Rambler on Magnesium and Sad Ironies

In this article [Vink et al., 1988: (http://www.jbc.org/cgi/reprint/263/2/757.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/3335524)] found that the depletion of intracellular free magnesium (Mg2+) correlated positively with the magnitude of the damage that was produced by experimental brain injuries in rats, and the administration of intravenous Mg2+, 5 minutes before the injuries, prevented much of the damage. The authors cited some interesting data on the pH dependence of the calculations, based on 31P-MRS data, of the intracellular free Mg2+ values, and the authors used data on the dissociation constant of MgATP(2-) at pH 7.2 (50 uM). It's interesting that the mean pre-injury, intracellular free Mg2+ concentration was 1.01 mM (1,010 uM), and the mean concentration was 0.26 mM (260 uM) by 3 hours post-injury. Vink et al. (1988) also cited research (reference 13, cited on p. 761) that had shown the rate of DNA synthesis in cultured fibroblasts to decrease logarithmically at intracellular free Mg2+ concentrations below 0.24 mM (240 uM). In that article, the rate of protein synthesis was down to almost nothing at those low concentrations, also. Resnick et al. (1997) [Resnick et al., 1997: (http://hyper.ahajournals.org/cgi/content/full/30/3/654)(http://www.ncbi.nlm.nih.gov/pubmed/9322999?dopt=Abstract)] found that the intracellular free Mg2+ levels were inversely correlated with the ages of people, and that means the levels decrease as people get older. It's interesting that the mean concentration of intracellular free Mg2+ in people who were hypertensive was 0.284 mM (284 uM), and the mean concentration in normotensive controls was only 0.383 mM (383 uM). One could argue that the rate of DNA synthesis in mitotic cells (fibroblasts) is going to be much higher at specific points in the cell cycle, but then why are the intracellular free Mg2+ levels in the brains of normal rats 3-4 times the levels in the brains of humans? I'll bet one reason is that laboratory animals generally receive higher intakes of magnesium, in addition to phosphate, etc. One could make the argument that the higher zinc or copper intakes of animals eating "rat chow," or whatever, would cause some neurotoxicity and balance out the benefits that have sometimes been associated with higher Mg2+ intakes. But the discrepancies between rat and human diets tend to not be as significant for some of those metals, like copper and zinc. That doesn't sound like a very good situation, with intracellular free Mg2+ concentrations being that low. This basic search on magnesium in relation to neuroprotection or neurotoxicity yielded 45,000+ results (http://scholar.google.com/scholar?hl=en&q=magnesium+neuroprotective+OR+neurotoxic+OR+ischemia+OR+neurodegenerative). In that search, there's one of the articles (Harkema et al., 1992) in which researchers have discussed the use of parenteral MgATP(2-) to protect against different kinds of trauma. If only someone could market a simple acylated prodrug of ATP (or the adenosine prodrug along with dibasic orthophosphate in a 1:3 ratio or something) that would release adenosine slowly enough not to produce hypotension but quickly enough to outperform the effects of oral ATP. They could have done it back in the 1960's, when researchers were obtaining the first use patents for acylated nucleosides. Think of the effects that type of simple approach (or a prodrug of inosine, etc.) could have had in clinical neuroscience, even in the years since 1992. It's moving up on 20 years since 1992. It's sadly ironic, in my mind, that it's ATP and nucleotides that have all of these effects, that have been researched heavily, and that aren't being utilized and probably won't be for a long time, in spite of the thousands of articles on all of these things. But the irony is that researchers have been dumping nucleotide triphosphates into PCR machines all over the place and have been using them in experiments like candy or "hamburger helper." In any case, no one would think magnesium could be a standalone treatment for strokes or anything, and there are all of those details, as discussed in past postings, related to the fact that magnesium supplementation tends to decrease serum phosphate levels, sometimes very significantly. But those issues are not all that difficult to address, as long as one is aware of the potentially-large magnitude of the interaction, etc.