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）：α-氨基丁酸A型（GABAA）受体是递质门控离子通道的Cys环家族的成员。受体通过构象变化响应突触释放的或环境递质，导致门打开，允许离子移动通过通道。 GABAA 受体活性的增强是许多静脉麻醉药（例如依托咪酯和异丙酚）麻醉作用的基础。虽然尚未在临床上积极使用，但神经活性类固醇是 GABAA 受体最有效的增强剂之一。丙泊酚、依托咪酯和神经活性类固醇也直接激活 GABAA 受体，尽管直接激活的浓度通常高于引起增强作用的浓度。我们的初步数据表明，一些神经活性类固醇强烈增强异丙酚或依托咪酯的门控。低浓度的 GABA 与低浓度的类固醇的组合会导致增强程度显着的、超累加的增加。在蝌蚪和小鼠行为测定中，低阈值浓度的增强类固醇的存在会导致剂量反应关系向左移动，从而失去正位，而在细胞系中，类固醇的存在不会影响依托咪酯引起的皮质醇释放抑制。本工作的总体目标是确定类固醇类似物和静脉麻醉药对 GABAA 受体相互作用的机制，并探讨研究结果的临床意义。我们将： i) 检查类固醇与变构激活剂对异源表达系统中表达的重组突触和突触外 GABA 的协同作用； ii) 在蝌蚪和小鼠行为测定中检查类固醇和静脉麻醉药协同作用的行为后果； iii) 探讨在类固醇存在的情况下减少产生镇静所需的麻醉剂剂量是否会导致脱靶效应减少。这些目标的完成将增加我们对GABAA受体在健康和疾病中如何发挥作用的理解，并为未来开发新型治疗方法奠定基础。