oxypurinol and Ischemic-Attack--Transient

The present study investigated the effect of the administration of oxypurinol (40 mg/kg), an inhibitor of xanthine oxidase, on adenosine and adenine nucleotide levels in the rat brain during ischemia and reperfusion. The brains of the animals were microwaved before, at the end of a 20-min period of cerebral ischemia, and after 5, 10, 45, and 90 min of reperfusion. Cerebral ischemia was elicited by four-vessel occlusion with arterial hypotension to 45-50 mm Hg. Adenosine and adenine nucleotide levels in the oxypurinol-pretreated (administered intravenously 20 min before ischemia) rats were compared with those in nontreated animals exposed to the same periods of ischemia and reperfusion. Oxypurinol administration resulted in significantly elevated ATP levels at the end of ischemia and 5 min after ischemia, but not at 10 min after ischemia. ADP levels were also elevated, in comparison with those in the control rats, at the end of the ischemic period. Conversely, AMP levels were significantly reduced at the end of ischemia and during the initial (5 min) period of reperfusion. Adenosine levels were lower in oxypurinol-treated rats, during ischemia, and in the initial reperfusion phase. Oxypurinol administration resulted in a significant increase in the energy charge both during ischemia and after 5 min of reperfusion. Physiological indices, namely, time to recovery of mean arterial blood pressure and time to onset of respiration, were also shortened in the oxypurinol-treated animals. These beneficial effects of oxypurinol may have been a result of its purine-sparing (salvage) effects and of its ability to inhibit free radical formation by the enzyme xanthine oxidase. Preservation of high-energy phosphates during ischemia likely contributes to the cerebroprotective potency of oxypurinol.

Topics: Adenine Nucleotides; Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Blood Pressure; Electrochemistry; Hydrogen-Ion Concentration; Ischemic Attack, Transient; Kinetics; Male; Oxypurinol; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Respiration; Xanthine Oxidase

We have previously demonstrated that oxypurinol (40 mg/kg i.p.), a xanthine oxidase inhibitor, can reduce focal ischemic brain injury in the rat when applied pre-ischemically. By using a model of occlusion of the middle cerebral artery (MCA) in tandem with occlusion of the ipsilateral carotid artery, the present study further demonstrates that delayed (60 min) administration of oxypurinol also exhibits a protective action on ischemic damage in the stroked rat brain. Oxypurinol significantly reduced the ischemic cerebral infarct zone by preventing the development of brain damage primarily in areas distant to the central lesion core. A corresponding amelioration of brain swelling and attenuation of neurological deficits were evident. Similar protection against focal ischemic brain damage was evident when the adenosine deaminase inhibitor, deoxycoformycin (500 micrograms/kg), was administered prior to the onset of ischemia. However, with delayed (60 min) administration deoxycoformycin had no protective effect. These findings support the hypothesis that manipulation of adenosine catabolism can be an effective therapeutic approach to the prevention or treatment of brain injuries, such as those occurring during ischemic stroke or cardiac arrest.

Topics: Animals; Cerebral Cortex; Cerebral Infarction; Drug Administration Schedule; Ischemic Attack, Transient; Male; Oxypurinol; Pentostatin; Rats; Rats, Inbred F344; Reference Values; Time Factors

Topics: Animals; Brain; Cerebral Cortex; Cerebral Infarction; Gerbillinae; Ischemic Attack, Transient; Oxypurinol; Purines; Rats; Reperfusion

Oxypurinol, an inhibitor of the enzyme xanthine oxidase, reduced ischemic hippocampal damage and the associated hypermotility in Mongolian gerbils. Cerebral ischemia was induced in unanesthetized gerbils by a bilateral 5-min occlusion of the carotid arteries. Oxypurinol (40 mg/kg, IP), administered 20 min prior to carotid occlusion, prevented the increase in locomotor activity observed in saline-injected ischemic animals and significantly reduced the damage to, and loss of, CA1 hippocampal neurons observed 5 days postischemia. These findings suggest that oxypurinol may be useful for the prevention of cerebral ischemic damage.

Topics: Animals; Enzyme Inhibitors; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Male; Oxypurinol; Pyrimidines; Xanthine Oxidase