Stroke and cardiac arrest constitute two of the most frequent causes of death in the U.S.A. and even when patients survive it is frequently with some degree of neurological impairment. A massive release of the excitotoxic amino acids, glutamate and aspartate, occurs in the brain during ischemia, and these, together with calcium entry into depolarized nerve cells and the generation of toxic oxygen-derived free radicals, are considered to be major causes of ischemic cellular damage. Adenosine, which is also released in the ischemic brain, attenuates the release of these excitatory amino acids and acts as an antagonist at membrane calcium channels. The adenosine metabolites hypoxanthine and xanthine are substrates for an enzyme, xanthine oxidase, which generates free radicals. The first objective of this proposal is to use two potent inhibitors of adenosine deaminase (deoxycoformycin and erythro-(hydroxynonyl) adenine), the enzyme which metabolizes adenosine to the inert product inosine, to elevate adenosine levels in the ischemic brain and to thus reduce excitatory amino acid release and membrane calcium permeability with the ensuing neuronal damage. Inhibition of adenosine deaminase also results in a decrease in hypoxanthine formation, thus depriving xanthine oxidase of its substrate, reducing free radical formation. Secondly, inhibitors of xanthine oxidase (allopurinol and oxypurinol) will be used to reduce free radical formation. Neurochemical experiments on amino acid and purine release from the rat cerebral cortex will be coupled with studies on the degree of actual protection against stroke deficits conferred by treatment with adenosine deaminase or xanthine oxidase inhibitors. The findings from these experiments could lead to the development of prophylactic and therapeutic uses of these enzyme inhibitors in individuals at risk for cardiac arrest or stroke. An obvious alternative approach for the use of porions in treatment of cerebral ischemia would be direct administration of a stable adenosine analog. The disadvantage of this strategy apart from the fact that these compounds may not cross the blood brain barrier, is that they also have potent hypotensive effects. Manipulation of the metabolism of endogenously released adenosine avoids these potential complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026912-03
Application #
3413040
Study Section
Neurology A Study Section (NEUA)
Project Start
1988-12-01
Project End
1991-11-30
Budget Start
1990-12-01
Budget End
1991-11-30
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Wayne State University
Department
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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