5-HT1A受体C（-1019）G基因多态性与抑郁症相关性研究进展

大量研究证实,5-羟色胺(5-HT)系统功能的降低和神经传递的减少是导致抑郁症等精神疾病的发病机制之一。近年来研究发现,一种新的功能性5-HT1A受体C(-1019)G基因多态性通过影响5-HT的神经传递,在抑郁症、焦虑症、抑郁焦虑相关的人格障碍及其他相关精神疾病(如广场恐怖症、精神分裂症、物质应用障碍等)的发病机制中起着重要的作用。并与部分三环类抗抑郁药、5-羟色胺重摄取抑制剂等的效应应答个体差异有着密切的关系。本文仅就该方面的研究进展作一简要综述。     

柴胡提取物对PMS肝气郁证模型大鼠额叶5-HT_(3A/3B)R分布与蛋白表达的影响

<正>经前期综合征肝气郁证(premenstrual syndrome,PMS)症状表现类似于现代医学中的抑郁样情绪改变,前期研究证明PMS肝气郁证的发生与脑内5-HT系统及其受体密切相关[1],柴胡提取物通过不同分子机制干预PMS肝气郁证的抑郁情绪[2-3]。但是柴胡提取物在5-HT3R水平对PMS肝气郁证经前抑郁情绪的干预机制尚未见报道,因此,本实验选取PMS肝气郁证为动物模型初步探讨柴胡提取物调控抑郁情绪的微观作用机制。     

常用抗抑郁药物的比较及合理应用

目的:按类别总结临床常用抗抑郁药的特点、机制、不良反应与特殊人群用药,为临床合理应用提供理论支持与建议。方法:通过查阅药品说明书与相关文献,对抗抑郁药的临床应用进行归纳总结。结果:常用抗抑郁药可分为3类,三环类尤适于激越性抑郁,不良反应较多;SSRIs尤适于淡漠性抑郁,存在5-HT综合征等相关不良反应;新型抗抑郁药具有多重作用机制,尤适于难治性或精神病性抑郁。结论:应用抗抑郁药应重视用药监护,复杂的药物相互作用和特殊人群用药注意事项,用药依从性也很关键。     

5-HT及5-HT3受体在慢性结石性胆囊炎胆囊中的表达

目的 探讨5-羟色胺(5-HT)及5羟色胺3受体(5-HLR)在慢性结石性胆囊炎发病机理中的作用。方法 应用免疫组织化学技术(SP法)检测30例慢性结石性胆囊炎、15例正常对照胆囊组织中5-HT含量及5-HT3受体表达的变化。结果 5HT含量在慢性结石性胆囊炎胆囊粘膜层中高于对照组(P＜0．05)，在平滑肌层中无差别。5-HT3受体在慢性结石性胆囊炎平滑肌层中表达低于对照组(P＜0．05)。结论 5-HT及5-HT受体在慢性结石性胆囊炎形成中有一定作用。     

维拉佐酮的药理和临床评价

重性抑郁障碍是一种严重的精神障碍,且容易复发。尽管多种药物均可治疗,但仍有许多患者无法获得满意的疗效。维拉佐酮为选择性5-HT再摄取抑制剂和5-HT_(1A)受体部分激动剂,用于治疗重性抑郁障碍。本文就其作用机制、药效学、药动学和临床评价等进行综述。     

5-HT受体激动剂和拮抗剂及其在功能性胃肠病中的应用

5-羟色胺（5-hydroxytryptamine，5-HT）又称血清素（serotonin），是重要的神经递质，人体内95％的5-HT在胃肠道的肠嗜铬细胞（enterochromaffin cells，EC）及肠神经元中合成，5-HT通过与其受体相互作用，在胃肠道动力、感觉和分泌中发挥重要作用。5-HT受体超家族可分为7种亚型（5-HT1-7受体）和更多的亚亚型。胃肠道内至少有5种受体，     

盐酸度洛西汀在糖尿病痛性周围神经病变治疗中的应用

糖尿病周围神经病变是糖尿病最常见的慢性并发症之一,发病机制尚未完全明了。度洛西汀能阻断5-羟色胺(5-HT)和去甲肾上腺素(NE)的吸收、转运及结合,强烈抑制5-HT和NE再摄取,使大脑和脊髓中的5-HT和NE浓度升高,使这两种神经递质在调控情感和对疼痛敏感程度方面的作用提高,增加机体对疼痛的耐受力,从而缓解疼痛。     

帕罗西汀的非精神科应用

帕罗西汀(Paroxetine)系苯基哌啶衍生物,是一种选择性5-羟色胺(5-HT)再摄取抑制剂(SSRIs),能强力和选择性地抑制神经元突触体的5-HT积聚,促进5-HT的传递.对组胺H受体、肾上腺素α或β受体、多巴胺D2受体的亲和力低,对脑中去甲肾上腺素受体不起作用,临床广泛用于治疗抑郁症.     

2型糖尿病引起的疲劳与骨骼肌5-羟色胺降解的相关性研究

疲劳是2型糖尿病(T2DM)常见的并发症。本文研究了T2DM性疲劳与骨骼肌5-羟色胺(5-HT)系统的关系。动物实验用高脂饲料喂养结合腹腔注射链脲佐菌素建立小鼠T2DM模型,用5-HT_2A受体(5-HT_2AR)拮抗剂盐酸沙格雷酯(SH)及5-HT合成抑制剂卡比多巴(CDP)分别或联合给药治疗。细胞实验用D-葡萄糖、棕榈酸或5-HT刺激C2C12细胞。用SH、CDP或单胺氧化酶A(MAO-A)抑制剂氯吉兰分别抑制5-HT_2AR、5-HT合成及5-HT降解。本文中动物福利和实验过程均遵循中国药科大学动物伦理委员会的规定。结果表明,小鼠骨骼肌及C2C12细胞均存在5-HT_2AR、5-HT合成酶及MAO-A表达。T2DM以及棕榈酸、D-葡萄糖刺激C2C12细胞时,它们的表达明显上调,且棕榈酸是比D-葡萄糖更敏感的刺激它们表达的因子。转棒实验及生化指标检测均表明,T2DM性疲劳起因于骨骼肌5-HT_2AR、5-HT合成及5-HT降解的增加。5-HT_2AR通过介导MAO-A表达、5-HT合成,间接调控5-HT降解。而MAO-A通过介导5-HT降解,调控细胞炎症、线粒体的ROS产生及膜电位去极化,还抑制过氧化物酶体增殖物激活受体-γ共激活因子-1(PGC-1)、肉碱棕榈酰转移酶1(CPT1)及ATP合成酶6(ATP6)表达,从而抑制线粒体功能,如脂肪酸β氧化和ATP合成。用SH和CDP可有效地治疗T2DM性疲劳,同时也可降血糖和血脂,且联合给药有明显的协同效应。     

5-羟色胺受体相关药物在临床治疗领域中应用

5-羟色胺（5-HT）是体内的一种多功能的生理活性物质。已知人类至少存在7种5-HTR,即5-HT1R、5-HT2R、5-HT3R、5-HT4R、5-HT5R、5-HT6R和5-HTTR,每个类型又分为若干亚型。广泛分布于体内许多部位,与焦虑,抑郁,攻击,强迫行为等机能障碍和反应影响人的睡眠,性欲、食欲、情感、痛觉、自主活动控制、消化等多种生理疾病的发病机制有关。     

Mechanism of block by fluoxetine of 5-hydroxytryptamine3 (5-HT3)-mediated currents in NCB-20 neuroblastoma cells

The effect of fluoxetine (Prozac) on 5-hydroxytryptamine(3) (5-HT(3))-mediated currents in NCB-20 neuroblastoma cells was examined using the whole-cell patch-clamp technique. Fluoxetine produced a significant reduction of peak amplitude without altering the activation time course of 5-HT(3)-mediated currents. These effects were concentration-dependent, with an IC(50) value of 4.15 microM. No voltage dependence was evident in fluoxetine's block of 5-HT(3)-mediated currents over the entire voltage range tested. The extent of block by pre-application of fluoxetine was significantly greater than that by co-application. Fluoxetine also increased the apparent rate of current desensitization to 5-HT application. Using a first-order kinetics analysis, the open-channel blocking rate constants were 0.06 microM(-1)s(-1) (k(+1), association rate constant) and 0.05 s(-1) (k(-1), dissociation rate constant), with an apparent K(d) (=k(-1)/k(+1)) of 0.83 microM. This value is close to an IC(50) of 1.11 microM obtained from the reduction in tau, the time constant of desensitization. Intracellular application of fluoxetine for long durations had no effect on the amplitude or kinetics of 5-HT(3)-mediated currents. Similarly, norfluoxetine, the major metabolite of fluoxetine, reduced the peak current, and enhanced the rate of current desensitization in a concentration-dependent manner with an IC(50) of 2.66 microM, indicating that norfluoxetine is more potent than fluoxetine in blocking 5-HT(3)-mediated currents. These results indicate that, at clinically relevant concentrations, fluoxetine and its metabolite, norfluoxetine, block 5-HT(3)-mediated currents in NCB-20 neuroblastoma cells.     

Kinetic studies with 5-azacytidine-5'-triphosphate and DNA-dependent RNA polymerase.

In order to further understand the biochemical mode of action of 5-azacytidine, a potent antileukemic agent, kinetic studies were performed with 5-azacytidine-5'-triphosphate (5-aza-CTP) and purified DNA-dependent RNA polymerase from Escherichia coli and calf thymus. RNA polymerase could catalyze the incorporation of the fradulent nucleotide, 5-aza-CTP, into RNA. The apparent K_m value for 5-aza-CTP was estimated to be 350 and 390 for the E. coli and calf thymus enzymes respectively. The K_m value for 5-aza-CTP was about 18-fold greater than the K_m value for CTP (20 μM). The apparent V_max value for CTP was about 2-fold greater than the V_max value for 5-aza-CTP. 5-Aza-CTP was a weak competitive inhibitor with respect to CTP; the apparent K_i value for 5-aza-CTP was estimated to be 680 and 810 μM for the E. coli and calf thymus enzymes respectively. On the other hand, CTP was a potent competitive inhibitor with respect to 5-aza-CTP; the apparent K_i value of CTP was estimated to be 16 μM. 5-Aza-CTP did not appear to inhibit the incorporation of UTP into RNA in the reaction catalyzed by RNA polymerase. These data suggest that the inhibition of RNA synthesis in cells by 5-aza-cytidine is not produced by the inhibition of RNA polymerase by 5-aza-CTP.     

Exclusion of exogenous 5-methyl-2'-deoxycytidine from DNA in human leukemic cells. A study with [2(-14)C]- and [methyl-14C]5-methyl-2'-deoxycytidine

Modification of DNA-cytosine by a 5-methyl group is thought to be an important mechanism which regulates the expression of eukaryotic genes. This modification takes place after semiconservative replication. There is very little evidence, if any, that 5MeCyt could be naturally incorporated into mammalian DNA in semiconservative replication. We have clarified the possibility of incorporating 5MedCyd pharmacologically into human leukemic cells in vitro. To this end, we developed a novel small-scale synthesis method for 14C-labeled 5MedCyd starting from commercially available [14C]dThd derivatives. Particular attention was focused upon possible incorporation of radioactive 5MedCyd derivatives into the acid-soluble cellular fraction as well as into nucleic acids and protein in human cells. The results showed that [2(-14)C]- and [methyl-14C]5MedCyd were incorporated into human leukemic cells to a similar extent. The radioactivity originating from these compounds was incorporated mainly into the acid-soluble pool and nucleic acids. The exact nature of the intracellular radioactive molecules in RNA is not known, but the radioactive label in DNA hydrolyzate co-chromatographed exclusively with thymine. Hence, 5MedCyd is deaminated to thymidine before incorporating into DNA. This deamination had taken place already (partially) in the culture medium. Human leukemic cells do effectively protect their DNA from incorporation of exogenous 5MedCyd.     

Disposition of 5-fluorouracil during chronic hepatic arterial infusion to patients with carcinoma in the liver and effect on circulating platelets

5-Fluorouracil was administered by continuous hepatic intra-arterial infusion to eight patients with the diagnosis of cancer of the gastrointestinal tract and hepatic metastases. Its elimination characteristics were investigated to see if they correlated with therapeutic effect or reduced clinical toxicity when the drug was given by this route. Urinary excretion of drug and metabolites was similar to findings after intravenous bolus doses. Disposition changes could not be correlated with therapeutic effect or clinical toxicity. A dose-related biphasic effect of 5-fluorouracil was found on circulating platelets. Doses greater than 6 mg kg^?1 d^?1 decreased the number of circulating platelets, while doses less than that resulted in an increase in circulating platelets. Further studies are required to determine the mechanism of the effect of 5-fluorouracil on platelets.     

Serotonin transporter (5-HTT) promoter genotype may influence the prolactin response to clomipramine

RATIONALE: A 44-base-pair insertion/deletion polymorphism in the promoter region of the human serotonin (5-HT) transporter (5-HTT) gene gives rise to a bi-allelic polymorphism designated long (l) and short (s). The s variant is associated with a lower expression of 5-HTT sites and a reduced efficiency of 5-HT reuptake. OBJECTIVE: The aim of the present study was to determine whether the increase in brain 5-HT function produced by acute 5-HT reuptake blockade is influenced by the 5-HTT promoter l/s polymorphism. METHODS: We measured the increase in plasma prolactin that follows acute administration of the tricyclic antidepressant clomipramine as an index of 5-HT neurotransmission in 14 healthy female subjects (7 with ss genotype and 7 with ll genotype) using a placebo-controlled crossover design. RESULTS: Clomipramine-induced prolactin release was significantly greater in subjects with the ll genotype. CONCLUSION: Our findings suggest that acute 5-HT reuptake blockade produces a greater increase in 5-HT neurotransmission in subjects with the ll genotype than in those with an ss genotype. These results are consistent with clinical data indicating that subjects with an ss genotype may have a poorer therapeutic response to selective serotonin reuptake inhibitor (SSRI) monotherapy.     

5-Methoxytryptamine and 2-methyl-5-hydroxytryptamine-induced desensitization as a discriminative tool for the 5-HT3 and putative 5-HT4 receptors in guinea pig ileum

Summary Agonist-induced desensitization has been utilized to discriminate and independently isolate the neuronal excitatory receptors to 5-hydroxytryptamine (5-HT) in the guinea pig ileum (5-HT₃ and putative 5-HT₄ receptors). Electrically stimulated longitudinal muscle myenteric plexus preparations, and non-stimulated segments of whole ileum were used. Exposure to 5-methoxytryptamine (10 mol/l) inhibited completely responses to 5-HT at the putative 5-HT₄ receptor without affecting 5-HT₃-mediated responses. Conversely, exposure to 2-methyl-5-HT (10 mol/l) inhibited completely responses to 5-HT at the 5-HT₃ receptor without affecting putative 5-HT₄-mediated responses. The inhibition with 5-methoxytryptamine and 2-methyl-5-HT, either alone or in combination, appeared selective as responses to KCI, DMPP, carbachol, histamine, and substance P were unaffected or only very slightly modified. Furthermore, the pA₂ values for ICS 205–930 at the putative 5-HT₄ (pA₂ = 6.2 to 6.5) and 5-HT₃ (pA₂ = 7.6 to 8.1) receptors (estimated in the presence of 2-methyl-5HT and 5-methoxytryptamine, respectively) were consistent with those estimated in the absence of desensitization.5-Methoxytryptamine, but not 2-methyl-5-HT, suppressed completely but reversibly the concentration-effect curve to renzapride, suggesting that responses to this agent are mediated exclusively via agonism at the putative 5-HT₄ receptor.It is concluded that 5-methoxytryptamine and 2-methyl-5-HT can be utilized as selective probes to discriminate the putative 5-HT₄ receptor from the 5-HT₃ receptor in guinea pig ileum. This finding is of importance as no selective antagonist exists for the putative 5-HT₄ receptor. Furthermore, the presently described method of agonist-induced desensitization and 5-HT receptor discrimination may be useful for the identification and characterization of the putative 5-HT₄ receptor in other tissues and species. Send offprint requests to D. E. Clarke at the above address     

Aromatic L-amino acid decarboxylase in calcitonin-producing cells

A common feature of the calcitonin-producing cells (C cells) is their capacity to produce and store arylethylamines. The activity of aromatic l-amino acid decarboxylase (DOPA/5-HTP decarboxylase) was measured radiometrically in the thyroid glands of various species and in the ultimobranchial gland of the chicken. The enzyme activity was well correlated with the number of amine-containing C cells, demonstrated by fluorescence microscopy in these tissues. The ultimobranchial gland had a conspicuously high activity of aromatic amino acid decarboxylase. The follicular cells of the thyroid appeared to have no or only a very low activity of this enzyme.     

注射用脱氧氟尿苷与5-氟尿嘧啶对照治疗恶性肿瘤121例

目的:验证和比较注射用脱氧氟尿苷(5'-DFUR)和5-氟尿嘧啶(5-FU)抗肿瘤疗效和安全性.方法:121例晚期恶性肿瘤患者进行5'-DFUR单药(n=22)或联合化疗(n=99),后者随机分为治疗组(n=54)和5-FU对照组(n=45).5'-DFUR用法为3 000mg·m-2,静脉滴注,d1～d5;5-FU用法为750mg·m-2,静脉滴注,d1～d5;单药和联合化疗组均给药21～28d为1个周期,2个周期为1个疗程.结果:可评价疗效119例患者,单药组有效率13.6%(3/22),各病种之间差异无显著性.联合化疗中,对照组有效率为11.6%(5/43),治疗组有效率为20.4%(11/54),两组之间差异无显著性,既往治疗与否与疗效无明显相关性.单药组主要不良反应为白细胞下降、恶心呕吐、乏力、腹泻、口腔溃疡等.联合化疗组的不良反应主要为骨髓抑制、恶心呕吐、乏力、神经毒性及口腔黏膜损伤等,治疗组和对照组差异无显著性.结论:5'-DFUR单药和联合其他药物对乳腺癌、胃肠道肿瘤均有一定疗效,但与5-FU对照组之间差异无显著性.     

Recent developments in C5/C5a inhibitors

Complement factor 5a (C5a) is formed upon complement system activation in response to infection, injury or disease. Whilst C5a is a potent mediator of immune and inflammatory processes, excessive production or inadequate regulation of C5a has been implicated in the pathogenesis of numerous immuno-inflammatory diseases, predominantly through experimental studies utilising animal models of disease. Both acute and chronic conditions may benefit from C5a inhibition, including rheumatoid arthritis, inflammatory bowel disease, asthma, psoriasis, haemorrhagic shock and neurodegenerative conditions. The potentially broad clinical application for treatments that inhibit the activity of C5a at C5a receptors and the large global market for anti-inflammatory therapeutics have made C5a and the C5a receptor attractive targets for academic and commercial drug development programmes. In the past 5 years, interest in C5a as a drug target has grown substantially, and this activity has resulted in a collection of patents and scientific papers reporting novel C5a and C5a receptor inhibitors and antagonists, and generated a secondary stream of patent applications broadly claiming the use of C5/C5a inhibitors as a method of treating various immune and inflammatory conditions. This paper will review the physiology and pathophysiology of C5a and discuss the development of C5a and C5a receptor inhibitors in light of the recent scientific and patent literature.     

Antagonism of baclofen's effects on rat striatal 5-HT metabolism: A model for 5-HT agonistic properties?

The increase in the rat striatal concentration of 5-hydroxyindoleacetic acid (5-HIAA) elicited by baclofen was antagonized by the 5-HT antagonists pipamperone (10/30 mg/kg i.p.), cyproheptadine (30 mg/kg i.p.), methiothepin (1 mg/kg i.p.), and GP 50 302 (1/3 mg/kg i.p.), but not by cinanserin (1–30 mg/kg i.p.), pizotifen (1–10 mg/kg i.p.), spiroperdol (0.1–1 mg/kg i.p.), or haloperidol (0.1–1 mg/kg i.p.). The 5-HT agonists, m-chlorophenylpiperazine (1 mg/kg i.p.) and MK 212 (3/10 mg/kg i.p.) also showed an antagonistic effect. Methysergide (5–20 mg/kg i.p.) and quipazine (2.5/5 mg/kg i.p.) were previously shown to act similarly, whereas mianserin (5–20 mg/kg i.p.) was inactive and methergoline at lower doses (0.25–0.5 mg/kg i.p.) increased the effect of baclofen, which was reversed at higher doses (1 mg/kg i.p.). The alterations by these compounds of the 5-HT increase elicited by baclofen were more or less similar; however, they were less clear-cut and occurred at higher doses. These interactions were not the result of interferences of the compounds with the absorption, distribution, or metabolism of baclofen nor with its effect on the nigrostriatal dopaminergic system, since the increase in dopamine concentrations it caused was not affected by any of the compounds. A comparison of our results with published data on the antagonism of 5-hydroxytryptophan-induced head twitches, on spiroperidol or 5-HT displacement, on 5-HT-stimulated adenylate cyclase, and with electrophysiological results suggests that the antagonistic effect of compounds interfering with the 5-HIAA elevating action of baclofen is not related to 5-HT receptor blocking properties of these drugs, Instead, it seems to be much more related to 5-HT agonists properties. It is speculated that this model might reveal presynaptic agonistic properties of drugs, but more data are needed to confirm or reject this.