Cerebral ischemia remains a major problem for patients requiring anesthesia and surgery. This is particularly true for some procedures including carotid endarterectomy, cardiopulmonary bypass, and intracranial aneurysm surgery. Our work is devoted to improving knowledge of the effects of anesthetics on ischemic brain damage so as to reduce perioperative neurologic morbidity. To this end, we have developed several rat models of cerebral ischemia which allow us to mimic intraoperative events and examine the roles of anesthetic agents in these processes. This proposal contains two conceptual components. The first is to further define roles and limitations for existing anesthetic agents as cerebral protectants against both global and focal ischemic insults. Our work has allowed us to predict that anesthetics, which reduce cerebral metabolic rate, will provide improved outcome from brief episodes of global ischemia of varying magnitudes of severity. We also believe that some anesthetics, barbiturates in particular, reduce focal ischemic brain damage by mechanisms other than simple reduction in energy requirements. If so, then substantially lower doses of drug may be as beneficial as the very deep anesthetic states previously found to be protective. We thus intend to examine a dose-response relationship between depth of barbiturate anesthesia during focal ischemia and ultimate histologic/neurologic outcome. Finally, the simple possibility has not been directly addressed as to whether the anesthetic state itself is protective. Recent advances in rat models of cerebral ischemia now allow us to compare and explain outcome differences between groups of animals undergoing ischemia while anesthetized vs awake. The second component of this proposal is to improve understanding concerning a new class of drugs that could serve as neuroprotective anesthetics. These drugs inhibit excitatory neurotransmission by selectively antagonizing postsynaptic glutamate receptors. Although originally developed as anti-ischemic drugs, these compounds also produce anesthesia. We have shown that such drugs potentiate one another if given simultaneously. The experiments proposed herein have been designed to further define functional relationships between different glutamate receptors in the postischemic brain by examining anesthetic and anticonvulsant properties of glutamate antagonists. This work will be supplemented by quantification of ischemia/anesthetic effects on glutamate receptor binding kinetics and glutamate dependent synthesis of nitric oxide. Because glutamate antagonists provide both cerebral protection and anesthesia, this work may allow an entirely new mechanistic approach for anesthesia to emerge which possesses major neuroprotective properties.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM039771-09
Application #
2180021
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1988-04-01
Project End
1997-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
9
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Duke University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Kudo, M; Aono, M; Lee, Y et al. (2001) Absence of direct antioxidant effects from volatile anesthetics in primary mixed neuronal-glial cultures. Anesthesiology 94:303-212
Kudo, M; Aono, M; Lee, Y et al. (2001) Effects of volatile anesthetics on N-methyl-D-aspartate excitotoxicity in primary rat neuronal-glial cultures. Anesthesiology 95:756-65
Mackensen, G B; Nellgard, B; Sarraf-Yazdi, S et al. (2000) Post-ischemic RSR13 amplifies the effect of dizocilpine on outcome from transient focal cerebral ischemia in the rat. Brain Res 853:15-21
Sheng, H; Kudo, M; Mackensen, G B et al. (2000) Mice overexpressing extracellular superoxide dismutase have increased resistance to global cerebral ischemia. Exp Neurol 163:392-8
Nellgard, B; Mackensen, G B; Massey, G et al. (2000) The effects of anesthetics on stress responses to forebrain ischemia and reperfusion in the rat. Anesth Analg 91:145-51
Nellgard, B; Mackensen, G B; Pineda, J et al. (2000) Anesthetic effects on cerebral metabolic rate predict histologic outcome from near-complete forebrain ischemia in the rat. Anesthesiology 93:431-6
Mackensen, G B; Nellgard, B; Kudo, M et al. (2000) Periischemic cerebral blood flow (CBF) does not explain beneficial effects of isoflurane on outcome from near-complete forebrain ischemia in rats. Anesthesiology 93:1102-6
Sheng, H; Brady, T C; Pearlstein, R D et al. (1999) Extracellular superoxide dismutase deficiency worsens outcome from focal cerebral ischemia in the mouse. Neurosci Lett 267:13-6
Miura, Y; Mackensen, G B; Nellgard, B et al. (1999) Effects of isoflurane, ketamine, and fentanyl/N2O on concentrations of brain and plasma catecholamines during near-complete cerebral ischemia in the rat. Anesth Analg 88:787-92
Sheng, H; Laskowitz, D T; Pearlstein, R D et al. (1999) Characterization of a recovery global cerebral ischemia model in the mouse. J Neurosci Methods 88:103-9

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