This article [Yudkoff et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11746421)] is interesting, and the authors hypothesize that increases in ketone availability to neurons, in the brain, produce their mild anticonvulsant effects by increasing the pool of glutamate that is available for GABA synthesis (this would be in GABAergic neurons, presumably, although the authors do not rule out the possibility that an increase in glutamate availability in astrocytes could increase the output of glutamine from astrocytes and thereby enhance GABA formation in neurons, etc.). Even though increases in the availabilities of beta-hydroxybutyrate and acetoacetate to the brain have been associated with antidepressant or anxiolytic and anticonvulsant effects (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=ketogenic+antidepressant+OR+anxiolytic+OR+mood), I don't think the 80% fat diet ("ketogenic diet") is a very realistic approach. The use of medium-chain triglycerides (octanoate, decanoate, etc.) has also been associated with fatty liver disease, and the entry of octanoate and decanoate into the mitochondria is not entirely carnitine-independent, as the authors of some articles have argued. Glycogen-depleting resistance exercise can elevate plasma free fatty acids (FFAs) for 2-4 days and can also elevate plasma ketone levels transiently, at least [(http://hardcorephysiologyfun.blogspot.com/2009/04/protection-against-ischemic-damage-by.html); (http://hardcorephysiologyfun.blogspot.com/2009/04/expression-of-creatine-kinase-by.html); (http://hardcorephysiologyfun.blogspot.com/2009/04/low-cholesterol-levels-and-risk-of.html)]. But circulating FFAs can be used in the biosynthesis of ketones by astrocytes, and adjacent astrocytes or neurons can then oxidize those ketones, etc. The mechanism by which ketones may produce anticonvulsant effects, as described by Yudkoff et al. (2001), is very similar to (essentially identical, to the extent that an increase in ketone oxidation can increase the pool of glutamate available for GABA synthesis by glutamic acid decarboxylase) the proposed mechanism by which exogenous glutamine can increase GABA formation in vivo in rats (http://hardcorephysiologyfun.blogspot.com/2009/03/gabaergic-effect-of-l-glutamine-in-rats.html). In my opinion, low-dose glutamine, which was used as an antidepressant augmentation approach in one small and obscure trial [Cocchi, 1976, cited here: (http://hardcorephysiologyfun.blogspot.com/2009/03/gabaergic-effect-of-l-glutamine-in-rats.html)], could substitute for or potentially work in concert with elevations in ketones as an energy substrate for astrocytes and neurons, but, past a certain dose, the glutamine-induced reductions in plasma FFAs may begin to become counterproductive with respect to astrocyte energy metabolism. Researchers have also found that glutamine can help to preserve the adenylate charge and total adenosine nucleotide content during ischemia, in many different tissues. That may be relevant to depression, and I've discussed various aspects of purine metabolism, in the brain, etc., in many past postings [(http://hardcorephysiologyfun.blogspot.com/2009/04/increase-in-nucleotide-absorption-and.html); (http://hardcorephysiologyfun.blogspot.com/2009/04/adenosine-pka-activity-creb-activation.html); (http://hardcorephysiologyfun.blogspot.com/2009/04/research-on-use-of-creatine-monohydrate.html); (http://hardcorephysiologyfun.blogspot.com/2009/03/adenosine-and-guanosine-in-animal.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/details-on-nucleotides-bioavailability.html)].
Yudkoff et al. (2001) think that the oxidation of ketones increases the intramitochondrial acetyl-CoA pool and leads to a shift in the equilibrium of the reversible aspartate aminotransferase (AA) enzymatic reaction, so as to favor glutamate formation. The authors suggest that this shift results from an increase in the consumption of oxaloacetate, one of the products of the AA reaction, by citrate synthase. Acetyl-CoA and oxaloacetate are substrates of citrate synthase, which forms citrate. The authors also note that ketone oxidation is likely to decrease the free CoA pool and thereby decrease the flux through the alpha-ketoglutarate dehydrogenase (KGDH) reaction of the TCA cycle. One issue I see is the fact that citrate synthase activity tends to be inhibited by a high acetyl-CoA/CoA ratio, but this is nonetheless a really good article. Also, they're basically saying that ketone oxidation lessens the flux of substrates through the TCA cycle (http://hardcorephysiologyfun.blogspot.com/2009/01/coenzyme-sequestration.html), given that the inhibition of the KGDH step limits the anaplerotic addition and removal of TCA cycle intermediates from the mitochondria by the malate-aspartate and malate-citrate shuttles that transfer those intermediates in and out of the mitochondria, thereby sustaining the TCA cycle. So ketone oxidation expands the pool of TCA cycle intermediates but diminishes oxidative metabolism by exacerbating the inhibition of the KGDH reaction? Are they saying ketone oxidation inhibits anaplerosis, by producing more inhibition of KGDH activity, and then increases anaplerosis by expanding the pools of citrate and citrate-derived TCA cycle intermediates that will supposedly enhance anaplerosis? The activity of AA is very high, normally, and increases in the transports of intermediates by the malate-aspartate (as discussed by the authors) and malate-citrate shuttles are not necessarily consistent with the inhibition of oxidative metabolism. It's possible that ketones buffer the pool of TCA cycle intermediates by slowing down oxidative metabolism and preventing the derangements in the cytosolic NADH/NAD+ ratio that can occur during, for example, "hyperglycolysis," following traumatic brain injuries. Then, when ketone levels fall, there's a larger pool of TCA cycle intermediates and more capacity for sustaining oxidative metabolism. What they say has a lot of truth to it, I think, but I also think that the effects of increases in ketone oxidation could be ironed out a little more.
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