Ammonia and Cerebral Energy Metabolism

This is an interesting article on hyperammonemia and the dysregulation of the brain's "glutamate-glutamine" cycle [Vaquero and Butterworth, 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16771837)]. This article focuses on hepatic encephalopathy and hepatic failure (liver failure), but there's reason to think this type of problem with cell energy metabolism, produced by either elevations in ammonia or by other changes, could occur in other disease states. One key point that the authors mention is that ammonia inhibits the alpha-ketoglutarate dehydrogenase complex, a thiamine-derived-cofactor-dependent multienzyme complex that plays a major role in the tricarboxylic acid (TCA) cycle but can be inhibited by, as discussed in the article I cited above, ammonia, and by the many factors that can conspire to produce sequestration of free coenzyme A (such as an increase in the oxidation of ketone bodies) [Russell et al., 1995: (http://ajpheart.physiology.org/cgi/content/abstract/268/1/H441) (http://www.ncbi.nlm.nih.gov/pubmed/7840294?dopt=Abstract)]. Even though I mentioned one article comparing the neuroprotective effects of beta-hydroxybutyrate (a ketone) to propionyl-L-carnitine [Puchowicz et al., 2008, cited here: (http://hardcorephysiologyfun.blogspot.com/2009/01/propionyl-l-carnitine-beta.html)], the article by Russell et al. (1995) shows that propionylcarnitine can prevent the kind of inhibition of the flux of substrates through the TCA cycle that coenzyme A sequestration, resulting from excessive accumulation of acetyl-CoA or acetoacetyl-CoA, produces.

There's quite a bit of research showing that carnitine esters can sometimes act as "indirect ammonia scavengers," (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=carnitine+ammonia+CoA) by disinhibiting the urea cycle enzymes that can be inhibited by CoA thioesters (acyl-CoA's), etc. I don't know how potent they are, though. In my opinion, propionyl-L-carnitine and acetyl-L-carnitine are generally more useful for whatever purposes one is applying them to, and they generally tend to elevate the overall carnitine pool (as L-carnitine does). Alpha-keto acids [or just keto acids or ketoacids: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=renal+%22keto+acids%22+OR+ketoacids)] have been used in people with renal failure, to act as an ammonia scavenger, as I understand it, at least in part. They tend to use branched-chain ketoacids such as ketoisocaproate and ketoisovalerate, I think it's called, and another one is the carbon skeleton of glutamine (alpha-ketoglutarate or 2-oxoglutarate). People involved in sports nutrition have tended to say that alpha-ketoglutarate, in something like arginine alpha-ketoglutarate, is more useful than glutamine because of the capacity of alpha-ketoglutarate to "scavenge" ammonia or at least not add to the ammonia burden. I don't have time to elaborate, and these topics are complex.