谷氨酸转运体EAAT2在抑郁症发病及治疗中的作用

谷氨酸转运体EAAT2(啮齿类动物命名为GLT-1:谷氨酸转运体1)是海马和前额叶星形胶质细胞上一种非常重要的谷氨酸转运体,其承担了细胞外大部分谷氨酸的摄取和转运,由于谷氨酸转运体EAAT2的作用在于降低突触间隙过高的谷氨酸水平,避免过高浓度的谷氨酸对神经元和神经胶质细胞的兴奋毒性作用,使之逐渐成为近年来抑郁症研究的热点。该文主要就谷氨酸转运体EAAT2在抑郁症中可能的病理生理作用,以及其可能作为新一代抗抑郁药作用的靶点进行综述。     

代谢型谷氨酸受体1缺失导致小鼠蛋白尿和肾小球损伤

谷氨酸是中枢神经系统中数量最多的神经递质。代谢型谷氨酸受体1(GRM1)表达于神经元突触前膜和突触后膜,并通过触发释放细胞内贮存的钙离子,经过一系列信号通路最终调节神经元兴奋性、突触可塑性以及参与神经递质释放     

盐酸埃他卡林对大鼠海马神经元谷氨酸受体功能及突触活动的影响

目的 :研究盐酸埃他卡林 (Ipt)对脑神经元谷氨酸受体功能及突触活动的影响。方法 :采用原代培养的大鼠海马神经元 ,应用膜片钳全细胞记录技术 ,记录Ipt对培养的海马神经元谷氨酸或天冬氨酸(NMDA)诱发电流及神经元突触后电流的影响。结果 :Ipt(1～ 1 0 0 μmol·L- 1)可浓度依赖性地对抗培养的海马神经元谷氨酸或NMDA诱发电流 ,并为ATP敏感性钾通道拮抗剂格列本脲 30 μmol·L- 1所对抗。Ipt抑制培养的海马神经元之间突触联系形成的自发兴奋性突触后电流 ,降低其发放频率 ,抑制其电流幅度 ;但对微小兴奋性突触后电流无显著性影响。结论 :Ipt可阻断脑神经元谷氨酸受体功能 ,抑制脑神经元谷氨酸的兴奋性突触传递 ,其作用与ATP敏感性钾通道相关     

谷氨酸转运体靶点药物的抗脑缺血作用研究进展

兴奋性氨基酸毒性是脑缺血损伤的主要机制之一。缺血期间谷氨酸的大量累积会导致神经元细胞、星形胶质细胞等神经细胞发生兴奋性毒性损伤,因此对缺血期间谷氨酸水平的调控一直是脑缺血防治药物研究的重点。近年来研究表明,通过上调星形胶质细胞上谷氨酸转运体GLAST(EAAT1)和GLT-1(EAAT2)的表达或活性,增加缺血时谷氨酸的摄取,维持突触间隙内谷氨酸的正常浓度,从而降低兴奋性毒性,减轻缺血性脑损伤。一些化合物如β-内酰胺类抗生素、尿酸、甲状腺激素、雌激素、山楂酸等已在体内或体外实验中被证实对谷氨酸转运体的调节作用,对抗谷氨酸毒性,发挥神经保护作用。研究和开发以星形胶质细胞谷氨酸转运体为作用靶点的药物,为缺血性脑损伤的预防和治疗提供了一条新的途径。     

氯胺酮麻醉期间大鼠脑内氨基酸递质水平的变化

氨基酸类递质是主要的中枢神经递质之一 ,对于精神意识活动的调整起着关键作用。现认为全麻药 (尤吸入全麻药 )可通过抑制突触前谷氨酸 (Ｇｌｕ)的释放、增强谷氨酸的再摄取及阻滞突触后兴奋性氨基酸受体而发挥全麻作用[1] 。药物对于天冬氨酸 (Ａｓｐ)、γ 氨基丁酸 (ＧＡＢＡ)和甘氨酸(Ｇｌｙ)的突触前作用则较为复杂 ,不如谷氨酸明显和统一[2 ] ,可能不是全麻药的主要作用部位。有些学者认为氯胺酮对各类氨基酸类递质的摄取与释放过程无明显影响[2 ] ,这些都是离体实验的结论 ,活体动物在麻醉状态下 ,中枢神经系统中的氨基酸类递质水平是…     

兴奋性谷氨酸转运蛋白2作为抑郁治疗靶点的研究进展

抑郁症是一种常见精神性疾病,其主要特征是持续的情绪低落和快感缺失.现有的药物存在起效慢、有效率低、副作用大等诸多不足,因此探索抑郁症的发病机制、研究新的治疗靶点具有重要意义.越来越多证据显示,兴奋性谷氨酸转运蛋白2(excitatory amino acid transporter 2,EAAT2)在抑郁症神经递质传递...     

盐酸埃他卡林对PD模型大鼠脑内突触体谷氨酸摄取的影响

目的　研究谷氨酸转运体功能改变与帕金森病(Parkinson’sdisease ,PD)发病的相关性 ,探讨新型ATP敏感性钾通道 (ATPsensitivepotassiumchannel,KATP)开放剂盐酸埃他卡林 (Iptakalimhydrochloride ,Ipt)对PD模型大鼠脑内突触体摄取谷氨酸的影响及其机制。方法　采用 6 hydrox ydopamine(6 OHDA)建立PD大鼠模型 ,制备脑组织突触体 ;用同位素标记法测定L [3 H] glutamate摄取活性。 结果　PD模型大鼠纹状体和皮层的谷氨酸转运功能明显降低 ;Ipt(10、5 0和 10 0 μmol·L-1)具有恢复转运功能的作用 ,此作用可被KATP阻断剂Glibenclamide (2 0 μmol·L-1)逆转。结论　谷氨酸转运体功能下降与PD发病密切相关 ;Ipt通过激活KATP发挥促进谷氨酸摄取的作用 ,有望成为新一代PD治疗药物     

周边γ-氨基丁酸通过GABA_B受体调控骶髓后联合核神经元谷氨酸能突触

目的研究突触周边γ-氨基丁酸(ambient GABA)通过GABAB受体调控骶髓后联合核(SDCN)神经元谷氨酸能突触的机制。方法在急性切取的骶段脊髓薄片上,利用全细胞膜片钳法记录骶髓后联合核神经元谷氨酸能兴奋性突触后电流(EPSCs),将GABAB受体用其特异性受体拮抗剂CGP52432阻断,观察谷氨酸突触终末上的GABAB受体被周边GABA作用的影响。结果在突触后GABAB受体被从胞内阻断的条件下,再灌流CGP52432阻断谷氨酸能突触前GABAB受体,可增加刺激引发的EPSCs(eEPSCs)幅度;改变配对刺激的两个EPSC比率(paired-pulse ratio,PPR),并激发沉默突触(silent synapse)。但CGP52432对微小兴奋性突触后电流(mEPSCs)无影响。结论位于SDCN神经元谷氨酸能突触前的GABAB受体受周边GABA调控。这种影响参与调节谷氨酸释放并可能参与痛觉信息在脊髓水平的传递。     

兴奋性氨基酸转运体研究进展

兴奋性氨基酸转运体 (EAAT)位于突触前膜、突触囊泡和神经胶质细胞膜上。它们对于兴奋性氨基酸的再循环 ,兴奋性信号的终止以及保护神经细胞免受兴奋性毒性损害具有特别重要的意义。本文介绍EAAT研究进展     

利鲁唑上调EAATs产生对MPTP诱导的帕金森模型小鼠的保护作用

目的探讨MPTP对EAATs的影响及利鲁唑对其诱发帕金森小鼠模型的保护作用。方法选取42只小鼠,随机分为3组:对照组(生理盐水组)、MPTP组(PD模型组)和MPTP+利鲁唑组(利鲁唑治疗组)。采用小鼠转棒实验和疲劳仪实验评价三组小鼠行为学差异;南京建成试剂盒检测纹状体谷氨酸(Glutamate,Glu)含量;Western blot和RT-PCR方法检测小鼠纹状体EAAT1及EAAT2的表达。结果与对照组比较,小鼠转棒潜伏期、疲劳耐力时间及跑步距离均明显减少(P<0.01),Glu含量明显增加(P<0.01),EAAT1及EAAT2 mRNA表达和蛋白水平显著下降。与MPTP组比较,利鲁唑治疗组小鼠转棒潜伏期、疲劳耐力时间及跑步距离均明显增加(P<0.01),Glu含量明显下降(P<0.01),EAAT1及EAAT2 mRNA表达和蛋白水平显著升高。结论利鲁唑可通过上调EAAT1和EAAT2对MPTP诱导的帕金森模型小鼠的运动功能起到保护作用。     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.