Down-Regulation of Estrogen Receptor Immunoreactivity by 17β-estradiol in the Guinea Pig Forebrain

Low amplitude pulses of estradiol-17β (E₂-17β) are more effective than large single bolus injections or constant exposure to E₂-17β in inducing progesterone-facilitated sex behavior in female rats and guinea pigs. The present study examined whether the increased responsiveness to E₂-17β is due to an increase in the number of estrogen receptors in the estrogen receptor rich areas of the hypothalamus and amygdala. Initial studies examined the rapid effects (20 min) of a high dose of E₂-17β (50 μg) on estrogen receptor immunostaining using either the H222 antibody or the ER 21 antiserum. ER 21 immunostaining was not affected by the E₂-17β treatment suggesting that it binds to both occupied and unoccupied estrogen receptors. Therefore the ER 21 antiserum was used to characterize the regulation of estrogen receptor immunoreactivity (ER-IR) by E₂-17β. ER-IR was examined for 48 h and serum E₂-17β for 24 h following a 2 μg s.c. injection of E₂-17β (a dose similar to that used in multiple pulse paradigms). Serum E₂-17β peaked 15 to 30 min following the injection and returned to baseline values by 1 h. In all but one area maximal suppression of ER-IR occurred at 12 h. In summary, 1) decreases in estrogen receptor immunoreactivity following E₂-17β are consistent with studies in which estrogen receptors were assayed by binding assays and estrogen receptor mRNA was determined by in situ hybridization; 2) the ER 21 antiserum is able to detect both occupied and unoccupied estrogen receptors and 3) H222 immunoreactivity is influenced by the presence of E₂-17β, so that the level of H222-IR is a reflection of ligand/receptor binding dynamics. The data suggest that up-regulation of estrogen receptors does not account for the increase in behavioral sensitivity which is observed following multiple pulses of E₂-17β.     

The effects of A 5-HT1A receptor agonist and antagonist on the 5-hydroxytryptamine release in the central nucleus of the amygdala: a microdialysis study with flesinoxan and WAY 100635

The modulation of extracellular 5-hydroxytryptamine (5-HT) in the central nucleus of the amygdala (CeA) by 5-HT_1A receptors was studied by intracerebral microdialysis in awake and freely moving rats. Local administration of 1 μM tetrodotoxin (TTX), 60 mM K⁺ and perfusion with Ca²⁺-free Ringer containing EGTA confirmed that the major part of dialysate 5-HT levels from the CeA is of neuronal origin. Administration of 300 nM of RU 24969, a 5-HT_1B receptor agonist, through the probe into the CeA decreased dialysate 5-HT levels to 67.2% of the baseline value. Systemic administration of the 5-HT_1A receptor agonists 8-OH-DPAT and flesinoxan dose-dependently decreased 5-HT levels in the CeA. The effect of 0.3 mg/kg of flesinoxan could be completely antagonized by systemic administration of 0.05 mg/kg WAY 100635, a 5-HT_1A receptor antagonist. WAY 100635 alone had only minimal effects at this dose. These data show that a major part of the extracellular 5-HT in the CeA stems from 5-HT neurons and that the amount of 5-HT released into this brain region can be modulated by 5-HT_1A receptors. Received: 11 September 1996 / Accepted: 25 November 1996     

血清sIL—2r表达水平与脓毒血症的严重程度及预后的关系

目的：探讨脓毒血症患者血清中可溶性白细胞介素２受体（ｓＩＬ２ｒ）的表达水平以及与该病严重程度及预后的关系。方法：采用双抗体夹心酶联免疫分析法检测２９例脓毒血症患者血清ｓＩＬ２ｒ表达水平的动态变化，并以３０例正常人作为对照；用ＡＰＡＣＨＥⅡ评分方法对脓毒血症患者进行疾病严重度评分。结果：①脓毒血症患者血清ｓＩＬ２ｒ表达水平较正常人明显升高（Ｐ＜００１）；②脓毒血症患者中死亡者与存活者的血清ｓＩＬ２ｒ表达水平比较，感染初期及晚期死亡者明显高于存活者（Ｐ＜００５）；③以本组患者感染ｄ１的ＡＰＡＣＨＥⅡ评分的中位数１６为分界点，将患者分为２组，２组的血清ｓＩＬ２ｒ水平有显著差别（Ｐ＜００５）。结论：脓毒血症患者血清ｓＩＬ２ｒ表达水平明显升高；该指标与脓毒血症患者的疾病的严重程度及预后有密切的关系。此项指标的检测对判断脓毒血症患者的病情严重度及预后可能有重要意义     

Toll-like receptors in Borrelia burgdorferi-induced inflammation

Lyme arthritis, the most common manifestation of late Lyme disease, has been associated with the presence of Borellia burgdorferi in the joint. However, it is still unclear whether the pathogen itself is able to elicit such a sustained inflammatory response, or whether an aberrant immunological reaction of the host is the main driving force. Borrelia antigens, including lipoproteins, flagellin and DNA, are ligands of Toll-like receptors, and can thus elicit a strong stimulation of host cells, such as neutrophils, mononuclear cells and resident tissue cells. Understanding the molecular basis of the signalling events caused by Borrelia lipoproteins will lead to a greater understanding of inflammation in Lyme arthritis and, hopefully, new treatment strategies for chronic antibiotic-resistant disease.     

Up-regulation of nicotinic acetylcholine receptors following chronic exposure of rats to mainstream cigarette smoke or α4β2 receptors to nicotine

Smokers are reported to have a higher density of central nicotinic acetylcholine receptors (nAChRs) that non-smokers at autopsy. Whether this increased receptor density is a response to smoking or a result of genetic variability is not known. While sub-chronic treatment of rats and mice with nicotine results in upregulation of central nAChRs, changes in receptor density in response to cigarette smoke have not been studied previously. In this study, male Sprague-Dawley rats were exposed nose-only for 13 weeks to mainstream cigarette smoke followed by assessment of [³H]nicotine binding in five brain regions of smoke- and sham-exposed animals. In smoke-exposed animals, there was a significant increase in nAChR density in the cortex, striatum, and cerebellum (35, 25, and 31% increases, respectively), while there was no significant change in receptor density in the thalamus and hippocampus. Smoke exposure did not alter markedly the affinity of the receptor for nicotine in these brain regions. Furthermore, up-regulation of nAChRs did not alter the biphasic binding properties by which nicotine binds to its receptor. There were no changes in the association (fast phase) or isomerization (slow phase) rate constants, and the percent contribution of slow and fast phase binding to nAChRs was not altered in the up-regulated receptor population compared with control. Similar results were observed following chronic nicotine exposure of cultured cortical cells from fetal rat brain or cells transfected with the α4β2 nAChR subtype. These results show that the up-regulation following smoke exposure in the rat is phenomenologically similar to that observed in vitro. These data provide preliminary evidence for a relationship between cigarette smoking and nAChR up-regulation in vivo and suggest that similar mechanisms of upregulation may underlie chronic smoke exposure of live animals and nicotine exposure of artificially expressed α4β2 receptors in vitro.     

Effect of pindolol on the prolactin response tod-denfluramine

We studied the effect of the 5-HT_1A receptor antagonist, pindolol, on the prolactin (PRL) response to the 5-HT releasing agent,d-fenfluramine (d-FEN), in ten healthy male volunteers. Pindolol pretreatment lowered baseline PRL levels but, when this effect was taken into account, did not significantly attenuate the PRL response tod-FEN. Within the limitations that attend the use of pindolol as a 5-HT_1A receptor antagonist, the data suggest that although 5-HT_1A receptors may play a role in the tonic release of PRL, they are not involved in the release of PRL produced byd-FEN. We propose that the PRL response tod-FEN may involve selective activation of postsynaptic 5-HT₂ receptors.     

高浓度氟引起SH-SY5Y神经细胞中α7尼古丁受体水平降低

目的：观察氟中毒对神经细胞中α7尼古丁受体的影响。方法：体外培养SH-SY5Y神经细胞，在培养液中加人不同浓度的氟化物，培养48h后测定细胞MTT水平；用放射配体结合实验测定α7尼古丁受体亚型含量；用Westem Bloting方法测定α7尼古丁受体亚单位蛋白水平。结果：经氟处理的神经细胞中MTT水平降低，α7尼古丁受体最大结合容量降低，α7尼古丁受体亚单位蛋白含量减少。结论：氟中毒可引起SH—SY5Y神经细胞中α7尼古丁受体表达降低。     

糖皮质激素受体与虚证的关系及中药的调节

糖皮质激素受体(glucocorticoid receptor, GR)属细胞内核受体超家族中的一员,是一种配基依赖型转录因子.GR几乎在机体的所有有核细胞中表达,在很多生理以及病理过程中发挥重要作用,包括维持内环境的稳定、抗应激、调节神经系统的功能等.另外,糖皮质激素的抗炎、抗自身免疫和抗肿瘤的作用也是由GR介导的,因此,GR也是重要的免疫系统调节因子.通过调节GR,可以对机体和细胞的生理、病理状态产生重要影响.中医药在调节糖皮质激素受体方面也进行了许多探索,为中医药作用机制研究奠定了现代生理病理学基础.     

Studies of neurotrophin biology in the developing trigeminal system

The accessibility of the primary sensory neurons of the trigeminal system at stages throughout their development in avian and mammalian embryos and the ease with which these neurons can be studied in vivo has facilitated investigation of several fundamental aspects of neurotrophin biology. Studies of the timing and sequence of action of neurotrophins and the expression of neurotrophins and their receptors in this well characterised neuronal system have led to a detailed understanding of the functions of neurotrophins in neuronal development. The concepts of neurotrophin independent survival, neurotrophin switching and neurotrophin cooperativity have largely arisen from work on the trigeminal system. Moreover, in vitro studies of trigeminal neurons provided some of the first evidence that the neurotrophin requirements of sensory neurons are related to sensory modality. The developing trigeminal system has been studied most extensively in mice and chickens, each of which has particular advantages for understanding different aspects of neurotrophin biology. In this review, I will outline these advantages and describe some of the main findings that have arisen from this work.     

Multiple sites of action of ( +)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (( +)-3PPP) in blood vessels

Functional effects of the σ ligand, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3PPP), were explored in perfused rat tail and rabbit ear arteries in vitro. In the rat tail artery (+)-3PPP inhibited contractile responses to adrenergic nerve stimulation, an effect which was reversed to potentiation by the dopamine D₂ receptor antagonist sulpiride. In the rabbit ear artery, however, (+)-3PPP potentiated contractile responses to nerve stimulation, an effect which was unchanged by sulpiride. In the rat tail artery, blockade of norepinephrine uptake by cocaine and deoxycorticosterone in the presence of sulpiride revealed two additional actions of (+)-3PPP. First, an inhibitory action on the monoamine uptake site was confirmed by direct measurement of [³H]norepmephrine accumulation. Second, at higher concentrations, an action to inhibit contractile responses to adrenergic nerve stimulation was manifested at a still unidentified site. These studies demonstrate that the observed functional effect of (+)-3PPP results from its combined actions on three individual sites with the net effect dependent on the relative densities of these different receptor sites in each type of vessel.