allopurinol and Carbon-Monoxide-Poisoning

Carbon monoxide poisoning is one of the important emergency situations manifested by primarily acute and chronic anoxic central nervous system (CNS) injuries and other organ damages. Current descriptions and therapeutic approaches have been focused on the anoxic pathophysiology. However, this point of view incompletely explains some of the outcomes and needs to be investigated extensively. Considering this, we propose that reactive oxygen species (ROS) including especially nitric oxide (NO) are likely to be a key concept to understand the emergency related to CO poisoning and to discover new therapeutic modalities in CO toxicity. If we consider the hypothesis that ROS is involved greatly in acute and chronic toxic effects of CO on CNS and some other vital organs such as heart, it follows that the antioxidant and anti-NO therapies might give the clinicians more opportunities to prevent deep CNS injury. In support of this, we review the subject in essence and summarize clinical and experimental studies that support a key role of ROS in the explanation of pathophysiology of CO toxicity as well as new treatment modalities after CO poisoning.

Topics: Animals; Antioxidants; Brain; Carbon Monoxide; Carbon Monoxide Poisoning; Central Nervous System; Humans; Hypoxanthine; Hypoxia; Microdialysis; Models, Theoretical; Nitric Oxide; Oxygen; Rats; Reactive Oxygen Species; Reperfusion Injury; Superoxides; Uric Acid; Xanthine Oxidase

Approximately half of those who survive severe carbon monoxide (CO) poisoning develop delayed neurologic sequelae. Growing evidence supports the crucial role of free radicals in delayed brain injury associated with CO toxicity. Xanthine oxidase (XO) has been reported to play a pivotal role in the generation of reactive oxygen species (ROS) in CO poisoning. A recent report indicates that allopurinol both attenuated oxidative stress and possessed anti-inflammatory properties in an animal model of acute liver failure. In this study, we aimed to explore the potential of allopurinol to reduce the severity of delayed neurologic sequelae. The rats were first exposed to 1000 ppm CO for 40 min and then to 3000 ppm CO for another 20 min. Following CO poisoning, the rats were injected with allopurinol (50 mg/kg, i.p.) six times. Results showed that allopurinol significantly reduced neuronal death and suppressed expression of pro-inflammatory factors, including tumor necrosis factor-α, intercellular adhesion molecule-1, ionized calcium-binding adapter molecule 1, and degraded myelin basic protein. Furthermore, behavioral studies revealed an improved performance in the Morris water maze test. Our findings indicated that allopurinol may have protective effects against delayed neurologic sequelae caused by CO toxicity.

Topics: Allopurinol; Animals; Anti-Inflammatory Agents; Behavior, Animal; Brain; Carbon Monoxide Poisoning; Cell Death; Cognition; Disease Models, Animal; Inflammation Mediators; Male; Maze Learning; Microglia; Neurons; Neuroprotective Agents; Neurotoxicity Syndromes; Rats, Sprague-Dawley; Severity of Illness Index; Time Factors

Acute carbon monoxide exposure produces a significant impairment in high-frequency auditory sensitivity that can be prevented using the N-methyl-D-aspartate receptor blocker MK-801. This finding suggests an excitotoxic component to carbon monoxide ototoxicity and establishes the potential for free radical formation. Free radical scavengers and inhibitors are protective in many organs, including the brain and cochlea, during hypoxic events such as ischemia/reperfusion and, in the cochlea, during noise exposure. This study evaluated the protection afforded by two such agents, phenyl-n-tert-butyl-nitrone (PBN), which acts as a general free radical scavenger, and allopurinol, which acts as a free radical inhibitor specific to the xanthine oxidase metabolic pathway. Guinea pigs were pretreated with PBN (100 mg/kg i.p.), allopurinol (100 mg/kg i.p.), or saline 1 hr prior to exposure to carbon monoxide (35 ml/kg i.p.) or to an equal volume of air. They were monitored at 15, 30, and 60 min after carbon monoxide exposure for alterations in compound action potential threshold and cochlear microphonic amplitude. The groups receiving carbon monoxide alone displayed characteristic compound action potential threshold elevations particularly at the higher test frequencies (16-40 kHz), consistent with earlier studies; no loss of cochlear microphonic amplitude was exhibited. Both free radical inhibitors, PBN and allopurinol, blocked loss of auditory threshold sensitivity produced by carbon monoxide. These data suggest that free radical generation may play a significant role in the impairment of high-frequency auditory sensitivity resulting from carbon monoxide.

Topics: Allopurinol; Animals; Carbon Monoxide Poisoning; Cell Hypoxia; Cochlea; Cochlear Microphonic Potentials; Cyclic N-Oxides; Free Radical Scavengers; Free Radicals; Guinea Pigs; Hearing Loss, Sensorineural; Neuroprotective Agents; Nitrogen Oxides; Oxidative Stress; Xanthine Oxidase

This study was conducted with rats to assess the involvement of leukocytes in a model of CO-mediated brain injury. Myeloperoxidase activity, measured as an index of leukocyte sequestration, was found to be increased 10-fold in brain microvessel segments prepared from rats immediately or 90 min after exposure to CO. Fluorescence and light microscopic examinations revealed leukocytes in microvessels taken from CO-poisoned rats, but not in that from control rats. Studies were then conducted with rats that had been made leukopenic or treated with monoclonal anti-CD-18 F(ab')2 fragments to inhibit leukocyte adherence to the vasculature. Neither of these groups of animals exhibited the biochemical changes observed in the brains of sham-treated rats: conversion of xanthine dehydrogenase (XD) to sulfhydryl-irreversible xanthine oxidase (XO), and lipid peroxidation, at 90 min following CO poisoning. Treatment with a synthetic serine protease inhibitor, gabexate mesylate, also prevented these biochemical changes if administered immediately after CO poisoning, but the agent did not inhibit leukocyte sequestration. Rats depleted of XD and XO by a tungsten diet, and those treated with allopurinol to inhibit XD and XO, also exhibited at least a 10-fold increase in myeloperoxidase activity in microvessels immediately after CO poisoning, but only a 5-fold increase at 90 min. In vitro studies demonstrated that B2 integrin-dependent polymorphonuclear leukocyte adherence was impaired immediately following CO poisoning although the adherence molecules were expressed on the membrane surface. Adherence function normalized by 45 min. The results suggest that leukocytes are responsible for the development of biochemical changes in brain following CO poisoning, and the sequence of events is as follows: leukocyte sequestration in the microvasculature, B2 integrin-dependent adherence, protease-mediated conversion of XD to XO, O2 radical-dependent lipid peroxidation.

Topics: Allopurinol; Animals; Brain; Carbon Monoxide Poisoning; Cell Adhesion; Gabexate; Leukocytes; Leukopenia; Male; Microcirculation; Oxidation-Reduction; Peroxidase; Protease Inhibitors; Rats; Rats, Wistar; Xanthine Dehydrogenase; Xanthine Oxidase

Exposure to hyperbaric oxygen [3 atmospheres absolute (ATA) for 45 min] inhibited carbon monoxide (CO)-mediated lipid peroxidation in the brains of rats by preventing the conversion of xanthine dehydrogenase to oxidase, a conversion process known to be due to the action of leukocytes. The effect was the same whether treatment was given 24 hr before or up to 45 min after poisoning. Hyperbaric oxygen did not inhibit the initial interaction of leukocytes with brain microvasculature, based on measurements of myeloperoxidase (MPO) in microvessel segments, but persistent adherence, which is due to B2 integrins, did not occur. Exposing rats to 3 ATA pressure (0.21 ATA O2) after CO poisoning had no significant effects. A progressive reduction in brain microvessel MPO titers occurred with exposure to O2 at 1, 2, or 3 ATA after CO poisoning, but 1 ATA O2 treatment did not significantly inhibit xanthine oxidase formation or lipid peroxidation. In vitro studies with polymorphonuclear leukocytes (PMN) from rats exposed to hyperbaric oxygen corroborated the absence of PMN B2 integrin function, but when these cells were stimulated they exhibited normal B2 integrin expression on their surface and also normal elastase release and superoxide radical production. Adherence functions of PMN that do not require B2 integrins appeared to remain intact after exposure to hyperbaric oxygen, as peritoneal neutrophilia in response to a glycogen challenge was not inhibited. B2 integrin function could be restored by incubating cells with 8 bromo cGMP, and incubation with phorbol ester stimulated the adherence function of both control and hyperbaric oxygen-exposed PMN. These results provide a clear mechanism for the inhibition of CO-mediated brain lipid peroxidation by hyperbaric oxygen and indicate that hyperoxia causes a discrete disturbance of PMN adherence function.

Topics: Animals; Brain; Carbon Monoxide Poisoning; Cell Adhesion; Cyclic GMP; Integrins; Lipid Peroxidation; Male; Neutrophils; Oxidation-Reduction; Oxygen; Peroxidase; Rats; Rats, Wistar; Superoxides; Xanthine Dehydrogenase; Xanthine Oxidase

The conversion of xanthine dehydrogenase to xanthine oxidase and lipid peroxidation were measured in brain from carbon monoxide- (CO) poisoned rats. Sulfhydryl-irreversible xanthine oxidase increased from a control level of 15% to a peak of 36% over the 90 min after CO poisoning, while the conjugated diene level doubled. Reversible xanthine oxidase was 3-6% of the total enzyme activity over this span of time but increased to 31% between 90 and 120 min after poisoning. Overall, reversible and irreversible xanthine oxidase represented 66% of total enzyme activity at 120 min after poisoning. Rats depleted of this enzyme by a tungsten diet and those treated with allopurinol before CO poisoning to inhibit enzyme activity exhibited no lipid peroxidation. Treatment immediately after poisoning with superoxide dismutase or deferoxamine inhibited lipid peroxidation but had no effect on irreversible oxidase formation. Biochemical changes only occurred after removal from CO, and changes could be delayed for hours by continuous exposure to 1,000 ppm CO. These results are consistent with the view that CO-mediated brain injury is a type of postischemic reperfusion phenomenon and indicate that xanthine oxidase-derived reactive oxygen species are responsible for lipid peroxidation.

Topics: Allopurinol; Animals; Antioxidants; Brain; Brain Chemistry; Carbon Monoxide Poisoning; Deferoxamine; Diet; Lipid Peroxidation; Male; Oxidoreductases; Rats; Rats, Wistar; Superoxide Dismutase; Tungsten

Topics: Acetylcysteine; Adult; Allopurinol; Carbon Monoxide Poisoning; Drug Therapy, Combination; Humans; Male