Uridine, Acetylcholine Release, and the Tricarboxylic Acid Cycle in Cholinergic Neurons

I wonder if this increase in acetylcholine synthesis and release, in response to oral uridine monophosphate alone (found by Lei Wang and Richard Wurtman and colleagues, in this article), without free choline, is a result of the ATP-buffering (or glycogen-storage-modifying) effects of uridine and not so much the effect of increasing phospholipid levels (as the authors show here):

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1852434

I mean, I wonder if it increases phospholipid biosynthesis, also, both by increasing ATP levels (through the entry of uridine-derived ribose-1-phosphate into the nonoxidative pentose cycle, etc.) and by the effect, the usual mechanism by which the increases in phospholipid biosynthesis are explained, of increasing cytidine and CDP-choline levels. The increased ACh synthesis and release could be due to an enhancement of ATP production, given that ATP derived from glycolysis could conceivably increase the availability of citrate (or even the small amount of acetyl-CoA transported intact out of mitochondria) and acetyl-CoA available for ACh formation in cholinergic neurons (Szutowicz et al: http://www.ncbi.nlm.nih.gov/pubmed/7824061).

The pool of acetyl-CoA available for ACh synthesis in cholinergic neurons is limited but was suggested to potentially be sensitive to small changes in pyruvate availability for oxidation in the tricarboxylic acid cycle, even in the absence of a metabolic insult [http://www.biochemjusa.org/bj/148/0017/1480017.pdf or pubmed (Gary Gibson et al.): http://www.ncbi.nlm.nih.gov/pubmed/1156396]. Uridine-derived ribose-1-phosphate may increase pyruvate production from glycolysis and thereby increase the amount of mitochondrially-derived citrate that is available for cytosolic acetyl-CoA formation and, consequently, ACh biosynthesis. Also, I'm not sure why a uridine-induced increase in phosphatidylcholine content wouldn't be expected to decrease free choline levels, especially since free choline levels, derived from phospholipid breakdown or in a manner that's independent of phospholipid breakdown (see article below), can increase during ischemia or during increases in NMDA receptor activation (Agusti Zapata et al.) (http://www.jneurosci.org/cgi/content/full/18/10/3597 or pubmed: http://www.ncbi.nlm.nih.gov/pubmed/9570791?dopt=Abstract). I'm saying that that type of effect is not consistent with the effects of uridine and, given that an increase in free choline could be expected to increase ACh synthesis (given the absence of something like the suppression of ACh synthesis in response to a prolonged metabolic insult), it seems to me that uridine does not increase choline availability by first increasing phosphatidylcholine (PC) formation. Rather, it seems like both the enhanced PC formation and ACh biosynthesis could be explained by the enhancement of glycolysis (and also by the increase in CDP-choline levels, due to pyrimidine availability and ATP buffering, and perhaps some metabolic effect of uracil catabolism).

This article shows that the phosphorolysis of uridine into uracil and ribose-1-phosphate is necessary for the protection against ATP depletion in astrocytes, and the participation in or activation of glycolysis by ribose-1-phosphate is thought to mediate this ATP-buffering effect (http://www.ncbi.nlm.nih.gov/pubmed/16839635). Here's a more recent article, extending those results and showing that oral uridine reduces the infarct volume in rats in response to middle cerebral arterial occlusion (http://www.ncbi.nlm.nih.gov/pubmed/18457515). That article also provides more evidence that the phosphorolysis of uridine into uracil and ribose-1-phosphate mediates neuroprotection by uridine, and the article also shows that astrocytes, as cells that have high levels of uridine phosphorylase activity, are important as mediators of the neuroprotective effects.