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Inhibition of α5 gabaa receptors has preventive but not therapeutic effects on isoflurane-induced memory impairment in aged rats

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Neural Regeneration Research 2019年第6期14卷 1029-1036页

作者： Zi-Fang Zhao Lei Du Teng Gao Lin Bao Yuan Luo Yi-Qing Yin Yong-An Wang Department of Anesthesiology China-Japan Friendship Hospital Department of Radiology China-Japan Friendship Hospital Department of Anesthesiology Beijing Shijitan Hospital Affiliated to Capital Medical University Institute of Pharmacology and Toxicology Academy of Military Medical Sciences

The α5 subunit-containing gamma-amino butyric acid type A receptors(α5 gabaaRs) are a distinct subpopulation that are specifically distributed in the mammalian hippocampus and also mediate tonic inhibitory currents in hippocampal neurons. These tonic currents can be enhanced by low-dose isoflurane, which is associated with learning and memory impairment. Inverse agonists of α5 gabaaRs, such as L-655,708, are able to reverse the short-term memory deficit caused by low-dose isoflurane in young animals. However, whether these negative allosteric modulators have the same effects on aged rats remains unclear. In the present study, we mainly investigated the effects of L-655,708 on low-dose(1.3%) isoflurane-induced learning and memory impairment in elderly rats. Young(3-month-old) and aged(24-month-old) Wistar rats were randomly assigned to receive L-655,708 0.5 hour before or 23.5 hours after 1.3% isoflurane anesthesia.The Morris Water Maze tests demonstrated that L-655,708 injected before or after anesthesia could reverse the memory deficit in young rats. But in aged rats, application of L-655,708 only before anesthesia showed similar effects. Reverse transcription-polymerase chain reaction showed that low-dose isoflurane decreased the mRNA expression of α5 gabaaRs in aging hippocampal neurons but increased that in young animals. These findings indicate that L-655,708 prevented but could not reverse 1.3% isoflurane-induced spatial learning and memory impairment in aged Wistar rats. All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Academy of Military Medical Science of China(approval No. NBCDSER-IACUC-2015128) in December 2015.

关键词： isoflurane postoperative cognitive dysfunction hippocampus inverse agonist α5 gabaa receptors L-655,708 aged Morris Water Maze memory impairment neural regeneration

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小脑顶核gabaa受体介导电针预处理调节交感神经活动减轻心肌缺血再灌注损伤的机制研究

小脑顶核GABAA受体介导电针预处理调节交感神经活动减轻心肌缺血...

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作者：王帅亚安徽中医药大学

学位级别：硕士

目的:观察小脑顶核(Fastigial nucleus,FN)GABA受体参与电针预处理对心肌缺血再灌注损伤(Myocardial ischemia-reperfusion injury,MIRI)大鼠心功能、交感神经活动及心肌损伤相关指标的影响,探讨电针预处理改善MIRI的神经调节机制。方法... 详细信息

目的:观察小脑顶核(Fastigial nucleus,FN)GABA受体参与电针预处理对心肌缺血再灌注损伤(Myocardial ischemia-reperfusion injury,MIRI)大鼠心功能、交感神经活动及心肌损伤相关指标的影响,探讨电针预处理改善MIRI的神经调节机制。方法:将雄性SD大鼠随机分为假手术组、模型组、电针心经组(电针组)、电针肾经组(对照组)、GABA受体激动剂组(激动剂组)、GABA受体抑制剂(抑制剂组)、生理盐水+模型组、生理盐水+电针组、GABA受体激动剂(激动剂)+电针组,每组12只。采用冠状动脉左前降支结扎法制备MIRI模型。电针组、激动剂+电针组、生理盐水+电针组于造模前连续7d给予电针双侧“神门-通里”段,30min/次,1次/d。对照组于造模前连续7d给予电针双侧“复溜-筑宾”段,30min/次,1次/d;激动剂组于造模前连续7d FN注射GABA受体激动剂麝香酮,抑制剂组于造模前连续7d FN注射GABA受体抑制剂荷包牡丹碱,生理盐水+模型组于造模前连续7d FN注射生理盐水。生理盐水+电针组在每次电针前30min FN注射生理盐水,激动剂+电针组在每次电针前30min FN注射麝香酮。用Power Lab标准Ⅱ导联系统采集各组大鼠心电图数据,分析ST段位移值变化及心率变异性(HRV);Hematoxylin-Eosin staining(HE染色)观察大鼠心肌组织病理变化;Triphenyltetrazolium chloride(TTC)观察大鼠心肌梗死面积;ELISA法检测血清肌酸激酶同工酶(Creatine Kinase-MB,CK-MB)、心肌肌钙蛋白I(Cardiac troponin I,c Tn I)和去甲肾上腺素(Noradrenaline,NE)的含量;免疫组织化学法、免疫荧光法和q PCR检测大鼠FN中GABA、GABA和GABA受体的阳性表达。结果1.HE染色结果显示,假手术组心肌细胞排列有序,边缘相对完整;模型组心肌纤维断裂明显,细胞间质水肿严重;电针组心肌组织损害程度减轻,电针对照组心肌组织存在明显的炎性细胞浸润。与假手术组比较,模型组大鼠ST段位移值升高(P0.05)。与模型组比较,模型+荷包牡丹碱组大鼠血清NE含量减少(P0.05);与模型+麝香酮组比较,模型+荷包牡丹碱组大鼠血清NE含量减少(P0.05);与模型+荷包牡丹碱组比较,模型+生理盐水组大鼠血清NE含量增加(P0.05);与电针+麝香酮组比较,电针+生理盐水组大鼠ST段位移值降低(P<0.01),心肌梗死面积减小(P<0.01),血清CK-MB、c Tn I、NE含量均减少(P<0.01),LF/HF比值明显降低(P<0.01),HRV频域分析表明交感神经兴奋性降低。

关键词：小脑顶核 gabaa 心肌缺血再灌注损伤电针预处理交感神经神经机制

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gabaa Receptor Modulation by Compounds Isolated from <i>Salvia triloba</i>L.

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Advances in Biological Chemistry 2014年第2期4卷 148-159页

作者： Abeer Abdelhalim Mary Chebib Talal Aburjai Graham A. R. Johnston Jane R. Hanrahan Adrien Albert Laboratory of Medicinal Chemistry School of Medical Sciences (Pharmacology) University of Sydney Sydney Australia Department of Pharmaceutical Sciences Faculty of Pharmacy University of Jordan Amman Jordan Faculty of Pharmacy University of Sydney Sydney Australia

Salvia triloba, traditionally known as Greek sage, has been used to enhance memory, as a sedative and to treat headaches. Pharmacological evaluation of purified extracts and isolated compounds of S. triloba were carried out on functional assays using two-electrode voltage clamp methods on recombinant GABA receptors expressed in Xenopus laevis oocytes. Bio-assay guided fractionation led to seven compounds being isolated from S. triloba: ursolic acid, carnosol, oleanolic acid, salvigenin, rosmanol, cirsimaritin and hispidulin. The purified extracts of S. triloba inhibited 54% of the current produced by 300 μM GABA at α1β2γ2L gabaa receptors. Ursolic acid, carnosol, oleanolic acid and rosmanol also acted as negative allosteric modulators. The flavonoids salvigenin, cirsimaritin and hispidulin acted as positive modulators when applied in the presence of low concentrations of GABA but in the presence of high concentrations of GABA acted as negative modulators, demonstrating a biphasic action. These results are consistent with the concept that Salvia triloba may have cognition enhancing properties. In most cases these activities are likely to be occurring via different modulatory sites on gabaa receptor complexes. It may be that the combination of these activities permits cognition enhancement whilst offering protection from convulsant activity.

关键词： gabaa Receptors Salvia triloba Flavonoids Sedative Anxiolytics Chromatography Allosteric Modulation

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The adjustment of γ-aminobutyric acid_A tonic subunits in Huntington＇s disease：from transcription to translation to synaptic levels into the neostriatum

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Neural Regeneration Research 2018年第4期13卷 584-590页

作者： Abraham Rosas-Arellano Argel Estrada-Mondragón Carola A.Mantellero Carlos Tejeda-Guzmán Maite A.Castro Instituto de Bioquimica y Microbiologia Facultad de Ciencias Universidad Austral de Chile Valdivia Chile Center for Interdisciplinary Studies on the Nervous System (CISNe) Universidad Austral de Chile Valdivia Chile Departamento de Fisiologla Biofisica y Neurociencias Cinvestav del IPN Ciudad de Mexico Mexico Queensland Brain Institute The University of Queensland Brisbane Australia Laboratorio de Neurociencias Departamento de Biologia Facultad de Quimica y Biologla Universidad de Santiago de Chile Santiago de Chile Chile

γ-Aminobutyric acid（GABA）,plays a key role in all stages of life,also is considered the main inhibitory neurotransmitter.GABA activates two kind of membrane receptors known as gabaa and GABAB,the first one is responsible to render tonic inhibition by pentameric receptors containing α4-6,β3,δ,or ρ1-3 subunits,they are located at perisynaptic and/or in extrasynaptic regions.The biophysical properties of gabaa tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation.On this basis,gabaa tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington＇s disease.Huntington＇s disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein.For experimental studies of Huntington＇s disease mouse models have been developed,such as R6/1,R6/2,Hdh Q92,Hdh Q150,as well as YAC128.In all of them,some key experimental reports are focused on neostriatum.The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures,its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively,they display strong expression of many types of gabaa receptors,including tonic subunits.The studies about of gabaa tonic subunits and Huntington＇s disease into the neostriatum are rising in recent years,suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition,a hallmark of Huntington＇s disease.

关键词： gabaa extrasynaptic and perisynaptic y-aminobutyric acidA receptors striatum R6/1, R6/2,HdhQ92, HdhQ111, HdhQ150, N171-82Q and YAC128 HD transgenics mice models chorea mutanthuntingtin inhibitory neurotransmission D1 medium sized spiny neurons D2 medium sized spiny neurons

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聚焦超声结合gabaa配体的神经调控技术

聚焦超声结合GABAA配体的神经调控技术

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作者：熊伟浙江大学

学位级别：硕士

血脑屏障(BBB)保护神经组织免受毒素和传染物质侵入的同时也阻止了大多数治疗性药物进入大脑。前人的研究表明聚焦超声(FUS)联合循环微泡共同作用下能够安全地暂时性开启血脑屏障。实验室之前的研究通过躯体感觉诱发电位(SSEPs)的变化... 详细信息

血脑屏障(BBB)保护神经组织免受毒素和传染物质侵入的同时也阻止了大多数治疗性药物进入大脑。前人的研究表明聚焦超声(FUS)联合循环微泡共同作用下能够安全地暂时性开启血脑屏障。实验室之前的研究通过躯体感觉诱发电位(SSEPs)的变化证明了单独聚焦超声诱导血脑屏障开放时伴随着神经调控效应的产生。本研究提出,聚焦超声诱导血脑屏障开放联合静脉注射Y-氨基丁酸A型(GABA)配体能够诱导出超强神经调控。通过尾静脉注射微泡后将机械强度值(MI)为0.5的聚焦超声作用于Sprague-Dawley大鼠左前肢初级躯体感觉皮层区(SIFL)90秒,在大鼠血脑屏障开启后通过尾静脉注射GABA受体激动剂蝇蕈醇(MUS,0.2,0.4及1.0mg/kg)或GABA受体拮抗剂木防己苦毒素(PTX,0.2,0.4及1.0mg/kg)。通过测试触痛觉阈值(MNT)来评估聚焦超声作用前后大鼠行为上的改变,记录SSEPs来分析相应神经元的活动情况,在FUS联合GABA配体作用后1.5小时牺牲大鼠进行c-fos,CAMKII,Dapi切片染色取得免疫组织化学变化。结果表明FUS作用后3小时内大鼠右前肢(FUS作用侧)MNT值相比于对侧发生了明显的改变。在FUS作用后1小时内FUS作用侧的SSEPs波形根据注射GABA配体的不同而呈现不同的趋势,而且其幅值在MUS或PTX药物组中呈现出浓度依赖性。c-fos,CAMKII和Dapi染色结果表明MUS和PTX在FUS开启BBB后能够进入到S1FL区抑制或激发相应神经元的活动。综上所述,FUS联合GABA配体诱导的超强神经调控能够影响大鼠触痛觉灵敏度、神经元活动和免疫组化表达,而且影响随着药物剂量升高而增加。本研究提出了一种新颖无创的、可恢复的局部神经调控方法,未来将在基础神经科学研究与临床应用中发挥重要作用。

关键词：聚焦超声血脑屏障神经调控 gabaa

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Pharmacological inhibition of cation-chloride cotransporters for neurological diseases

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Neural Regeneration Research 2015年第12期10卷 1924-1925页

作者： Rachel Nepomuceno Dandan Sun Department of Neurology University of Pittsburgh Veterans Affairs Pittsburgh Health Care System Geriatric ResearchEducational and Clinical Center

γ-Aminobutyric acid（GABA）is a major neurotransmitter and plays important roles in both the developing and mature central nervous system（CNS）.One way that GABA can act is by binding to fast,ionotropic gabaa recept... 详细信息

关键词： Cl Pharmacological inhibition of cation-chloride cotransporters for neurological diseases gabaa

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爪蟾视觉发育过程中抑制性gabaa受体功能的变化(英文)

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中国神经科学杂志 2003年第4期19卷 216-222页

作者：王红温小红蔡浩然北京大学第一医院中心实验室北京100034

目的 :阐明从幼年 (变态脱尾后 2～ 12周 )到成年 (变态脱尾后 5～ 10月 )爪蟾的视顶盖神经元突触受体变化。方法 :盲法脑片全细胞电压钳技术。结果 :成年视顶盖神经元的微抑制性突触后电流 (mIPSCs)的发放频率 (Hz)和平均振幅 (pA)分... 详细信息

目的 :阐明从幼年 (变态脱尾后 2～ 12周 )到成年 (变态脱尾后 5～ 10月 )爪蟾的视顶盖神经元突触受体变化。方法 :盲法脑片全细胞电压钳技术。结果 :成年视顶盖神经元的微抑制性突触后电流 (mIPSCs)的发放频率 (Hz)和平均振幅 (pA)分别为 2 .6 5± 0 .6 9和 9.82± 1.30 ,而幼年的分别为 0 .6 8± 0 .2 3和 15 .36± 2 .4 0 ,其中成年动物的mIPSCs的频率是幼年频率的 3.90倍 ;乙酰胆碱受体 (nAChR)激动剂carbachol均可使幼年及成年的mIPSCs频率增加 ,增强效率有所不同 ,幼年增加至对照组的 192 .0 % ,而成年组仅为 14 6 .2 %。结论 :随着视顶盖神经元的成熟 ,其突触gabaa受体功能也相应增强。

关键词：爪蟾视觉发育 gabaa 受体功能视顶盖神经元突触受体电压钳

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Neonatal seizures and disruption to neurotransmitter systems

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Neural Regeneration Research 2017年第2期12卷 216-217页

作者： Stephanie M.Miller Kate Goasdoue S.Tracey Bjorkman The University of Queensland UQ Centre for Clinical ResearchHerston QLD Australia

Seizure disorders and epilepsies are well documented to be associated with long-term neurological and cognitive deficits in the adult and pediatric patients,but what about seizures in the newborn？The neonatal brain i... 详细信息

关键词： AEDs Neonatal seizures and disruption to neurotransmitter systems gabaa Cl NMDA

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CoMFA analysis on a set of new noncompetitive GABA_A receptor antagonists:fipronil and related analogs

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计算机与应用化学 2005年第12期22卷 1168-1172页

作者： HAO Yanli JU Xiulian School of Chemical Engineering and Pharmacy Hubei Key Laboratory of Novel Reactor and Green Chemical Technology WuhanInstitute of Chemical Technology Wuhan 430074 Hubei China

Fipronil and related analogs, a set of new noncompetitive gabaa receptor antagonists, were investigated using comparative molecular field analysis (CoMFA) to explore their three-dimensional quantitative structure-activity relationships (3D-QSAR). Considering the structural complexity of molecules of fipronil and related analogs, three different alignments were performed in this paper. CoMFA model for housefly receptor yield the leave-one-out and cross-validated correlation coefficient q2 value of 0.511 and the conventional correlation coefficient r2 value of 0.997. The new compounds with higher activity would be designed from this model. CoMFA model for rat receptor was not successful using all these three alignments, the reason of which maybe that some molecules adopt different conformations for rat receptor.

关键词：促肾上腺皮质释放因子 CRF 抑制剂 CoMFA gabaa γ-氨基酪酸神经系统

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背侧纹状体gabaa受体gabaaα1参与ATS成瘾的机制研究

背侧纹状体GABAA受体GABAAα1参与ATS成瘾的机制研究

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中华医学会第十三次全国精神医学学术会议

作者：焦东亮刘瑶赵敏刘景根上海交通大学医学院附属上海市精神卫生中心中国科学院上海药物研究所

目的研究背侧纹状体gabaa受体及gabaaα1参与甲基苯丙胺成瘾的主要机制,为阐明安非他命类兴奋剂(Amphetamine-type stimulants,ATS))成瘾的机理,以及开发新的有效的治疗ATS成瘾的药物提供实验基础。方法甲基苯丙胺1mg/kg腹腔注射大鼠,... 详细信息

目的研究背侧纹状体gabaa受体及gabaaα1参与甲基苯丙胺成瘾的主要机制,为阐明安非他命类兴奋剂(Amphetamine-type stimulants,ATS))成瘾的机理,以及开发新的有效的治疗ATS成瘾的药物提供实验基础。方法甲基苯丙胺1mg/kg腹腔注射大鼠,制作条件位置偏爱(conditioned place preference,CPP)的动物模型;用Western blot检测CPP大鼠前额叶皮层、背侧纹状体、伏隔核、背侧海马、杏仁核五个脑区的gabaaα1的表达;在制作C2PP模型前10分钟分别向相应的脑核团微注射zolpidem(gabaaα1激动剂)、muscimol(gabaa激动剂)和bicuculine(gabaa抑制剂),观测这些药物对大鼠甲基苯丙胺成瘾行为的影响。结果甲基苯丙胺C PP大鼠的五个脑区中,只有背侧纹状体gabaaα1的表达下调(Pgabaa受体是广泛分布于中枢神经系统内、最为普遍的抑制性神经递质受体,gabaaα1是其分布最广泛的亚基,最近有研究表明gabaaα1的激活会影响学习记忆的形成。本研究检测了甲基苯丙胺CPP大鼠成瘾相关脑区的gabaaα1的表达,发现只有背侧纹状体gabaaα1表达下调,gabaa受体及gabaaα1的激活可以明显抑制ATS成瘾的形成,提示背侧纹状体在ATS成瘾学习记忆过程中具有重要的作用,作用机制可能与gabaa参与调节的基底节-皮层神经环路相关。围绕gabaa受体及gabaaα1可能开发出有效的预防和治疗ATS成瘾的药物。

关键词： ATS 背侧纹状体 gabaa gabaaα1

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