allopurinol and Cerebral-Infarction

Microinfarcts are common in patients with cognitive decline and dementia. Allopurinol (ALLO), a xanthine oxidase (XO) enzyme inhibitor, has been found to reduce proinflammatory molecules and oxidative stress in the vasculature. We here examined the effect of pre-treatment with allopurinol on the cortical microinfarction. C57BL/6J mice were subjected to a permanent single penetrating arteriole occlusion induced by two-photon laser irradiation. Infarction volume, the activation of glial cells and nitrosative stress in the ischemic brain was assessed using immunohistochemistry. Pre-treatment with ALLO achieved 42% reduction of infarct volume and significantly reduced microglia infiltration, astrocyte proliferation and nitrosative stress in the ischemic brain. These data indicate that ALLO protects against microinfarcts possibly through inhibition of nitrosative stress and attenuation of microglia infiltration as well as astrocytes reactivation.

Topics: Allopurinol; Animals; Arterioles; Astrocytes; Brain; Cell Proliferation; Cerebral Infarction; Disease Models, Animal; Enzyme Inhibitors; Fluorescent Antibody Technique; Lasers; Male; Mice, Inbred C57BL; Microglia; Neurons; Neuroprotective Agents; Xanthine Oxidase

Toxic oxidants (oxygen free radicals) have been implicated in the formation of brain edema from ischemia-reperfusion injury or tumor growth. We investigated the ability of an iron chelator, a calcium channel blocker, and a xanthine oxidase inhibitor to reduce formation of brain edema following a cold lesion in cats. The agents were given independently of each other in an attempt to inhibit the Haber-Weiss reaction, prevent Ca++ modulated uncoupling of oxidative phosphorylation, and inhibit the generation of toxic oxidants via xanthine oxidase, respectively. Pentastarch-deferoxamine conjugate at a dose of 50 mg/kg was given 15 minutes before and 60 minutes after the cold lesion. Nimodipine was given at a dose of 1 mg/kg 1 hour before and 2 hours after the cold lesion. Allopurinol was given at a dose of 50 mg/kg 24 hours before, at the time of the lesion and, 24 and 48 hours after the lesion. Gravimetric measurements of multiple brain areas were performed at 24 hours post-lesion in the pentastarch-deferoxamine and nimodipine groups and at 72 hours post-lesion in the allopurinol group. None of these agents led to significant reduction in brain edema formation as measured with a gravimetric column of kerosene and bromobenzene. Pentastarch-deferoxamine conjugate was utilized to avoid the confounding effects of arterial hypotension which is seen with intravenous deferoxamine. There was even a suggestion of increased edema in the periventricular white matter in animals treated with nimodipine. Taken together, independent inhibition of the Haber-Weiss reaction, of calcium channels, or of xanthine oxidase does not reduce formation of brain edema in the cold lesion model.

Topics: Allopurinol; Animals; Brain Edema; Brain Injuries; Calcium; Cats; Cerebral Cortex; Cerebral Infarction; Deferoxamine; Dose-Response Relationship, Drug; Freezing; Nimodipine; Reactive Oxygen Species; Water-Electrolyte Balance

During cellular ischemia and death, many changes occur in the cell. These include the build-up of purines and lipid peroxidation. In this study, we evaluated the effectiveness of allopurinol, which blocks purine breakdown, and deferoxamine, which inhibits lipid peroxidation, as cytoprotective agents. Rats were subjected to middle cerebral artery occlusion and were treated with high or low doses of allopurinol or high or low doses of deferoxamine, with normal saline used as a control. Treatments were given 1 hour before, 1 hour after, or 5 hours after occlusion. The outcome was based on neurological status and infarct size. Both infarct size and neurological status were found to be improved in all treatment groups when compared to controls. This study suggests that the use of these agents prevents cellular damage during ischemia.

Topics: Allopurinol; Animals; Brain Ischemia; Cell Death; Cerebral Infarction; Deferoxamine; Rats

Free radicals have been shown to play an important role in ischemia-reperfusion injury in several organ systems; however, the role of free radicals in central nervous system ischemia has been less well studied. Many potential free radical-generating systems exist. The primary products of these reactions, superoxide and hydrogen peroxide, may combine to produce hydroxyl radicals. Of the many potential sources of free radical generation, the enzyme xanthine oxidase has been shown to be important in ischemia in noncerebral tissue. We investigated the effect of the hydroxyl radical scavenger dimethylthiourea and the xanthine oxidase inhibitor allopurinol on infarct volume in a model of continuous partial ischemia. Male Sprague-Dawley rats were treated with dimethylthiourea or allopurinol before middle cerebral artery occlusion. Infarct volume was measured by triphenyltetrazolium chloride staining of brains removed 3 or 24 hours after occlusion. Stroke volume was reduced by 30% after dimethylthiourea treatment and by 32-35% after allopurinol treatment. At 24 hours after stroke, cortical tissue was more effectively protected than caudate tissue with both agents. Pretreatment with dimethylthiourea and allopurinol also significantly reduced cerebral edema formation and improved blood-brain barrier function as measured by fluorescein uptake. Our results imply that hydroxyl radicals are important in tissue injury secondary to partial cerebral ischemia and that xanthine oxidase may be the primary source of these radicals.

Topics: Allopurinol; Animals; Arterial Occlusive Diseases; Blood-Brain Barrier; Brain Chemistry; Cerebral Arteries; Cerebral Infarction; Disease Models, Animal; Drug Evaluation, Preclinical; Male; Rats; Rats, Inbred Strains; Staining and Labeling; Stroke Volume; Thiourea; Time Factors