Oxidative Stress and the CNS

Response to Dr. Fernandez

Phyllis Paterson

Dear Dr. Fernandez,

I believe in the mid-eighties that a number of seleno-organic compounds were synthesized and tested for their antitumour activity and usefulness in treating cardiac disease (based on the role of Se in Keshan Disease). While they were more active than their sulfur analogs, their use was quite limited by the toxicity associated with delivery of selenium into the body pool.  When the compound ebselen was synthesized, the intent was to prepare a compound that would deliver Se in a better-tolerated form for incorporation into the active site of  GPx. Surprisingly, the compound was found to reduce hydroperoxides directly in a manner similar to GPx.  While GPx is specific for GSH, I believe ebselen can react with any thiol group to reduce hydroperoxides.  However, the selenium is not bioavailable, thus the toxicity of ebselen is low.  I have seen reports that ebselen inhibits a variety of inflammatory reactions associated with hydroperoxide production, that it inhibits lipoxygenases and cycloxygenase and inhibits inducible NO synthase.  There are reports of clinical trials in stroke (Stroke 29:12-17, 1998) and subarachnoid hemorrhage (Neurosurgery 42:269-77, 1998) as well as other inflammatory disorders.   A number of successor GPx mimetics have since been synthesized, and a recent paper has shown protective effects in endothelial cells undergoing inflammatory stress (Free Rad Biol Med 25:270-281, 1998).

By the way, I think your bioavailability question was directed to the site of action, but if you are interested in bioavailability of dietary Se, most of it is organic selenium (selenocysteine, selenomethionine, selenocystathionine, methylselenocysteine) except for what people consume in vitamin-mineral supplements.  The bioavailability for these dietary sources was studied for some time by nutritional scientists, but I think it is now apparent that this is not an important issue as Se absorption from most sources is very high. i.e. Se homeostasis is not regulated via absorption.

Somewhat aside but related to your question regarding selenium bioavailability, we are currently studying the effect of iron deficiency on glutathione peroxidase expression in brain.  As noted in our paper in this symposium and by others, the brain may be able to retain selenium at the expense of other tissues when selenium supply is limited.  However, it has been shown by Moriarty et al. (J Nutr 125: 293-301) that iron deficiency decreases GPx mRNA in liver by 49%, with decreases in GPx protein and GPx activity of 55% and 60%, respectively. In brain, only GPx activity was measured but it was found to be decreased by 24%, a substantial decrease.  The mechanisms responsible are unknown, but the findings are interesting, given that GPx is the exception among mammalian peroxidases in not containing iron.  Of course, there may be many mechanisms involved, but one that we are considering is that iron status alters selenium bioavailability.  We are hypothesizing that the hierarchy that appears to exist during selenium deficiency for partitioning selenium to selenoproteins and tissues is not present during iron deficiency, thus increasing the vulnerability of the brain to oxidative stress.

Phyllis Paterson

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