。老年大鼠和去卵巢大鼠端脑大部分区域内ER、NGF和ChAT的
表达活性及阳性细胞数目均显著下降，而补充17β－雌二醇后得到回升，并基本恢复到正常水平，表明雌激素通过ER对端脑内NGF和ChAT的表达有促进作用，这种作用可能部分地与雌激素对NGF的上调而作用于胆碱能神经元有关，也可能是雌激素通过ER直接调控了ChAT的表达，增强神经信息的传递。
4. 垂体中广泛分布着ER、NGF和ChAT三种免疫阳性产物，即分布于垂体前叶、中间叶和后叶。细胞定位形式为ER主要分布于细胞浆和细胞膜，有少部分位于细胞核；NGF主要位于细胞浆和细胞膜；ChAT免疫阳性纤维终末包绕于腺细胞周围。揭示ER、NGF和ChAT参与了垂体生理功能发挥的过程。老龄化大鼠和去卵巢大鼠垂体中ER、NGF和ChAT免疫阳性细胞数目和表达强度均显著下降，而补充17β－雌二醇后其数目和强度均恢复到正常水平，且三者分布和强度的变化趋势一致，表明雌激素在垂体结构和功能维持上发挥了重要作用，通过ER促进NGF和ChAT表达而共同调节垂体的生殖内分泌活动。
5. 雌激素对体外培养神经元的生长、发育影响显著，可促进胞体生长、突起伸长，但对发出的突起数量影响不大。另外，可延长培养神经元的存活时间，阻止神经元退化、萎缩和死亡。雌激素对体外培养神经元的神经分泌功能影响显著，可显著提高ER、NGF和ChAT阳性神经元的数量并呈现出培养时间依赖性的变化。另外，雌激素还可促进培养神经元ER、NGF和ChAT的表达，也随着培养时间而呈现变化。总的来说，雌激素通过ER可直接或间接的作用于培养神经元，发挥神经营养和调控神经信息传递的作用。
The effects of estrogen on the expression of ER, NGF and ChAT in rats brain was studied by using technique of immunohistochemical ultrasensitive SP in Sprague-Dawley rat. The model of aging and ovariectomized female rat were established to study the expression and distribution of ER, NGF and ChAT in the cerebellum, diencephalons, telencephalon and pituitary after 17β-estradiol treatment, and the mechanism of its effects were discussed. In addition, the modulation of 17β-estradiol on growth and neuroendocrine in primary cultural neurons in vitro were researched. The main results as follows:
1. The immunoreactive productions were distributed in stratum Purkinje cell, nucleus golbosus, nucleus interpositus and nucleus fastigii of cerebellum, and the ER positive production mainly located in plasma, cytoplasmic membrane and neurite, also exited in nucleus. It showed that ER, NGF and ChAT played a key role in cerebellum, and the action of estrogen in cerebellum could via genomic and nongenomic mechanism. The general tendency of the expression of ER, NGF and ChAT positive production in cerebellum cortex and nuclei of the aging and ovariectomized rat is significantly decreased, while the intensity and quantity of the immunoreactive production ascended predominantly after 17β-estradiol treatment, simultaneously, the positive neurite of Purkinje cell showed the same tendency. The above results suggested that the estrogen upregulated the expression of NGF and ChAT, and played a vital role in sustaining and protecting the structure and function of cerebellum neurons. Furthermore, the similarity of their changing tendency implied that they were correlated and cooperated during the course of effect of estrogen on cerebellum.
2. ER, NGF and ChAT immunoreactive productions were widely presented in diencephalons, mainly in nucleus habenula, nucleus corpus geniculatum lateral, nucleus medialis thalami, nucleus lateral thalami, nucleus paraventricularis, nucleus paratenialis, nucleus rhomboidens, grisea periventricularis hypothalami, nucleus periventricularis hypothalami, nucleus paraventricularis hypoythalami, nucleus ventromedialis hypothalami, anterior region and posterior region hypothalami. ER immunoreactive production existed in several formation, located in plasma, cytoplasmic membrane, nucleus and neurite, while the positive production of NGF and ChAT mainly existed in plasma and neurite, which suggested that ER, NGF and ChAT played a critical role in diencephalons, and the action of estrogen was complicated and via both genomic and non- genomic mechanism. The ER, NGF and ChAT immunoreactive production in diencephalons rat is significantly reduced in aging and ovariectomized rat, and treating with estrogen could greatly improve the immunoreactive intensity and positive cell number. The results illustrated that estrogen could upregulate the expression of NGF and ChAT by conjunction with ER. Estrogen is essential in sustaining the structure and function of neurons of diencephalons. Moreover, the effects of estrogen in diencephalons are correlated with NGF and ChAT.
3. The positive production of ER, NGF and ChAT were detected in cirguli cortex, parieta lobe, frontal lobe, piriformis cortex and nucleus amydgaloideus corticalis, hippocampus gyrus fasciolaris, subiculum, CA2 and CA3, and mainly presented in nucleus medial septal, nucleus lateral septal and nucleus of diagonal band vertical division in septal-diagonal band area. In addition, the ER immunoreactive production located in plasma, nucleus, cytomembrane and neurite. The above results suggested that ER, NGF and ChAT played a key role in telencephalon, and the mechanism of its effect could be via genomic and /or nongenomic way. In the mostly part of telencephalon, the intensity and number of ER, NGF and ChAT positive production were significantly decreased in both aging and ovariectomized rat, which could be inhibited by treating with 17β-estradiol, even back to the normal level, which suggested that estrogen could upregulate NGF and ChAT, which could be partly re
引文
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