SYNERGISTIC ACTIONS OF INTRAVENOUS ANESTHETICS

静脉麻醉药的协同作用

• 批准号: 8758980
• 负责人: GUSTAV AKK
• 金额: $ 30.5万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758980
• 关键词: Adverse effects; Affect; Agonist; Aminobutyric Acids; Anesthesia procedures; Anesthetics; Animals; Anions; Area; Barbiturates; Behavioral; Behavioral Assay; Binding Sites; Brain; Chemosensitization; Clinical; Data; Development; Disease; Dose; Etomidate; Family; Foundations; Future; GABA-A Receptor; Gated Ion Channel; General anesthetic drugs; Goals; Health; Hydrocortisone; Intravenous Anesthetics; Ion Channel; Ions; Lead; Measures; Movement; Mus; Nature; Pharmaceutical Preparations; Pharmacology; Physiology; Property; Propofol; Receptor Activation; Recombinants; Sedation procedure; Site; Specificity; Steroids; Synapses; System; Tadpoles; Work; barbituric acid salt; base; clinically significant; dosage; gamma-Aminobutyric Acid; insight; member; neurosteroids; novel therapeutic intervention; public health relevance; receptor; receptor function; research study; response; steroid analog

DESCRIPTION (provided by applicant): The ?-aminobutyric acid type A (GABAA) receptor is a member of the Cys-loop family of transmitter-gated ion channels. The receptors respond to synaptically-released or ambient transmitter with a conformational change, resulting in the opening of the gate that allows ion movement through the channel. Potentiation of GABAA receptor activity underlies the anesthetic effects of many intravenous anesthetics, such as etomidate and propofol. Although not in active clinical use, neuroactive steroids are among the most potent and efficacious potentiators of the GABAA receptor. Propofol, etomidate and neuroactive steroids also directly activate the GABAA receptor, although the concentrations for direct activation are typically higher than those that cause potentiation. Our preliminary data demonstrate that some neuroactive steroids strongly potentiate gating by propofol or etomidate. Combination of a low concentration of GABA with a low concentration of steroid results in a remarkable, supra-additive, increase in the extent of potentiation. In tadpole and mouse behavioral assays, the presence of a low, subthreshold concentration of a potentiating steroid results in a leftward shift in the dose-response relationship for loss of righting whereas in a cel line the presence of a steroid does not affect etomidate-elicited suppression of cortisol release. The overall goal of the present work is to determine the mechanism of interactions of steroid analogues and intravenous anesthetics on GABAA receptors, and to explore the clinical significance of the findings. We will: i) examine the synergistic effects of steroids with allosterc activators on recombinant synaptic and extrasynaptic GABA expressed in heterologous expression systems; ii) examine the behavioral consequences of synergistic effects of steroids and intravenous anesthetics in tadpole and mouse behavioral assays; and iii) probe whether reduced doses of anesthetics required to produce sedation in the presence of steroids lead to reduced off-target effects. The completion of these aims will increase our understanding of how the GABAA receptor functions in health and disease, and lay a foundation for future development of novel therapeutic approaches.

描述（由申请人提供）：A-氨基丁酸A型（GABAA）受体是发射机门控离子通道的Cys-Loop家族的成员。受体对构象变化的突触发行或环境发射器的反应，导致门的打开，使离子通过通道运动。 GABAA受体活性的增强是许多静脉麻醉药（例如依托氨基和丙泊酚）的麻醉作用的基础。尽管没有积极的临床用途，但神经活性类固醇是GABAA受体中最有效，最有效的增强剂之一。丙泊酚，依托氨基和神经活性类固醇也直接激活了GABAA受体，尽管直接激活的浓度通常高于引起增强的浓度。我们的初步数据表明，某些神经活性类固醇通过丙泊酚或依他太座强烈增强门控。低浓度的GABA与低浓度类固醇的组合会导致显着的，超addive的增强程度增加。在t和小鼠的行为测定中，存在增强类固醇的低，阈值浓度的存在导致剂量反应关系的向左移动，以丧失矫正，而在CEL线中，类固醇的存在并不影响eTomaties-Etomatide-Etomatie-Etomaties-eperient-hiperited抑制皮质醇的抑制。本工作的总体目标是确定类固醇类似物和静脉麻醉药在GABAA受体上的相互作用机制，并探索发现结果的临床意义。我们将：i）检查类固醇与异基因激活剂对异源表达系统中表达的重组突触和外鼻外GABA的协同作用； ii）检查t和小鼠行为测定中类固醇和静脉麻醉的协同作用的行为后果； iii）探测在存在类固醇的情况下产生镇静所需的麻醉剂量是否会导致脱靶效应降低。这些目标的完成将增加我们对GABAA受体如何在健康和疾病中发挥作用的理解，并为新型治疗方法的未来发展奠定基础。