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The role that reactive oxygen species (ROS) play in the genesis of oxygen- induced seizures has been investigated by several groups. You should keep in mind that these studies were all done in normal animals (rats or mice) and that they were not done to try to develop schemes by which oxygen tolerance could be increased, but rather to investigate the role, if any, of ROS in oxygen seizures. Keep in mind, also, that not all ROS are radicals, but they are reactive. The idea that ROS are important in oxygen seizures has been around for some time. However, investigation of ROS is difficult because of the very short half-life of these compounds. Torbati et al (6) used "spin trapping" by which ROS are bound to organic compounds which are much more stable. These adducts between the spin traps and ROS can then be detected by electron spin resonance spectroscopy. They found that in rats exposed to 5 ATA of oxygen, ROS were generated in the brain and the appearance of the ROS preceded the onset of an overt seizure in the animal. This suggests that ROS are generated in brain during hyperoxic exposure, but does not directly link the ROS to the seizure. Several other groups of investigators have used glutathione (a thiol based ROS scavenger) and demonstrated that treatment of animals with glutathione extended the time to oxygen induced seizure and also extended survival time (2, 4, 5) . This suggests that generation of ROS may be important in the genesis of the seizure. Glutathione can react with the enzyme glutathione peroxidase and hydrogen peroxide (a ROS but not a radical) to form a nontoxic compound, glutathione disulfide (2) . Glutathione peroxidase is a selenium-dependent enzyme, and rats deficient in selenium are not protected against oxygen induced seizures by glutathione (presumably because their glutathione peroxidase cannot function properly (2) ). Rats fed supplemental beta-carotene (a natural antioxidant) are significantly protected from oxygen induced seizures (time to seizure was doubled) (1) . This study is very interesting because to be effective, the beta-carotene had to be natural which is a 1:1 mixture of cis and trans isomers. Synthetic beta-carotene which was all trans isomer was not effective. Beta-carotene is a precursor of vitamin A, and in this study some data suggested that the protection from seizures was related to increased levels of vitamin A (remember, vitamin A is hepatotoxic - if you take large doses, you will kill your liver). It is also interesting that these rats were fed enough beta-carotene to turn their fur yellow. This data strengthens the argument that ROS are important in the genesis of oxygen seizures. In a more definitive study, Yusa et al used intravenous administration of liposome encapsulated superoxide dismutase (SOD) and catalase to increase the levels of these enzymes in rat brain (7) . Treatment with SOD/catalase extended the time to seizure by about 3 fold. Both SOD and catalase are enzymes with highly specific actions, and an increase in the tolerance to hyperbaric oxygen by SOD/catalase is relatively good proof that ROS are involved in the genesis of oxygen seizures. In this study, catalase (which converts hydrogen peroxide to water and oxygen) was more protective that SOD, which suggests that hydrogen peroxide may be more important in the seizure than superoxide (which SOD converts to hydrogen peroxide). The single study that I am aware of with vitamin E demonstrated that mice deprived of vitamin E were more likely to have a hyperoxic seizure than mice fed a normal diet (3) . There are obviously many other studies with ROS in other tissues, particularly lung, but I think that the above studies gives a good overview of the current state of the literature of ROS and oxygen seizures. I know of no studies evaluating the role of ROS in oxygen seizures in humans. It's hard to get institutional review boards to allow you to do things to humans that will surely make them seize. All of this is provided for the general information of the readers, and to allow them to better assess statements about ROS and hyperoxia. I hope that this is helpful and at least informative. Eddie Brian eddie-brian@ui*.ed* 1. Bitterman, N., Y. Melamed and A. Ben-Amotz. �-Carotine and CNS oxygen toxicity in rats. J. Appl. Physiol. 76: 1073-1076, 1994. 2. Jenkinson, S. G., J. M. Jordan and C. A. Duncan. Effects of selenium deficiency on glutathione-induced protection from hyperbaric hyperoxia in rat. Am. J. Physiol. 257: L393-L398, 1989. 3. Kann, H. E., Jr., C. E. Mengel, W. Smith and B. Horton. Oxygen toxicity and vitamine E. Aerospace Medicine 35: 840-844, 1964. 4. Peacock, M. D., D. A. Schenk, R. A. Lawrence, J. A. Morgan and S. G. Jenkinson. Elimination of glutathione-induced protection from hyperbaric hyperoxia by acivicin. J. Appl. Physiol. 76: 1279-1284, 1994. 5. Sanders, A. P., R. M. Felien, Jr., R. S. Kramer and W. D. Currie. Protection against the chronic effects of hyperbaric xoygen toxicity by succinate and reduced glutathione. Aerospace Medicine 43: 533-536, 1972. 6. Torbati, D., D. F. Chruch, J. M. Keller and W. Pryor. Free radical generation in the brain preceeds hyperbaric oxygen-induced convulsions. Free Radical Biology and Medicine 13: 101-106, 1992. 7. Yusa, T., J. D. Crapo and B. A. Freeman. Liposome-mediated augemntation of brain SOD and catalase inhibits CNS O2 toxicity. J. Appl. Physiol. 57: 1674- 1681, 1984.
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