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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067139-02
Application #
6699672
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2003-02-01
Project End
2007-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$298,760
Indirect Cost
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Wise-Faberowski, Lisa; Robinson, Prairie Neeley; Rich, Sarah et al. (2009) Oxygen and glucose deprivation in an organotypic hippocampal slice model of the developing rat brain: the effects on N-methyl-D-aspartate subunit composition. Anesth Analg 109:205-10
Wise-Faberowski, Lisa; Warner, David S; Spasojevic, Ivan et al. (2009) Effect of lipophilicity of Mn (III) ortho N-alkylpyridyl- and diortho N, N'-diethylimidazolylporphyrins in two in-vitro models of oxygen and glucose deprivation-induced neuronal death. Free Radic Res 43:329-39
Sakai, Hiroaki; Sheng, Huaxin; Yates, Robert B et al. (2007) Isoflurane provides long-term protection against focal cerebral ischemia in the rat. Anesthesiology 106:92-9;discussion 8-10
Wise-Faberowski, Lisa; Pearlstein, Robert D; Warner, David S (2006) NMDA-induced apoptosis in mixed neuronal/glial cortical cell cultures: the effects of isoflurane and dizocilpine. J Neurosurg Anesthesiol 18:240-6
Elsersy, Hazem; Mixco, Javier; Sheng, Huaxin et al. (2006) Selective gamma-aminobutyric acid type A receptor antagonism reverses isoflurane ischemic neuroprotection. Anesthesiology 105:81-90
Wise-Faberowski, Lisa; Zhang, Haito; Ing, Richard et al. (2005) Isoflurane-induced neuronal degeneration: an evaluation in organotypic hippocampal slice cultures. Anesth Analg 101:651-7, table of contents
Elsersy, Hazem; Sheng, Huaxin; Lynch, John R et al. (2004) Effects of isoflurane versus fentanyl-nitrous oxide anesthesia on long-term outcome from severe forebrain ischemia in the rat. Anesthesiology 100:1160-6
Wise-Faberowski, Lisa; Aono, Mitsuo; Pearlstein, Robert D et al. (2004) Apoptosis is not enhanced in primary mixed neuronal/glial cultures protected by isoflurane against N-methyl-D-aspartate excitotoxicity. Anesth Analg 99:1708-14, table of contents
Yokoo, Noriko; Sheng, Huaxin; Mixco, Javier et al. (2004) Intraischemic nitrous oxide alters neither neurologic nor histologic outcome: a comparison with dizocilpine. Anesth Analg 99:896-903, table of contents
Bickler, Philip E; Warner, David S; Stratmann, Greg et al. (2003) gamma-Aminobutyric acid-A receptors contribute to isoflurane neuroprotection in organotypic hippocampal cultures. Anesth Analg 97:564-71, table of contents

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