There isn't even an easy way to express the comparison, despite the relative simplicity of the issue. But the animal studies and cell culture studies have generally shown that, to produce robust neuroprotection against damage due to mitochondrial toxins (i.e. 3-nitropropionic acid), the plasma uridine level should be kept above 80 uM for at least half the day (12+ hours). It's similar in cell culture studies. The extracellular uridine concentration has to be in that vicinity of 100 uM or so, ideally. That doesn't mean that there wouldn't be beneficial effects at lower plasma levels, in the context of less severe mitochondrial impairment. The assumption has generally been that that "requirement" stems from the need to supply pyrimidines to polymerase-gamma (based on the whole rho-naught, mtDNA-depleted cells that display uridine and pyruvate auxotrophy), to maintain mitochondrial DNA replication, but it's fairly clear, based on a number of animal studies, that that's not likely to be an especially important mechanism in vivo. I should say that the supply of the pyrimidines themselves (per se), for mtDNA replication, is, at least, unlikely to be a major mechanism. It's conceivable that the maintenance of the astrocytic glycogen content, for example, and glycogen utilization and glycolytic ATP production (as has been shown in multiple organs, including the skeletal muscles, heart, etc.) is required for the maintenance of mtDNA replication. But I think it's basically that it buffers energy metabolism by various mechanisms, such as by increasing glucose uptake. That article that I discussed recently, on cultured deoxyguanosine-kinase-deficient cells, basically shows that ATP depletion and guanosine nucleotide depletion can compromise mtDNA replication, but that's not really anything new. Additionally, there's a considerable amount of research showing that CDP-choline can increase glucose uptake, and it's probably just a result of the same types of mechanisms by which uridine exerts its effects.
But as far as the issue of choline goes, how could choline *possibly* produce any protective effect? There's already going to be a gross excess of free choline during ischemia, and there just isn't any mechanism by which it could produce protection. It's like expecting magic, expecting growth in cells without supplying any glucose or any alternative substrates to prevent the cells from dying. Why would one expect that? There's just no conceivable mechanism by which dumping extra choline into the brain could contribute to neuroprotection, and there's just this endless, bizarre, ongoing problem with all the junk animal research on choline.
For example, if I were trying to get my candidate elected, in a national election, would sending out "magic" vote-getters, to try to get "special votes" that would carry extra weight, bypass the will of the voters or make 1+1 = 270 instead of 2 electoral votes? That's a terribly obnoxious analogy, but that's what some people are really talking about with some of these approaches to neuroprotection. There just isn't any way around the issue of energy metabolism, and there never will be.
But it's like there's no one who's interested in mechanisms anymore, except the business about maintaining phospholipid metabolism. It's fine to focus on that, but why does uridine or cytidine decrease free fatty acids (FFA's) during ischemia? Is it just the one enzyme that's affected (i.e. CTP:phosphocholine cytidylyltransferase)? Is that the only enzyme or protein whose activity or functions is/are going to be affected by pyrimidines? I think it just boils down to ATP-buffering, and that doesn't mean there shouldn't be any more research or that it's a magic bullet. I guess it wouldn't even matter all that much what the mechanisms are, if something like uridine were actually being made use of. A lot of the research on uridine in humans should have been done 50 years ago. There's research that's 30 or 40 years old, showing that uridine can protect cultured cells against glucose deprivation, etc. It's nothing special, necessarily, but uridine makes most of these other things people talk about look like child's play.
It's that aspect of all of this, this area of research, that just feels like something that's been dying for a very long time, slowly and intractably, crying out for some kind of sense. It's this kind of motionless and paralyzing death, while everything seems to be moving more and more rapidly, on the surface, at least, and I just almost can't believe it sometimes.
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