Anesthetics, GABA and the Injured Brain

麻醉剂、GABA 和受伤的大脑

基本信息

批准号：
6699672
负责人：
DAVID WARNER
金额：
$ 29.88万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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）：围手术期的中风仍然是手术期间的主要风险。挥发性麻醉剂可以预防实验性脑缺血，但没有定义该机制。我们假设这种挥发性麻醉剂增强了GABA能神经传递，并增强了CII涌入。这种超极使神经元延迟了缺血性去极化和Ca2 ++流入。该假设来自观察结果，即挥发性麻醉剂增强了GABAA受体和Bicuculline（GABAA拮抗剂），可以在体外逆转异氟烷保护。我们还假设挥发性麻醉性GABA能特性比谷氨酸受体拮抗性能更重要。我们提出了这些具体目的：1）在大鼠前脑缺血期间定义异氟烷保护的剂量反应/与Muscimol的功效进行比较，Muscimol（一种GABAA受体激动剂/比较）与缺血性去极化和缺血性去极化和缺血性的脑内代谢率的时间进行比较； 2）确定针对严重的前脑缺血的异氟烷神经保护是否永久； 3）比较选择性NMDA/AMPA受体拮抗作用与异氟烷的相对神经保护作用，这也具有GABA能增强； 4）确定GABAA增强在异氟烷防御严重前脑缺血中的作用。对于特定目的＃4，我们将检查：a）a）如果抗异氟硫素防护剂或纹状体NMDA微型注射会被GABAA拮抗剂（Flurothyl，bicuculline，flumazenil，flumazenil）逆转，B）如果等异氟尿液延迟了偶然的Ca2+ ca2 +++ ca2+++ ca2+++ ca2+++ ca2+++ ca2+++ ca2++ ca2+++ ca2++ ca2+++ ca2++ ca2 +++在Gabaa拮抗剂的情况下，c）如果通过延长缺血持续时间对这种延迟进行校正，等效地逆转了神经保护，d）Gabaa beta亚基 - 触头靶向删除（敲除）或纹状体抗异源性的寡核苷酸对含量的差异性含量含量含量含量含量。异氟烷在有机型海马切片中提供了保护，可抵抗NMDA兴奋毒性或氧/葡萄糖剥夺以及对CI-take的各自影响，f）f）摄取的程度是由GABAA，GABAA，GABAB和Strychnine敏感的Glycine Grycine受体和Glycine受体和Glycine受体以及Glycine受体和Glycine受体和GLYCINE受体和Glycine受体以及Glycine受体和Glycine受体和Glycine受体，以及）在NMDA刺激的突触瘤中，异氟烷和GABAA拮抗剂在CI-++摄取中的关系之间的关系。我们认为，已知对麻醉至关重要的挥发性麻醉剂的Gabaa能药理特性是赋予大脑保护的相同特性。