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.
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