腺苷受体调节睡眠觉醒作用机制进展

腺苷是ATP代谢产物,在脑内广泛存在。腺苷受体分为A1、A2A、A2B和A3四种受体(re-ceptor,R)亚型。研究显示:内源性腺苷可能通过A1R和A2AR发挥睡眠调节作用。A1R在中枢系统分布广泛,兴奋位于觉醒系统组胺能、基底前脑胆碱能神经上的A1R,诱发睡眠;腺苷A2AR相对集中分布于前脑区,兴奋A2AR可引起强大的睡眠效应;A2AR可能介导内源性前列腺素D2的睡眠调节作用,是咖啡因促觉醒作用的主要靶点。A1R和A2AR在睡眠觉醒调节中的贡献,至今仍有很大争议,本文综述腺苷受体睡眠调节作用研究进展。     

前列腺素DP受体缺乏小鼠的睡眠-觉醒特征

目的：探讨前列腺素DP受体（DPR）对小鼠睡眠-觉醒调节的影响。方法：在苯巴比妥麻醉下，于DPR基因敲除（KO）小鼠及其野生型（WT）小鼠大脑皮层及颈部肌肉分别植入脑电（Electroencephalogram，EEG）和肌电（Electromyogram，EMG）电极，用EEG／EMG睡眠记录系统于20：00时开始连续记录24小时两种小鼠的脑电和肌电波，并用SLEEPSIGN软件进行分析。结果：两种小鼠表现出相同的睡眠一觉醒节律，且明时（8：00-20：00）及暗时（20：00—8：00）时相内两种小鼠的非快动眼（NREM）睡眠和快动眼（REM）睡眠总量无差异。但与WT小鼠相比，DPR-KO小鼠明时内的觉醒频率显著增高，NREM睡眠的平均时程显著缩短；且DPR-KO小鼠睡眠呈现低活性的θ波和高活性的δ波。结论：DPR在介导前列腺素D2诱导的睡眠中起着关键性调节作用。缺乏DPR将导致小鼠呈现低强度片段化的NREM睡眠和高警戒状态的REM睡眠。     

中枢组胺能神经系统调节睡眠-觉醒机制研究进展

哺乳动物组胺能神经元集中分布于下丘脑后部的结节乳头核(tuberomammillary nucleus,TMN),其神经纤维投射至全脑。研究发现,中枢组胺的释放与觉醒时相呈正相关,觉醒期的释放量是睡眠期的4倍;内源性物质前列腺素E2和神经肽阿立新(orexin)激活TMN组胺能神经元,增加组胺释放,促进觉醒;前列腺素D2和腺苷抑制组胺能神经元活性,诱导睡眠。本文综述组胺能神经系统调节睡眠-觉醒研究进展,讨论拟(抗)组胺类药物用于促觉醒或(和)镇静催眠的可能性。     

内源性睡眠促进物质研究进展

睡眠和觉醒的发生及转换可能是脑内神经递质和内源性睡眠促进物质共同作用的结果,同时受昼夜节律调控。Ishimori和Piéron首次发现犬睡眠剥夺后,脑脊液中某种化学物质增多,诱发睡眠,并将其命名为促眠素,即内源性睡眠促进物质。目前已发现前列腺素D2、核苷、细胞因子、神经肽、激素、胺类衍生物及一氧化氮等二十多种内源性睡眠促进物质。本文综述前列腺素D2、腺苷、白细胞介素1和肿瘤坏死因子等调节睡眠的作用机制研究进展。     

多巴胺D2受体调控睡眠-觉醒研究进展

脑内多巴胺（dopamine,DA）参与觉醒相关的运动、认知和奖赏等行为调控。DA能神经元主要位于黑质致密部和腹侧被盖区。DA受体（receptor,R）包括：D1R、D2 R（D2S和D2L）、D3R、D4R和D5R五种亚型。中枢神经内D1R和D2R数目占绝对优势,D2R对内源性DA的亲和力显著高于D1R。近年来,药理学和基因剔除动物等研究发现：D2R是维持觉醒的重要受体,本文综述其研究进展。     

前列腺素的血管活性及其与心血管疾病的关系

前列腺素(prostaglandin,PG)是一类具有广泛生理活性的内源性化合物,哺乳动物许多组织、细胞都能合成前列腺素.在正常生理状态下,血管释放内皮依赖的血管收缩物质和内皮依赖的血管舒张物质,如:前列环素(PGI2)和血栓素A 2(TXA 2),它们共同维持着血管张力的平衡.体内产生的前列腺素不仅对心血管系统的生理功能产生作用,而且前列腺素产生异常与某些心血管疾病的发生亦有关.本文主要总结前列腺素所产生的血管效应,并简要阐述心血管疾病中前列腺素的变化.     

腺苷A2A受体的药理学

由不同类哺乳动物克隆获得的腺苷Ａ２Ａ受体被生理浓度的腺苷激活，进而刺激ｃＡＭＰ一其它介质的形成，嗜中性白细胞、血小板和务砭中均发现这类受体，中枢神经系统中某些细胞内含量尤其丰富。尾状它们与多巴胺Ｄ２受体共存，Ａ２Ａ受体的兴奋造成Ｄ２受体介导的神经传递的减低，作用于Ａ２Ａ受体的药物，可用于修饰对神经和精神疾病有重要关系的多巴胺能神经传递。本文论述了近期开发的Ａ２Ａ受体拮抗剂怎样用来阐明被Ａ２Ａ受体     

原花青素对RAW264.7细胞膜相关前列腺素E2合成酶-1表达的影响

目的探讨原花青素对RAW264.7细胞膜相关前列腺素E2合成酶-1(mPGES-1)表达的影响。方法酶免疫测定法(EIA)检测原花青素对PGE2生成的影响,逆转录聚合酶链反应(RT-PCR)检测mPGES-1mRNA的表达,Western blotting检测mPGES-1蛋白的表达。结果脂多糖(LPS)可以促进RAW264.7细胞PGE2的生成同时上调mPGES-1mRNA和蛋白的表达,而原花青素(4、20 mg.L-1)下调LPS诱导的RAW264.7细胞mPGES-1mRNA和蛋白的表达,从而抑制LPS诱导的RAW264.7细胞PGE2的生成。结论原花青素在mRNA和蛋白水平抑制LPS诱导的RAW264.7细胞mPGES-1表达从而减少PGE2的合成,这可能是原花青素抗炎的机制之一。     

原花青素对RAW264.7细胞膜相关前列腺素E2合成酶-1表达的影响

目的 探讨原花青素对RAW264.7细胞膜相关前列腺素E2合成酶-1(mPGES-1)表达的影响.方法 酶免疫测定法(EIA)检测原花青素对PGE2生成的影响,逆转录聚合酶链反应(RT-PCR)检测mPGES-1mRNA的表达,Western blotting检测mPGES-1蛋白的表达.结果 脂多糖(LPS)可以促进RAW264.7细胞PGE2的生成同时上调mPGES-1mRNA和蛋白的表达,而原花青素(4、20mg·L-1)下调LPS诱导的RAW264.7细胞mPGE-1mRNA和蛋白的表达,从而抑制LPS诱导的RAW264.7细胞PGE2的生成.结论 原花青素在mRNA和蛋白水平抑制LPS诱导的RAW264.7细胞mPGES-1表达从而减少PGE2的合成,这可能是原花青素抗炎的机制之一.     

前列腺素E2受体作为肝细胞癌可能药物作用靶点的研究进展

肝细胞癌(HCC)患者的总生存时间很短,目前尚无有效的全身治疗药物.环氧化酶-2(COX-2)在大多数恶性肿瘤(包括HCC)中都存在过表达.研究显示,COX-2抑制剂通过抑制前列腺素E2(PGE2)合酶的活性,发挥抗HCC作用,但效果有限,长期用药不良反应大.PGE2与不同的前列腺素受体(EPR)作用产生效应,对肝脏的生理和病理功能起到重要调节作用,而EPR在介导PGE2信号的传递中起到重要作用,可能为HCC的治疗提供新的思路.文中综述PGE及其受体对肝脏功能的调节作用及PGE2-EPR信号转导在HCC发生中的作用与机制,将为开发有效的抗肿瘤药物提供新的治疗策略.     

The use of prostaglandin D2 receptor antagonists to treat allergic rhinitis

Two applications describe 1-(heteroarylmethoxybenzoyl)-2-methylindolylacetic acid derivatives that are active as prostaglandin D₂ receptor (DP) antagonists. Both indol-3-ylacetic acid and indol-4-ylacetic acid derivatives have good affinity for the DP receptor. The use of these antagonists for the treatment of various inflammatory diseases is claimed but the preferred indication is allergic rhinitis, with the development compound by Ono Pharm., ONO4217Na, likely to be described in one of the applications.     

Regional differences in the adenosine A(2) receptor-mediated modulation of contractions in rat vas deferens

Adenosine receptors involved in modulation of contractions were characterized in the bisected rat vas deferens by combining pharmacological and immunohistochemical approaches. In both portions, noradrenaline-elicited contractions were enhanced by the adenosine A₁ receptor agonist N⁶-cyclopentyladenosine (CPA), and inhibited by the non-selective adenosine receptor agonist 5′-N-ethylcarboxamidoadenosine (NECA) in the presence of the adenosine A₁ receptor antagonist 1,3-dipropyl-8-cyclopentyl-l,3-dipropylxanthine (DPCPX). The adenosine A_2A receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5′-N-ethylcarboxamidoadenosine (CGS 21680) also inhibited noradrenaline-elicited contractions but only in the prostatic portion. Contractions elicited by the stable ATP analogue ,β-methyleneATP (,β-MeATP) were inhibited only by NECA in the presence of DPCPX and only in the prostatic portion. This study provides functional evidence for the presence, in both portions of the rat vas deferens, of an adenosine A₁ receptor-mediated enhancement and of an adenosine A₂ receptor-mediated inhibition of contractions. The latter effect is mediated by both A_2A and A_2B subtypes in the prostatic portion but only by the A_2B subtype in the epididymal portion. This regional variation is supported by the immunohistochemical results that revealed an adenosine A_2A receptor immunoreactivity not co-localized with nerve fibres more abundant in the prostatic than in the epididymal portion.     

The effect of MK-0524, a prostaglandin D2 receptor antagonist, on prostaglandin D2-induced nasal airway obstruction in healthy volunteers

Introduction Nasal congestion in allergic rhinitis results from tissue edema and vasodilatation in the nasal mucosa. Of the mediators released by mast cells in response to allergens, prostaglandin (PG) D₂ is regarded as the most potent inducer of nasal congestion. Intranasal administration of PGD₂ reproduces the nasal blockade experienced by patients with seasonal allergic rhinitis (SAR) via its action on the PGD₂ (DP) receptor to induce nasal vasodilatation. Intranasal challenge with PGD₂ can be a useful tool for evaluating DP-receptor antagonists. Objective The main purpose of this study was to examine the ability of MK-0524, a DP receptor antagonist in development for the treatment of SAR, to block PGD₂ induced nasal congestion in healthy volunteers. Methods To this end, a double-blind, placebo-controlled, randomized, 3-period study was performed in 15 healthy subjects. During each period, subjects received MK-0524 25 mg, MK-0524 100 mg or placebo qd for 3 days. Twenty-four hours following the last dose, nasal provocations with PGD₂ were performed to determine the PD₇₅, which is the intranasal dose of PGD₂ that provokes a 75% increase in baseline total nasal airway resistance as performed by active anterior rhinomanometry. Results Following treatment with MK-0524, the PD₇₅ (mean±SD) was significantly shifted from 15.8 ± 18.3 μg/nostril during the placebo period to more than 512 μg/nostril both following the 25- and 100-mg (maximum challenge dose tested) dose regimen. Conclusion Whether this >45 fold increase in PD₇₅ will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.     

芸香苷对急性胰腺炎大鼠磷脂酶A2和Ca2+浓度的影响

目的探讨芸香苷(Rutoside,Ru)对急性胰腺炎(AP)大鼠磷脂酶A2(PLA2)和Ca2 浓度的影响。方法脱氧胆酸钠逆行胆胰管注射和胆胰管结扎诱发大鼠AP模型。检测造模后6、12 h血清中Ca2 含量和造模后24 h胰腺组织中PLA2和Ca2 含量。结果Ru 60、120 mg.kg-1(sc)可明显升高造模后12 h AP大鼠的血清Ca2 浓度。Ru(30、60、120 mg.kg-1,sc)可明显增加胰腺组织降低的PLA2含量,降低模型大鼠的胰腺组织过高的Ca2 水平。结论Ru提高胰腺组织PLA2含量,提示Ru可能对胰腺组织PLA2的释放及激活具有抑制作用;Ru能有效防止AP大鼠低钙血症的发生,并降低胰腺组织细胞Ca2 超载。     

PGD2 metabolism in plasma: kinetics and relationship with bioactivity on DP1 and CRTH2 receptors

Prostaglandin (PG)D(2), an important mediator in allergic diseases, is rapidly transformed in plasma to active metabolites that bind and activate two distinct receptors, DP1 and CRTH2. Since the rate of PGD(2) degradation and the bioactivity of the resulting metabolites are still unclear, the aim of our study was to analyze the kinetics and biological effects of PGD(2) metabolites formed in plasma. Eosinophil shape change was taken as a parameter of chemotactic activation mediated by CRTH2 whereas inhibition of platelet aggregation served as a measure of DP1 activity. PGD(2) was degraded in plasma with an apparent half-life of approximately 30 min, accompanied by a loss of potency in inhibiting platelet aggregation as well as inducing eosinophil stimulation. Incubation of PGD(2) in plasma for 120 min caused an increase in the IC(50) for platelet aggregation by a factor of 6.5 and an increase of the EC(50) for eosinophil shape change by a factor of 7.2. However, tandem mass spectrometry analysis showed that incubation of PGD(2) in plasma for 120 min resulted in clearance of PGD(2) of more than 92%, which was mirrored by a continuous formation of Delta(12)-PGD(2) and Delta(12)-PGJ(2), whereas only small amounts of 15d-PGD(2) and 15d-PGJ(2) were detected. Interestingly, a rapid degradation of PGD(2) was also observed in serum, which was not prevented by pepsin digestion of serum preceding the addition of PGD(2). Therefore, despite extensive non-enzymatic metabolization of PGD(2) in plasma, its biological activity with respect to DP1 and CRTH2 is maintained through the formation of bioactive metabolites.     

Discovery of a Novel Series of CRTH2 (DP2) Receptor Antagonists Devoid of Carboxylic Acids

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Effect of serotonergic agents on adenosine A2 receptor mediated catalepsy in mice

The effect of serotonergic agents was studied on the adenosine A₂ receptor agonist NECA-induced catalepsy in mice. The 5-HT releaser fenfluramine, the 5-HT_1A agonist 8-OH-DPAT, the 5-HT_2A/1C receptor agonist DOI and the 5-HT_2A/1C receptor antagonists ketanserin and mianserin reversed NECA-induced catalepsy. p-MPPI and ketanserin reversed the anticataleptic actions of 8-OH-DPAT and DOI, respectively. Further, the 5-HT reuptake inhibitor fluoxetine, the 5-HT_1B/1C receptor agonist TFMPP, the 5-HT synthesis inhibitor p-CPA, the selective 5-HT_1A receptor antagonist p-MPPI, the 5-HT_1A/1B receptor antagonist pindolol and the 5-HT₃ receptor antagonist LY 278, 584 had no effect on NECA-induced catalepsy. The anticataleptic action of fenfluramine was not affected by pretreatment with p-CPA. In p-CPA treated rats, ketanserin did not affect the anticataleptic effect of fenfluramine, whereas p-MPPI partially reversed this effect. It is concluded that modulation of serotonergic neurotransmission at 5-HT_1A and 5-HT_2A/1C receptors affects the cataleptic action of experimental antipsychotic agents with adenosine A₂ receptor agonistic activity. Received: 5 May 1997/Final version: 2 September 1997     

Effects of N-cyclopentyladenosine and caffeine on sleep regulation in the rat

To study the role of adenosine in sleep regulation, the adenosine A₁ receptor agonist N⁶-cyclopentyladenosine (CPA) and the antagonist caffeine were administered to rats. Intraperitoneal (i.p.) CPA 1 mg/kg but not 0.1 mg/kg, suppressed rapid-eye-movement (REM) sleep and enhanced electroencephalographic (EEG) slow-wave activity (power density 0.75–4.0 Hz) in non-REM sleep. The latter effect was remarkably similar to the response to 6-h sleep deprivation. The effects persisted when CPA-induced hypothermia was prevented. Caffeine (10 and 15 mg/kg i.p.) elicited a dose-dependent increase in waking followed by a prolonged increase of slow-wave activity in non-REM sleep. The combination of caffeine (15 mg/kg) and sleep deprivation caused less increase in slow-wave activity than sleep deprivation alone, indicating that caffeine may reduce the buildup of sleep pressure during waking. The results are consistent with the involvement of adenosine in the regulation of non-REM sleep.     

G Protein coupling of CGS 21680 binding sites in the rat hippocampus and cortex is different from that of adenosine A1 and striatal A2A receptors

The effect of guanine nucleotide-binding protein (G protein) modifiers on the binding of the adenosine A_2A receptor agonist 2-[4-(2-p-carboxyethyl[³H])phenyl-amino]-5’-N-ethylcarboxamidoadenosine ([³H]CGS 21680) and of the adenosine A₁ receptor agonist [³H]R-phenylisopropyladenosine ([³H]R-PIA) to rat cortical and striatal membranes was studied. Guanosine 5’-(β,γ-imido)triphosphate (1–300 μM), which uncouples all G proteins, more effectively inhibited [³H]CGS 21680 (30 nM) binding in the cortex than [³H]R-PIA (2 nM) binding to cortical or striatal membranes or [³H]CGS 21680 (30 nM) binding in the striatum. N-Ethylmaleimide (1–300 μM) or pertussis toxin (1–100 μg/ml), which uncouple G_i/G_o protein-coupled receptors, more effectively inhibited [³H]R-PIA binding to cortical or striatal membranes and [³H]CGS 21680 binding in the cortex than [³H]CGS 21680 binding in the striatum. Cholera toxin (2.5–250 μg/ml), which uncouples G_s protein-coupled receptors, more effectively inhibited [³H]CGS 21680 binding in the striatum than [³H]CGS 21680 binding in the cortex and less effectively inhibited [³H]R-PIA binding to cortical or striatal membranes. Treatment of solubilised cortical membranes with pertussis toxin (50 μg/ml) decreased [³H]CGS 21680 (30–100 nM) binding which almost fully recovered after reconstitution with G_i/G_o proteins. The K _i for displacement of [2-³H]-(4-{2-[7-amino-2-(2-furyl)(1,2,4)triazolo(2,3-a)(1,3,5)triazin-5-ylamino]ethyl}phenol) ([³H]ZM 241385, 1 nM) by CGS 21680 was 110 nM (95%CI: 98–122 nM) in non-treated, 230 (167–292) nM in pertussis toxin (25 μg/ml)-treated and 222 (150–295) nM in cholera toxin (50 μg/ml)-treated cortical membranes; in contrast, the K _i for displacement of [³H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine ([³H]SCH 58261, 1 nM) by CGS 21680 was 74 (57–91) nM in non-treated, 71 (44–100) nM in pertussis toxin-treated and 147 (100–193) nM in cholera toxin-treated cortical membranes. Finally, CGS 21680 displaced monophasically the binding of the A₁ antagonist, [³H]8-cyclopentyl-1,3-dipropylxanthine (2 nM), and the A₁ agonist, [³H]R-PIA (2 nM), in 2 or 10 mM Mg²⁺-medium, either at 25°C or 37°C, in cortical or striatal membranes. These results indicate that CGS 21680 does not bind to A₁ receptors and that limbic CGS 21680 binding sites differ from striatal-like A_2A receptors since they couple to G_i/G_o proteins, as well as to G_s proteins. Received: 22 July 1998 / Accepted: 18 January 1999     

Differential regulation of adenosine A(1) and A(2A) receptors in serotonin transporter and monoamine oxidase A-deficient mice.

The serotonin (5HT) transporter (5HTT) removes 5HT from the synaptic cleft and is thus critical to the control of serotonergic neurotransmission. Mice with a targeted inactivation of the 5HTT represent a novel and unique tool to study serotonergic system functioning. Because the release of 5HT is regulated by adenosine, we investigated 5HTT-deficient mice for possible adaptive changes of adenosine A₁ and A_2A receptors. A₁ and A_2A receptors were studied by means of quantitative autoradiography using the radioligands [³H]8-cyclopentyl-1,3-dipropylxanthine and [³H]CGS 21680, respectively. A comparison of 5HTT knockout versus control mice revealed upregulation of A₁ receptors in the dorsal raphe nucleus (DRN, +21%), but not in any of the serotonergic projection areas, and downregulation of A_2A receptors in basal ganglia. The adaptive changes of A₁ and A_2A receptors in 5HTT-deficient mice are likely to represent a compensatory neuroprotective effect mediated by the adenosinergic modulatory system. For comparison, these receptors were also studied in monoamine oxidase A (MAOA) knockout mice and in 5HTT/MAOA double knockout mice. 5HTT/MAOA double knockout mice showed adaptive changes of adenosine A₁ and A_2A receptors similar to 5HTT knockout mice, while investigation of MAOA-deficient mice revealed an upregulation of A_2A receptors, which may relate to a role of both MAOA and adenosine A_2A receptors in anxiety.