雌激素的非基因组途径在哺乳动物雌性生殖过程中的作用机制

雌激素的非基因组调节模式在雌性生殖系统中广泛存在．雌激素通过基因组、非基因组及两种调节模式的整合在不同组织中行使多种生理功能．卵巢中雌激素能通过非基因组效应对卵细胞起到保护作用．子宫中雌激素对多种基因的表达都是通过非基因组模式．对雌激素非基因组效应的研究将有利于进一步了解雌激素的作用机制．     

糖皮质激素的非基因组作用

糖皮质激素是由肾上腺皮质分泌的类固醇激素,是调节物质代谢和应激反应的重要激素,同时具有强大的抗炎和免疫抑制的特性。糖皮质激素除通过基因组机制起作用外,还通过非基因组机制影响激素的分泌、神经元兴奋性、行为、细胞形态、糖代谢等各种生命活动。     

雌激素对MAPK信号转导通路的作用机制

雌激素可以通过基因组作用和非基因组作用对细胞功能起调节作用。本文主要综述了其非基因组作用,即通过膜受体激活细胞内MAPK(ERK、p38、JNK)信号传导通路的过程。雌激素对ERK主要起促进作用,引起细胞增殖、分化以及血管扩张等生物学效应;对p38也起促进作用,而在不同的细胞中对JNK的作用不同,进而调节细胞凋亡、癌症发生等生命现象。     

脑星形胶质细胞生物学功能研究进展

脑星形胶质细胞是中枢神经系统（CNS）内在数目占绝对优势的一类大胶质细胞,被认为在神经元的整个发育过程中起重要作用。本文主要就参与星形胶质细胞调节神经元活动的主要功能分子,星形胶质细胞在中枢神经系统的生物学功能,及其与疾病的关系作一简要回顾。     

雌激素的神经保护作用

雌激素是一种性激素 ,它的主要生理作用是促进女性生殖器官的发育与成熟 ,刺激女性副性征出现 ,并影响代谢功能。然而 ,雌激素的作用并不仅局限于此 ,它在大脑的正常发育、分化中也起着重要作用。目前发现 ,雌激素除了能通过调节下丘脑ＧｎＲＨ神经元的活动影响生殖外 ,对大脑其它神经元还有着电生理、神经营养和代谢等多方面作用 ,而其中备受关注的是它对中枢神经元的保护作用。临床证实 ,雌激素替代治疗 (ＥＲＴ)可以明显改善绝经后妇女的认知功能 ,对于老年性痴呆病 (Ａｌｚｈｅｉｍｅｒ’ｓｄｉｓｅａｓｅ ,ＡＤ)、缺血性脑损伤以及神经…     

5-脂氧合酶在中枢神经系统的作用

5－脂氧合酶（5LO）是机体催化花生四烯酸生成生物活性分子白三烯的关键酶,中枢神经系统神经元有5LO的显著表达,海马和小脑表达水平最高。5LO在体外神经元发育、老化及多种脑损伤过程中表达增高。5LO可能通过酶和非酶功能在中枢神经系统的生理和病理机制中发挥作用。糖皮质激素、褪黑素等参与5LO的转录调节。     

雌激素对多巴胺能神经元功能调节作用的研究进展

帕金森病（Parkinson‘s disease,PD)是中枢神经系统多巴胺（Dopamine,DA) 能神经元退行性疾病,其发病率具有明显的性别差异。性腺类固醇激素,尤其是雌激素,可在垂体、下丘脑、中脑边缘系统和黑质－纹状体（nigrostriatal,NS)系统等水平影响DA能神经递质系统的功能。而且,雌激素的使用剂量和时间的不同,可影响DA能神经元的活性。本文就雌激素与DA的关系及PD发病具有性别差异方面的新近进展作简要概述。     

雌激素心血管作用的研究进展

雌激素受体广泛分布于心血管系统,具有抗心律失常作用,抗动脉粥样硬化效应和舒血管效应,并可调控动脉压力感受器反射,雌激素通过基因组机制和非基因组机制发挥心血管保护效应。     

围神经元网、硫酸软骨素蛋白多糖受体及其对神经可塑性的调节作用（英文）

围神经元网是中枢神经系统中一种包绕在特定类型神经元胞体和近端神经突周围的细胞外基质网络。在1883年,围神经元网最早被Camillo Golgi所描述,直到近几十年,研究人员才对其分子组成、发育成熟以及潜在的功能有密集的研究。研究表明,围神经元网主要由透明质酸、硫酸软骨素蛋白多糖、连接蛋白和肌腱蛋白-R组成。围神经元网在神经发育的晚期才渐次出现,它的发育成熟水平和神经可塑性水平的高低呈负相关。功能上,一方面,围神经网络被认为在稳定细胞外微环境、维持被包裹神经元的性能和保护被包裹的神经元免受有害物质的影响等方面起到了重要的作用,围神经元网的异常可以导致诸如癫痫、中风和阿尔茨海默病等中枢神经系统的机能障碍;另一方面,围神经元网作为包裹在细胞外的一道屏障限制了神经可塑性的发生和阻碍了神经损伤后的再生。在成年动物中,用软骨素酶法降解围神经元网可以促进脊髓损伤后的功能修复以及恢复活动依赖的中枢神经系统可塑性调节机制,表明围神经元网在调节神经可塑性方面起到了非常重要的作用。本文就早期发育中活动依赖的围神经网络的形成和围神经网络信号通路中的重要分子——硫酸软骨素蛋白多糖受体的研究进展进行综述,并就它们如何调节神经可塑性展开讨论。     

皮质酮对大鼠延髓头端腹外侧区神经元活动的影响

实验用多管微电极细胞外记录氨基甲酸乙酯麻醉的SD大鼠延髓头端腹外侧区（RVLM）神经元的活动,用电刺激主动脉神经和静脉注射苯肾上腺素激活压力感受器反射等方法鉴定心血管神经元,在RVLM内共记录到145个自发放电的神经元,其中33个为心血管神经元,31个为伤害调制性神经元,81个为未知功能神经元。33个心血管神经元微电泳硫酸皮质酮（CORT）后,25个（76%）神经元放电迅速加快,8个（24%）自发放电没有变化。伤害刺激引起兴奋的31个伤害调制性神经元,微电泳CORT后19个（64%）神经元放电抑制,而2个（6%）兴奋,其余10个（30%）没有反应,功能不明的81个神经元在微电泳CORT后,32个（40%0兴奋,5个（6%）抑制,44个（54%）没有反应,以上结果证明CORT可能通过非基因组机制快速影响RVLM神经元的活动,提示在应激等情况下CORT的快速作用机制可能在心血管和抗伤害等活动整合中具有一定意义。     

Effects of estrogen in the CNS.

Awareness of estrogen's effects on neural function is broadening rapidly. Areas of recent progress include increased understanding of estrogen signaling through both genomic and nongenomic pathways, as well as the mechanisms by which estrogen can induce or maintain synapses and protect neurons from a variety of insults. Findings in these areas demonstrate a role for estrogen that goes beyond direct control of reproductive function.     

Glutamate antagonism fails to reverse mitochondrial dysfunction in late phase of experimental neonatal asphyxia in rats

Because estrogen plays important neurotrophic and neuroprotective roles in the brain by activating estrogen receptors (ERs), disruption of normal estrogen signaling can leave neurons vulnerable to a variety of insults, including β-amyloid peptide (Aβ). Aroclor1254 (A1254) belongs to the endocrine-disrupting chemical (EDC) polychlorinated biphenyls and has anti-estrogenic properties. In the present study, we evaluated the effect of A1254 on the protective activity of estrogen against Aβ toxicity in differentiated cholinergic SN56 cells. Aged Aβ25-35 causes apoptotic cell death in differentiated SN56 cells, and the cytotoxic evidences are effectively rescued by estrogen. We found that A1254 abolishes the neuroprotective activity of estrogen against Aβ toxicity, and attenuates the suppressive effect of estrogen on Aβ-induced tau phosphorylation and JNK activation. The effects of A1254 on the neuroprotective effects of estrogen in Aβ toxicity are very similar to the effects of the estrogen receptor antagonist ICI182,780. Thus, exposure to EDCs that have anti-estrogenic activity might interfere with normal estrogen-activated neuroprotective signaling events and leave neurons more vulnerable to dangerous stimuli. Our present results provide new understanding of the mechanisms contributing to the harmful effects of EDCs on the function and viability of neurons, and the possible relevance of EDCs in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease.     

Estrogen: A multifunctional messenger to nigrostriatal dopaminergic neurons

Gonadal steroids affect a wide variety of functions in the mammalian brain ranging from the regulation of neuroendocrine systems and the modulation of behavior to the stimulation of differentiation and plasticity of distinct neuronal populations and circuits. The last decades have also demonstrated that estrogen serves as a neuroprotective factor for distinct neurodegenerative disorders. Such neuroprotective effects of estrogen are most obvious for Parkinson's and Alzheimer's disease. Despite this knowledge, little is known about the mechanisms and cellular targets by that estrogen might elicit its protective influence. In the past, we have intensively studied the effects of estrogen on midbrain dopaminergic neurons which represent the most affected cell population during Parkinson's disease. These studies were mainly performed on developing dopaminergic cells and revealed that estrogen is an important regulator of plasticity and function of this neuronal phenotype. Precisely, we found that dopaminergic neurons are direct targets for estrogen and that estrogen stimulates neurite extension/branching and the expression of tyrosine hydroxylase, the key enzyme in dopamine synthesis. Together with other in vivo studies, we might draw the conclusion that estrogen is required for the plasticity and activity of the developing and adult nigrostriatal system. The presence of the estrogen-synthesizing enzyme aromatase within the nigrostriatal system further supports this idea. Surprisingly, estrogen effects on nigrostriatal cell function are not only transmitted by classical nuclear estrogen receptors but also depend on nonclassical estrogen actions mediated through putative membrane receptors coupled to diverse intracellular signaling cascades. In the future, it has to be elucidated whether nonclassical mechanisms besides genomic actions also contribute to estrogen-mediated neuroprotection in the adult CNS.     

17beta-Estradiol and the phytoestrogen genistein attenuate neuronal apoptosis induced by the endoplasmic reticulum calcium-ATPase inhibitor thapsigargin

Estrogenic compounds have been shown to protect neurons from a variety of toxic stimuli in vitro and in vivo and depletion of estrogen at menopause has been associated with increased risk of neurodegenerative diseases. Genistein is an isoflavone soy derivative that binds to estrogen receptors with selective estrogen receptor modulator (SERM) properties. Recent FDA recommendations of soy intake for cholesterol reduction have prompted investigation into the potentially estrogenic role of dietary soy phytochemicals in the brain. In this study, we have shown that 50nM genistein significantly reduces neuronal apoptosis in an estrogen receptor-dependent manner. The importance of apoptosis in the brain has been recognized with regard to organization of the developing brain as well as degeneration in response to disease or stroke; however, the effects of estrogenic compounds on neuronal apoptosis have not been thoroughly examined. We developed a model of apoptotic toxicity in primary cortical neurons by using the endoplasmic reticulum (ER) calcium-ATPase inhibitor, thapsigargin, to test potential anti-apoptotic effects of 17beta-estradiol and genistein. Estrogen receptor beta, but not estrogen receptor alpha, was detected in our primary neuron cultures. Thapsigargin-induced apoptosis was confirmed by loss of mitochondrial function, DNA laddering, nuclear condensation and fragmentation, and caspase activation. Both 17beta-estradiol and genistein reduced the number of apoptotic neurons and reduced the number of neurons containing active caspase-3. This effect was blocked by co-addition of ICI 182780. Our results demonstrate that genistein and 17beta-estradiol have comparable anti-apoptotic properties in primary cortical neurons and that these properties are mediated through estrogen receptors.     

Estrogen activates protein kinase C in neurons: role in neuroprotection

It has been previously demonstrated that estrogen can protect neurons from a variety of insults, including beta-amyloid (Abeta). Recent studies have shown that estrogen can rapidly modulate intracellular signaling pathways involved in cell survival. In particular, estrogen activates protein kinase C (PKC) in a variety of cell types. This enzyme plays a key role in many cellular events, including regulation of apoptosis. In this study, we show that 17beta-estradiol (E2) rapidly increases PKC activity in primary cultures of rat cerebrocortical neurons. A 1 h pre-treatment with E2 or phorbol-12-myristate-13-acetate (PMA), a potent activator of PKC, protects neurons against Abeta toxicity. Protection afforded by both PMA and E2 is blocked by pharmacological inhibitors of PKC. Further, depletion of PKC levels resulting from prolonged PMA exposure prevents subsequent E2 or PMA protection. Our results indicate that E2 activates PKC in neurons, and that PKC activation is an important step in estrogen protection against Abeta. These data provide new understanding into the mechanism(s) underlying estrogen neuroprotection, an action with therapeutic relevance to Alzheimer's disease and other age-related neurodegenerative disorders.     

Donepezil plus estradiol treatment enhances learning and delay-dependent memory performance by young ovariectomized rats with partial loss of septal cholinergic neurons

Effects of estrogen therapy on cognitive performance appear to diminish with age and time following the loss of ovarian function. We hypothesize that this is due to a reduction in basal forebrain cholinergic function and that treatment with a cholinergic enhancer can reverse the effect. This study tested whether combining the cholinesterase inhibitor donepezil with estradiol treatment can enhance/restore estradiol effects on cognitive performance in young ovariectomized rats with selective lesions of septal cholinergic neurons. 192IgG-saporin was injected directly into the medial septum to produce selective cholinergic lesions. Rats were then treated with donepezil (Don, daily injections of 3 mg/kg/day, i.p.) or vehicle, and then with 17β-estradiol (E2, administered by silastic capsule implanted s.c.) or an empty capsule. Rats were trained on a delayed matching-to-position (DMP) T-maze task which previous studies have shown is sensitive to ovariectomy and estrogen replacement. Results show that neither estradiol nor donepezil alone significantly enhanced acquisition of the DMP task in rats with cholinergic lesions. Combination therapy was effective, however, depending on the severity of the lesion. Don + E2 significantly enhanced acquisition of the task in rats with partial lesions (< 50% loss of cholinergic neurons), but not in rats with severe lesions. This effect was due largely to a reduction in perseverative behavior. Don + E2 also improved working memory in rats with partial lesions, as evidenced by significantly better performance than controls during increased intertrial delays. These findings suggest that even partial loss of septal cholinergic neurons can reduce effects of estrogen therapy on cognitive performance, and demonstrate that combining a cholinesterase inhibitor with estrogen therapy can help to restore beneficial effects on performance. We propose that combination therapy may have similar beneficial effects in women, particularly in older women who have not used estrogen therapy for many years and are beginning to show signs of cognitive impairment or early Alzheimer's disease.     

Estrogen and hippocampal synaptic plasticity

During the past several years, there has been increasing interest in the effects of estrogen on neural function. This enthusiasm is driven, in part, by the results of early clinical studies suggesting that estrogen therapy given after menopause may prevent, or at least delay, the onset of Alzheimer's disease in older women. However, later clinical trials of women with probable Alzheimer's disease had contrary results. Much of the current research related to estrogen and brain function is focused in two directions. One involves clinical studies that examine the potential of estrogen in protecting against cognitive decline during normal aging and against Alzheimer's disease (neuroprotection). The other direction, which is the primary focus of this review, involves laboratory studies that examine the mechanisms by which estrogen can modify the structure of nerve cells and alter the way neurons communicate with other cells in the brain (neuroplasticity). In this review, we examine recent evidence from experimental and clinical research on the rapid effects of estrogen on several mechanisms that involve synaptic plasticity in the nervous system,including hippocampal excitability, long-term potentiation and depression related to sex and aging differences, cellular neuroprotection and probable molecular mechanisms of the action of estrogen in brain tissue.     

17 beta-Estradiol inhibits angiotensin II activation of area postrema neurons

It is well established that the area postrema, as a circumventricular organ, is susceptible to modulation by circulating hormones and peptides. Furthermore, activation of the area postrema has been shown to modulate central neurons involved in the regulation of cardiovascular function and blood pressure. In particular, the vasoactive peptide angiotensin II (ANG II) has been shown to inhibit baroreflex regulation of heart rate and increase sympathetic outflow and blood pressure via activation of area postrema neurons. Estrogen is thought to protect against hypertension in both humans and animal models and has been shown in a number of systems to alter the effects of ANG II. The purpose of the present study was to determine the effects of estrogen on ANG II activation of area postrema neurons. In this study, the effects of ANG II and KCl on fura 2-measured cytosolic Ca2+ concentration ([Ca2+]i) responses in cultured area postrema neurons in the presence and absence of 12-h exposure to 100 nM 17 beta-estradiol (E2) were evaluated. In neurons incubated in control vehicle media, 50 nM ANG II increased [Ca2+]i by 92 +/- 12%. In neurons preincubated with 100 nM E2, ANG II increased [Ca2+]i by only 68 +/- 11%, for a total inhibition of the ANG II-evoked response of 24%. Coapplication of the estrogen receptor antagonist ICI-182,780 did not inhibit the effects of E2. In the same cells in which the effects of E2 on ANG II-evoked responses were tested, the effects of incubation in E on the depolarization-induced increased [Ca2+2]i due to 60 mM KCl were also tested. Incubation of the cells with 100 nM E increased the KCl-evoked [Ca2+2]i response, and this response was blocked by ICI-182,780. These results suggest that in the area postrema, estrogen may utilize multiple pathways to modulate neural activity and responses to ANG II.