Cardiac arrest and stroke are two of the major causes of death and when patients survive it is often with neurological impairment. A massive release of glutamate and aspartate occurs during ischemia, precipitating entry of calcium ions into cells. Resultant effects include a failure of ion pumps, membrane disruption, and the generation, during reperfusion, of toxic oxygen-derived free radicals. The mechanisms underlying ischemia-induced amino acid transmitter release will be studied. Data obtained in this laboratory suggest that this may result from a depolarization-induced reversal of the high affinity, sodium dependent glutamate transporter and not as a calcium-dependent vesicular release. Several experiments are proposed to explore this issue. If glutamate release from ischemic cortical cells is transporter-mediated, it would raise the possibility of using inhibitors of the transporter to control release and injury. Adenine nucleotide loss during ischemia is an important element in the injury process and the rate of recovery of nucleotides during reperfusion is likely to be a significant factor in preventing delayed neuronal death. The loss of adenine nucleotides and their recovery during reperfusion will be measured. Agents which prevent adenosine metabolism will be tested for their """"""""purine sparing and salvage"""""""" potential. A recent dramatic development has been the discovery that cycloheximide, a protein synthesis inhibitor, attenuates damage even when administered 24 hrs postischemia. These studies will be extended to evaluate puromycin, as well as cycloheximide, for cerebroprotective activity using rat and gerbil stroke models. The role of the vasodilator nitric oxide in the regulation of cerebral blood flow and prevention of ischemic injury will be evaluated in rats and gerbils. Studies will be conducted on acetylcholine release from the ischemic cerebral cortex to determine whether or not the pattern parallels that for glutamate and aspartate. The glutamate antagonist atropine, will be tested for cerebroprotective activity. Finally, a study of the susceptibility of female gerbils to cerebral ischemic injury will be compared with that of the males. These experiments will shed further light on the events underlying cerebral ischemic injury and should lead to novel approaches to the prevention and treatment of stroke related damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026912-06
Application #
2266193
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-12-01
Project End
1995-07-14
Budget Start
1993-12-01
Budget End
1995-07-14
Support Year
6
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Wayne State University
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Phillis, John W; O'Regan, Michael H (2003) Studies on taurine efflux from the rat cerebral cortex during exposure to hyposmotic, high K+ and ouabain-containing aCSF. Adv Exp Med Biol 526:433-44
Phillis, John W; O'Regan, Michael H (2002) Energy utilization in the ischemic/reperfused brain. Int Rev Neurobiol 51:377-414
Phillis, J W; Ren, J; O'Regan, M H (2001) Studies on the effects of lactate transport inhibition, pyruvate, glucose and glutamine on amino acid, lactate and glucose release from the ischemic rat cerebral cortex. J Neurochem 76:247-57
Guyot, L L; Diaz, F G; O'Regan, M H et al. (2001) Real-time measurement of glutamate release from the ischemic penumbra of the rat cerebral cortex using a focal middle cerebral artery occlusion model. Neurosci Lett 299:37-40
Guyot, L L; Diaz, F G; O'Regan, M H et al. (2001) The effect of streptozotocin-induced diabetes on the release of excitotoxic and other amino acids from the ischemic rat cerebral cortex. Neurosurgery 48:385-90; discussion 390-1
Guyot, L L; Diaz, F G; O'Regan, M H et al. (2000) Topical glucose and accumulation of excitotoxic and other amino acids in ischemic cerebral cortex. Horm Metab Res 32:9-Jun
Phillis, J W; Ren, J; O'Regan, M H (2000) Transporter reversal as a mechanism of glutamate release from the ischemic rat cerebral cortex: studies with DL-threo-beta-benzyloxyaspartate. Brain Res 868:105-12
Guyot, L L; Diaz, F G; O'Regan, M H et al. (2000) Topical insulin and accumulation of excitotoxic and other amino acids in ischemic rat cerebral cortex. Proc Soc Exp Biol Med 224:28-31
Guyot, L L; Diaz, F G; O'Regan, M H et al. (2000) The effect of intravenous insulin on accumulation of excitotoxic and other amino acids in the ischemic rat cerebral cortex. Neurosci Lett 288:61-5
Phillis, J W; Ren, J; O'Regan, M H (2000) Inhibition of Na(+)/H(+) exchange by 5-(N-ethyl-N-isopropyl)-amiloride reduces free fatty acid efflux from the ischemic reperfused rat cerebral cortex. Brain Res 884:155-62

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