This article [Rumschik et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19183267)] is interesting, and Rumschik et al. (2009) found that inorganic phosphate (Pi) can chelate zinc and reduce the influx of free zinc into neurons in ex vivo preparations of brain tissue. This is relevant to Alzheimer's disease and other neurodegenerative conditions (and also to depression and other psychiatric conditions, etc.), in my opinion, because an excess of free zinc is generally very toxic to cells and can shut down oxidative metabolism and induce necrotic or apoptotic cell death (see past postings). Rumschik et al. (2009) also found that histidine can enhance the "solubility" of zinc, in the sense that the complex formed by the chelation of zinc by histidine can be transported into cells through dipeptide or amino acid transporters. That's not exactly an enhancement of the solubility of zinc but just means that the zinc-histidine (zinc histidylate or whatever) complex is more soluble than the zinc-phosphate complex(es) are. Glutamine did not meaningfully enhance the solubility, and hence the influx, of zinc, and that's a good thing. The authors mentioned that insoluble, extracellular zinc-phosphate complexes could conceivably become pathological and serve as a site for the nucleation or seeding of Abeta-peptide-containing, extracellular plaques (i.e. a pro-aggregating effect), etc., but I would guess that maintaining an adequate amount of intracellular phosphate in neurons and in the CSF would, in comparison to the effects of intracellular (and extracellular, to some extent) phosphate depletion, tend to exert a net neuroprotective effect. That's just my opinion, but the research has generally shown that intracellular Pi depletion produces neuropathy and neuropathological effects by multiple mechanisms. I tend to think Pi could exert similar effects intracellularly, especially given that the intracellular Pi levels are higher than the extracellular Pi levels. The authors mentioned that the assumption, in the context of ex vivo or in vitro research, has been that the extracellular and CSF Pi levels are around 1 mM, but the human CSF Pi concentration is apparently around 0.47 to 0.50 mM, under normal circumstances. That's potentially important, because, even though the steady-state intracellular and extracellular fluid Pi levels, in different cell types, have generally been found to be relatively independent of one another, the intracellular Pi concentration can correlate with and increase in response to boluses (even small "boluses," meaning significant, single dosages). A relatively higher extracellular fluid Pi concentration might more effectively buffer the intracellular Pi levels during miniature "Pi crises," such as after exercise or, more significantly, after ischemic insults (exercise produces mild ischemia in many organs, but I'm referring to would-be brain injuries, here). There's a tendency to think that all values within a normal range of values, for a blood test or physiological parameter, are equally "good" or equally "normal," but the research on the extracellular and intracellular levels of uric acid and other compounds has shown that this can be a problematic assumption. Small changes in the extracellular uric acid levels can drastically affect the rates of nitric oxide output (and, hence, fairly directly, the peroxynitrite output) by the nitric oxide synthases and the macrophages or monocytes that express those enzymes.
I should mention that increases in acidity, meaning an increase in H(+) availability, can enhance the release of zinc from storage vesicles [Colvin et al., 2000: (http://crab-lab.zool.ohiou.edu/colvin/neurochem.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/10762091); Colvin, 2002: (http://ajpcell.physiology.org/cgi/content/full/282/2/C317)(http://www.ncbi.nlm.nih.gov/pubmed/11788343)], and one could make the argument that the potential for an alkalinizing effect of Pi supplementation, such as in the lower dosage range, on the extracellular fluid could further reduce the kinds of wild fluctuations in free zinc concentrations that can be neurotoxic. But the pH dependences of zinc influx and zinc release are complex (Colvin, 2002), and that suggestion of mine is likely to be an oversimplification. Nonetheless, Pi obviously plays a general role in buffering pH changes, and that acid-base buffering effect could be protective against zinc-mediated neurotoxicity.
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