Design,Synthesis and Evaluation of Antidepressant Activity of Novel 2‐Methoxy 1, 8 Naphthyridine 3‐Carboxamides as 5‐HT3 Receptor Antagonists

A series of novel 1,8‐naphthyridine‐3‐carboxamides as 5‐HT₃ receptor antagonists were synthesized with an intention to explore the antidepressant activity of these compounds. The title carboxamides were designed using ligand‐based approach keeping in consideration the structural requirement of the pharmacophore of 5‐HT₃ receptor antagonists. The compounds were synthesized using appropriate synthetic route from the starting material nicotinamide. 5‐HT₃ receptor antagonism of all the compounds, which was denoted in the form of pA₂ value, was determined in longitudinal muscle myenteric plexus preparation from guinea‐pig ileum against 5‐HT₃ agonist, 2‐methyl‐5‐HT. Compound 8g (2‐methoxy‐1, 8‐naphthyridin‐3‐yl) (2‐methoxy phenyl piperazine‐1‐yl) methanone was identified as the most active compound, which expressed a pA₂ value of 7.67. The antidepressant activity of all the compounds was examined in mice model of forced swim test (FST); importantly, none of the compounds was found to cause any significant changes in the locomotor activity of mice at the tested dose levels. In FST, the compounds with considerably higher pA₂ value exhibited promising antidepressant‐like activity, whereas compounds with lower pA₂ value did not show antidepressant‐like activity as compared to the control group.     

In Search of Potent 5‐HT6 Receptor Inverse Agonists

A series of non‐sulfonamide/non‐sulfone derived potent 5‐HT₆ receptor inverse agonists has been disclosed. Representative compound 9 ( K _i = 14 nm ) displayed selectivity against a set of family members as well as brain permeability 6 h post‐oral administration. In addition, the separated enantiomers of compound 9 displayed difference in activity indicating the influence of chirality on potency.     

Venlafaxine alters microvascular perfusion, [I]-beta-CIT binding and BDI scores in flushing postmenopausal women

Background

Although 70% of postmenopausal women suffer from hot flashes the pathophysiology is poorly understood. The serotonin and noradrenaline reuptake inhibitor (SNRI) venlafaxine provides relief of flushing although the mechanism is unknown and could involve a central effect and/or a peripheral effect. Using single photon emission computed tomography (SPECT) we studied the central serotonin transporter (SERT) in vivo using [¹²³I]-beta-carbomethoxy-3-β-(4-iodophenyl)tropane (beta-CIT) and, as previous studies have shown that reactivity of the skin blood vessels is enhanced in those who flush, we examined cutaneous microvascular perfusion.

Methods

Cutaneous microvascular perfusion was assessed in 31 postmenopausal women, with flushing, using laser Doppler imaging with iontophoresis (LDI + ION), before and after 8 weeks of treatment with venlafaxine. A sub-group of 14 of these women also had SPECT imaging at both time points to evaluate the availability of SERT in the brain. Flush frequency and score was recorded, and Beck Depression Inventory (BDI) II scores were assessed before and after treatment.

Results

Following treatment with venlafaxine, there was a significant reduction in the [¹²³I]-beta-CIT binding ratio, BDI scores, flushing and endothelial dependent perfusion response. [¹²³I]-Beta-CIT reduction was associated with BDI reduction (r² = 0.54; F = 8.8; p = 0.004), but not flushing reduction or perfusion reduction.

Conclusions

Venlafaxine resulted in a decrease in BDI II scores with an associated reduction in [¹²³I]-beta-CIT binding in a group of non-depressed women. It also improved flush frequency and severity which may be as a result of decreases seen in enhanced cutaneous microvascular perfusion.     

Sumatriptan mediated growth hormone responses do not alter throughout the menstrual cycle

The objective of this study was to determine the effects of oral sumatriptan on growth hormone (GH) release throughout the menstrual cycle in healthy female volunteers. A placebo-controlled cross-over design was employed. Subjects were tested a total of six times over two consecutive menstrual cycles; twice in the early follicular phase, twice in midcycle and twice in the late luteal phase. Oral sumatriptan (100 mg) and placebo were administered on alternate visits. Twelve healthy female volunteers aged between 18-40 years with regular menses and not taking oral contraceptives were recruited. Baseline blood samples at 0 min were taken for GH, oestrogen and progesterone estimation. GH was measured at +60, +90, +120 and +180 min following administration of oral sumatriptan 100 mg or matched placebo. GH, progesterone and oestrogen were measured by radioimmunoassay. At each phase of the menstrual cycle serum GH levels peaked at 60-90 min following administration of oral sumatriptan compared to placebo which showed no response. Analysing GH response to sumatriptan and placebo over time for the three phases of the menstrual cycle (three-way ANOVA) demonstrates that the GH response to sumatriptan did not alter.     

黄芪多糖对毒胡萝卜素诱导人结肠癌系HT29细胞内质网应激的影响

目的探讨黄芪多糖(Astragalus polysaccharides,AP)对毒胡萝卜素内酯(Thapsigargin,Tg)诱导人结肠癌系HT29细胞发生内质网应激(Endoplasmic Reticulum Stress,ERS)时内质网结构变化及相关分子GRP78和CHOP的影响。方法常规培养HT29细胞后,将细胞分为4组:①空白细胞组(Control组):细胞不做任何药物处理;②细胞模型组(Model组):采用1μmol/L Tg诱导HT29细胞建立ERS模型;③黄芪多糖低浓度组(AP-L组);④黄芪多糖高浓度组(AP-H组)。CCK8法检测黄芪多糖对HT29细胞活性,透射电镜观察内质网结构变化,Real-time PCR法检测ERS时GRP78、CHOP mRNA表达情况。结果黄芪多糖浓度分别为1、10μg/mL,且分别作用HT29细胞12、24、36、48 h时,细胞存活率随着浓度的增加而增加,说明对细胞无明显毒副作用。透射电镜观察Control组内质网结构呈网膜状结构,网膜腔不扩张;Model组内质网形态迥异,大小不一,呈空泡状改变,部分可见融合成簇现象;AP-L组内质网网膜腔扩张程度减轻,空泡体积减小和数量减少;AP-H组内质网形态基本恢复正常,呈网膜状结构,可见数量较少,形态较小的空泡状结构。Real-time PCR法检测结果:与Control组相比,Model组HT29细胞GRP78、CHOP mRNA表达明显增加(P<0.05);与Model组比较,AP-L组和AP-H组HT29细胞GRP78、CHOP mRNA表达均减少(P<0.05);与AP-L组比较,AP-H组HT29细胞GRP78、CHOP mRNA表达减少(P<0.05)。结论黄芪多糖能够抑制Tg诱导HT29细胞发生ERS,其机制可能与降低GRP78和CHOP的表达、减轻内质网应激有关。     

Prenatal stress‐related alterations in synaptic transmission and 5‐HT7 receptor‐mediated effects in the rat dorsal raphe nucleus are ameliorated by the 5‐HT7 receptor antagonist SB 269970

Early life adversity exerts a detrimental influence on developing brain neuronal networks and its consequences may include mental health disorders. In rats, prenatal stress may lead to anxiety and depressive‐like behavior in the offspring. Several lines of evidence implicated an involvement of prenatal stress in alterations of the brain serotonergic system functions, but the effects of prenatal stress on its core, the dorsal raphe nucleus (DRN), still remain incompletely understood. The present study was aimed at finding whether prenatal stress induces modifications in the glutamatergic and GABAergic inputs to DRN projection cells and whether it affects DRN 5‐HT₇ receptors, which modulate activity of these synapses. Prenatal stress resulted in an increase in basal frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and in a decrease in basal frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from putative projection neurons in DRN slices ex vivo. While there were no changes in the excitability of DRN projection neurons, the 5‐HT₇ receptor‐mediated reduction in the sEPSC frequency and rise in the sIPSC frequency, seen in control rats, were largely absent in slices obtained from prenatally stressed rats. Repeated administration of SB 269970, a 5‐HT₇ receptor antagonist, resulted in a reversal of prenatal stress‐induced alterations in 5‐HT₇ receptor‐mediated effects on the sEPSC/sIPSC frequency. Moreover, the treatment reversed prenatal stress‐induced alterations in basal excitatory transmission and partially reversed the effect of stress on basal inhibitory transmission in the DRN.     

无先兆偏头痛患者血单胺类递质变化的研究

目的 了解5－羟色胺（5－TH）、5－羟吲哚乙酸（5－HIAA）、多巴胺（DA）、去甲肾上腺素（NE）在无先兆偏头痛发病中的作用。方法 用荧光分光光度法检测35例无先兆偏头痛患者（发作期16例、间歇期19例）和23例正常人血浆及血小板5－HT、5－HIAA、DA、NE含量。结果 无先兆偏头痛患者发作期组血浆5－HT含量低于对照组（P＜0.05),而5－HIAA含量高于对照组（P＜0.01）;间歇期组5－HT含量高于发作期组,而5－HIAA含量低于发作期组（P＜0.01）;发作期组血浆DA、NE含量均低于对照组（P＜0.01）间歇期组血浆DA与发作期组相比亦有显著性差异（P＜0.01）。无先兆偏头痛患者发作期组血小板5－HT含量高于对照组和间歇期组,而5－HIAA含量低于对照组和间歇期组（P＜0.01）;而发作期组血小板NE含量高于对照组和间歇期组（P＜0.01）;DA含量则低于对照组和间歇期组（P＜0.01）。结论 单胺类递质对偏头痛的发生可能有重要意义。     

Maternal and child health workforce profile and density in China since 1949: a systematic review

Background

Routine sources of information on the maternal and child health workforce in China are without clear definition and categorisation. The aim of the study was to systematically review all the evidence on China's maternal and child health workforce profile (ie, level of education, training, qualification, and professional title), and determine the density of the maternal and child health workforce.

Exendin-4通过拮抗钙超载改善Aβ_(31-35)诱导的HT22海马神经细胞per1基因异常表达

目的:探讨Exendin-4对Aβ_(31-35)所致的HT22神经细胞per1基因异常表达的影响及可能作用机制。方法:本研究采用海马神经细胞HT22作为实验对象。以1%血清饥饿1 h来诱导细胞同步化(CT0)。MTT实验检测细胞存活率;倒置显微镜下观察细胞形态变化;Real-time PCR检测各CT时间per1基因的表达变化;选择per1表达差异最显著的CT时间点,采用流式细胞术检测细胞内钙离子浓度的变化情况。结果:(1)Exendin-4可以明显提高Aβ_(31-35)所致的HT22细胞存活率的下降;(2)镜下观察可见,经Exendin-4预处理后部分改善了Aβ_(31-35)对细胞的损伤作用,细胞形态有所恢复;(3)Aβ_(31-35)使per1基因在CT16时各处理组的相对表达量明显不同;与对照组相比,Aβ_(31-35)使per1基因表达量明显升高;经Exendin-4预处理后,per1基因的表达得到一定程度的恢复,差异具有统计学意义;(4)在CT16时各处理组细胞荧光强度值明显不同,与对照组相比,Aβ_(31-35)使细胞荧光强度明显增强;经Exendin-4预处理后,细胞荧光强度值明显降低,差异具有统计学意义,此结果与加入尼莫地平的结果类似。加入尼莫地平预处理后,检测各个CT时间per1基因表达变化,与Exendin-4预处理组得到的结果类似。结论:Exendin-4通过拮抗钙超载改善Aβ_(31-35)诱导的HT22海马神经细胞per1基因的异常表达。     

胚胎及新生大鼠胃肠道5-羟色胺及胃泌素免疫反应细胞的形态学研究

本研究用免疫组织化学ＰＡＰ法，较系统地观察了５－羟色胺、胃泌素免疫反应细胞在胚胎及新生大鼠胃肠道的个体发生及分布。结果表明：５－羟色胺免疫反应细胞最早见于第１９ｄ胚胎的小肠各段。胚胎第２１ｄ及新生期分布于胃肠道各段。５－羟色胺免疫反应细胞形态多样。胚胎期胃肠道中胃泌素免疫反应细胞也始见于第１９ｄ胚胎鼠的胃和小肠。胚胎第２１ｄ和新生期，胃泌素免疫反应细胞渐多，但也仅见于胃和小肠各段，结肠和直肠中未见胃泌素免疫反应细胞。本文对大鼠胃肠道两种免疫反应细胞在胚胎发育中的可能功能进行了讨论。