Anesthetics, GABA and the Injured Brain

麻醉剂、GABA 和受伤的大脑

• 批准号: 6844675
• 负责人: DAVID WARNER
• 金额: $ 29.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844675
• 关键词: GABA receptor; NMDA receptors; anesthetics; brain injury; calcium flux; cerebral ischemia /hypoxia; chlorine; electroencephalography; gamma aminobutyrate; glutamate receptor; hippocampus; inhibitor /antagonist; isoflurane; laboratory mouse; laboratory rat; medical complication; neural transmission; neurons; neuroprotectants; prosencephalon; stroke; tissue /cell culture

DESCRIPTION (provided by applicant): Perioperative stroke remains a major risk during surgery. Volatile anesthetics protect against experimental brain ischemia but the mechanism is not defined. We hypothesize that volatile anesthetics potentiate GABAergic neurotransmission and enhance CI- influx. This hyperpolarizes neurons delaying time to ischemic depolarization and Ca2++ influx. This hypothesis is derived from observations that volatile anesthetics potentiate GABAA receptors and bicuculline, a GABAA antagonist, reverses isoflurane protection in vitro. We also hypothesize that volatile anesthetic GABAergic properties are more important to protection than glutamate receptor antagonistic properties. We propose these Specific Aims: 1) Define a dose-response for isoflurane protection during rat forebrain ischemia/Compare with efficacy of muscimol, a GABAA receptor agonist/Compare with time to onset of ischemic depolarization and pre-ischemic cerebral metabolic rate; 2) Determine if isoflurane neuroprotection against severe forebrain ischemia is permanent; 3) Compare the relative neuroprotective effect of selective NMDA/AMPA receptor antagonism to isoflurane, which also possesses GABAergic potentiation; 4) Determine the role of GABAA potentiation in isoflurane protection against severe forebrain ischemia. For Specific Aim #4, we will examine: a) if isoflurane protection against forebrain ischemia or striatal NMDA microinjections is reversed by GABAA antagonists (flurothyl, bicuculline, flumazenil), b) if isoflurane delays time to ischemia induced Ca2++ influx and if this is reversed by GABAA antagonists, c) if correction for this delay, by extending ischemia duration, equivalently reverses neuroprotection, d) effects of GABAA beta subunit-targeted deletion (knockout) or striatal antisense oligonucleotide microinjection on in vivo isoflurane protection, e) the extent to which isoflurane provides protection in organotypic hippocampal slices against NMDA excitotoxicity or oxygen/glucose deprivation and respective effects on CI- uptake, f) the extent to which this is reversed by antagonists of the GABAA, GABAB, and strychnine sensitive glycine receptors, and g) relationships between isoflurane and GABAA antagonists on CI- and Ca ++uptake in NMDA stimulated synaptoneurosomes. We believe that GABAAergic pharmacologic properties of volatile anesthetics known to be critical for anesthesia are the same properties that confer cerebral protection.

描述（由申请人提供）：围手术期卒中仍然是手术中的主要风险。挥发性麻醉剂对实验性脑缺血有保护作用，但其机制尚不明确。我们假设挥发性麻醉药增强gaba能神经传递并增强CI-内流。这种超极化神经元延迟时间缺血性去极化和Ca2++内流。这一假设来自于对挥发性麻醉剂增强GABAA受体和双管碱（GABAA拮抗剂）在体外逆转异氟烷保护作用的观察。我们还假设挥发性麻醉剂gaba能特性比谷氨酸受体拮抗特性对保护更重要。我们提出以下具体目标：1)确定异氟醚在大鼠前脑缺血时的剂量效应/与GABAA受体激动剂muscimol的疗效比较/与缺血去极化发病时间和缺血前脑代谢率比较；2)确定异氟醚对严重前脑缺血的神经保护是否是永久性的；3)比较选择性NMDA/AMPA受体拮抗剂与具有gaba能增强作用的异氟醚的相对神经保护作用；4)确定GABAA增强在异氟醚对严重前脑缺血的保护作用。对于具体目标#4，我们将检查：a)如果异氟醚对前脑缺血或纹状体NMDA微注射的保护作用被GABAA拮抗剂（氟酰、双库兰、氟马西尼）逆转，b)如果异氟醚延迟缺血诱导Ca2++内流的时间，如果这被GABAA拮抗剂逆转，c)如果通过延长缺血持续时间来纠正这种延迟，相当于逆转神经保护作用，d) GABAA β亚基靶向缺失（敲除）或纹状体反义寡核苷酸显微注射对体内异氟烷保护的影响，e)异氟烷在器官型海马切片中对NMDA兴奋性毒性或氧/葡萄糖剥夺提供保护的程度以及各自对CI摄取的影响，f) GABAA、GABAB和士的宁敏感甘氨酸受体拮抗剂在多大程度上逆转了这种作用。g)异氟醚和GABAA拮抗剂对NMDA刺激下突触体CI-和Ca ++摄取的关系。我们认为，挥发性麻醉药的gaba能药理学特性对麻醉至关重要，与赋予大脑保护的特性相同。