The basics of ketogenic diet: works of Shaffer and Wilder & Winter

Glucose,Ketogenic diet,Ketone bodies,Ketosis, ketogenesis,Methodology — Tags: , — 6:16 am

It is interesting that while the ketogenic diet becomes well researched as a method for improving energy metabolism during quite a few medical conditions and the number of original research articles as well as reviews grow currently approaching 15,000, only 19 out of all of them cite the original work, which in fact is the basis of the diet. >>> Read more

The ketogenic diet is no longer considered a strictly anti-epileptic diet: its suggested and tested applications includes a broad spectrum of disorders of energy metabolism. The ketogenic ratio formula used in clinics for calculating the ketogenic diet composition was offered by Wilder and Winter in 1922 (1). They argued that the levels of ketogenic substances depend on the ratio between fatty acids and glucose of the metabolizing foods. The ratio when ketogenesis is initiated they called the threshold of ketogenesis: “When the proportion of acetoacetic acid to glucose in such mixtures was that of 1 (or possibly 2) molecules of acetoacetic acid to 1 of glucose, the former substance was completely oxidized. When the proportion of glucose was less, a considerable fraction of acetoacetic acid escaped oxidation.”

Shaffer (2, 3) calculated the number of molecules of ketogenic substrates corresponding to the number of molecules of glucose and concluded that the maximal ratio compatible with the oxidation of the ketogeniec compounds was reached when a ratio of of ketogenic molecules to the number of glucose molecules was 1: 1. He subsequently considered that each glucose molecule is ketolytic for 2 molecules of acetoacetic acid, a 2:l ratio.

Wilder and Winter, 1922 included in their formula the following measurements obtained in clinical settings:

1) basal metabolism for 24 hour periods plus 10 per cent for the specific dynamic action of food and 10 per cent for movements;

2) the calories from the protein metabolism assessed by nitrogen excretion;

3) the calories from fat metabolism taken as the sum of the calories of protein and carbohydrate combined subtracted from the total calories of the day.

The values for carbohydrate and fat are used in the calculation of the ratio between the ketogenic molecules and the glucose molecules (2, 3).

“Under the conditions of these experiments, provided these assumptions are tenable, the ratio between the ketogenic and the glucose molecules at which a clinically significant ketosis appears has a value of at least 2: 1. A ratio of this value implies that every molecule of glucose is ketolytic for 2 molecules of acetoacetic acid.”

References

  1. Wilder R., Winter M. Thew threshold of ketogenesis. J. Biol. Chem. 1922 52: 393-401.
  2. Shaffer, P. A., Antiketogenesis. I. An in vitro analogy, J. Biol.Chem., 1921, xlvii, 433.
  3. Shaffer, P. A., Antiketogenesis. II. The ketogenic antiketogenic balance in man, J. Biol. Chem., 1921, xlvii, 449.

 

 

 

Alzheimer’s disease and a long-standing exposure to glucose in the Western diet

Alzheimer's,Glucose,Ketone bodies,Lactate — 6:35 am

 

Chronic exposure to glucose due to the traditional Western diet impairs neuronal function and causes apoptosis (programmed neuronal death), concluded Drs Seneff & Wainwright (UK) and Mascitelli (Italy). Their reasoning was roughly the following:

The amyloid-beta peptide (AB) in Alzheimer’s disease (AD) plaques so far seen as a hallmark of this disease, in fact may be an early attempt of protection from its development.  AB switches neuronal metabolism from glycolysis-based to the use of other substrates, e.g., lactate and ketone bodies. This is a very important adjustment in the AD case since there’s an insulin resistance in the AD brain indicating an inadequate ability to utilize glucose. Moreover, the levels of advanced glycation end-products (harmful in any case) are increased in AD. The damage they induce interferes with delivery of fats and cholesterol to astrocytes, and consequently to neurons. This is important because for smooth communication between neurons, sufficient levels of fat and cholesterol is required and the AD CSF is deficient in both. Synthesis of AB is increased when lipid supply is deficient. In the condition of this deficiency, there’s an increase in synthesis of excitatory neurotransmitter glutamate leading to oxidative damage and toxic overexcitability.

The good news is, wrote the authors, a simple dietary change towards lower carbohydrate intake and higher fats intake, may be efficiently protective against AD.

Source:

European Journal of Internal Medicine 22 (2011) 134–140

Sweet and sour recipes for the brain 4. “Physiological” concentrations: what and where?

Excitatory GABA,Ketone bodies,Lactate,Methodology,Pyruvate — 6:27 am

Part 2. Energy substrates: too sour?
Part 3. Let the neurons breathe!

What concentrations are physiological and what are not (usually called pharmacological)? The physiological ones  normally refer to the levels of a substance relevant to the naturally occurring, which, logically, for neurons is the milieu they strive in. It is called extracellular fluid (ECF) and is notorious for dramatic differences with not only blood (plasma) but even with the cerebrospinal fluid (CSF).

“Importantly, microdialysis data have shown that both in adult humans and in rats,the basal glucose levels are about 1–2 mM in the ECF of the neocortex and hippocampus [32,33,37,38] compared with 5–7 mM in the blood, whereas concentrations of lactate are about 2–5 mM in the ECF [32,34,39,40] compared with 1–2 mM in the adult blood.” (Zilberter et al., 2010). The authors further stressed the imperative of providing adequate means for energy substrates to be utilized in the artificial milieu, in which brain slices are placed:

“In brain slices, energy deficiency cannot be managed in the same way as in whole-body homeostasis, resulting in higher ES levels in  slices than in vivo. The importance of a proper oxygen supply should be stressed [55], because oxidative phosphorylation is proportional to the presence of O2. Therefore, at an inadequate oxygen level, the efficacy of ES might be negligible. It is not surprising that energy metabolism in slices differs from that occurring in the living brain, and is probably impaired [52–54].”

Khakhalin (2011) wrote in his recent review that effects of ES on GABA action has been shown for “…4-5  mM concentrations of beta-hydroxybutyrate  (Rheims et al. 2009), lactate and pyruvate (Holmgren et al. 2010), and was later confirmed by independent research groups for similar concentrations of pyruvate (Tyzio et al. 2011), and lactate (Ruusuvuori et al. 2010).” He continued arguing whether  the concentrations were  ”physiological ” in the experiments showing equal results in different authors who made, however, different conclusions: Tyzio et al. state that the physiological concentration of pyruvate is 1.6 – the one they measured in plasma.

“This comparison may be not valid, however, as it is well known from microdialysis studies that the extracellular fluid, immediately surrounding neural cells, differs in its composition not only from the blood plasma, but even from the cerebrospinal fluid. In particular, concentration of lactate in the extracellular fluid of rats and humans was found to be 2-5 times higher than in the blood plasma… 4-5 mM concentrations are likely to be physiologically relevant… On the other hand, at these concentrations both lactate and pyruvate induce noticeable changes in GABA- and glutamatergic transmission in developing neural networks. It means that some changes in experimental protocols and related theoretical paradigms may still be necessary.”

Kasischke (2011) in his comment on the article by Ivanov et al., 2011, wrote: “From the very beginning, the authors took great care to ensure both viability and functionality of their preparations.”

“An important implication of this methodological tour de force is that under many previously reported experiments the requirements for viability may been met while the functionality may have been compromised.”

References

 

  1. Zilberter Y, Zilberter T, Bregestovski P. (2010) Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis. Trends Pharmacol Sci., 31(9):394-401
  2. [32,33,3437,38,39,40,52-55]  are cited in Zilberter et al. (2010)
  3. Khakhalin A (May 18, 2011). Questioning the depolarizing effects of GABA during early brain development. J Neurophysiol doi: 0.1152/jn.00293.2011.
  4. Tyzio et al. (2011) and  Ruusuvuori et al. (2010) are cited in Khakhalin ( 2011).
  5. Kasischke K (2011). Lactate fuels the neonatal brain. Frontiers in Neuroenergetics; 3, 4

“Brain metabolism in vitro” and those sour energy substrates

Brain metabolism,Energy Substrates,Excitatory GABA,Glucose,Ketone bodies,Lactate,Pyruvate — Tags: , — 10:31 am

Part 2. Energy substrates: too sour?
Part 3. Let the neurons breathe!
This paper suggests that the developmental switch in the reversal potential for gamma-aminobutyric acid (GABA) is regulated by different energy sources

This paper suggests that the developmental switch in the reversal potential for gamma-aminobutyric acid (GABA) is regulated by different energy sources

An evaluation of our article (1) appeared in the “Faculty of 1000 postpublication peer reviews” the conclusion being:

The findings of Rheims et al. have a potentially major impact on our understanding of GABAergic function during development, bringing back an element of inhibition in developing neuronal networks that appeared to rely entirely on excitatory connections (2).

This article (1) along with the article (3) later became an indirect subject of another evaluation (4) although formally, the evaluation concerned a different paper (5), which has been commended because (the author’s words):

“It settles an important issue related to brain metabolism in vitro and the role of acidification in brain patterns.”

The acidification issue doesn’t seem to be resolved either in 5 nor in 4, so a comment to the evaluation appeared in May 2011,  stating among other things the following:

We showed that inhibition of spontaneous network activity in neonatal hippocampal slices by energy substrates is not correlated with intracellular acidification (7) and that they work altering intrinsic features of energy metabolism namely NAD(P)H and oxygen utilization (8).

Another data challenged in 5 is whether lactate as efficient as an energy substrate: “Lactate is not an efficient replacement for glucose” wrote Dr Ben-Ari and Y. Zilberter in his comment referred to the paper 8 titled “Lactate effectively covers energy demands during neuronal network activity in neonatal hippocampal slices” and the work of Wyss et al. (9) titled “In Vivo Evidence for Lactate as a Neuronal Energy Source”.

References

1. Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y. (2009) J Neurochem.  Aug;110(4):1330-8. Epub 2009 Jun 22. (on Brain Fuels)

2. Scimemi A, Diamond J: 2009. F1000.com/1166168

3. Holmgren CD, Mukhtarov M, Malkov AE, Popova IY, Bregestovski P, Zilberter Y. (2010) J Neurochem. Feb;112(4):900-12. Epub 2009 Nov 24. (on Brain Fuels)

4. Ben-Ari Y: 2011. F1000.com/6913961

5. Ruusuvuori E, Kirilkin I, Pandya N, Kaila K (2010) J Neurosci.  Nov 17; 30(46):15638-42

6. Zilberter Y, Zilberter T, Bregestovski P. (2010) Trends Pharmacol Sci., 31(9):394-401 (on Brain Fuels)

7. Mukhtarov, M., Ivanov, A., Zilberter, Y., and Bregestovski, P. (2011) J Neurochem 116, 316-321

8. Ivanov A, Mukhtarov M, Bregestovski P and Zilberter Y (2011) Front. Neuroenerg. 3:2.

9. Wyss M, Jolivet R, Buck A, Magistretti P, and Weber B. (2011)  J Neuroscience, 31(20):7477-7485

Sweet and sour recipes for the brain. 1. “Sweet slices are fine”?

Applications,Energy Substrates,Glucose,Ketone bodies,Lactate,Pyruvate — 10:32 am

Part 2. Energy substrates: too sour?
Part 3. Let the neurons breathe!

Is glucose the absolutely exclusive fuel for the brain? In popular articles, you might always read that yes, it is.

Meanwhile, in special scientific literature the role of quite a few energy carriers including ketone bodies (mostly beta-hydroxybutirate, BHB), lactate, and pyruvate was unquestioned for decades. Recently, a series of three research reports published in the Journal of Neuroscience (Tyzio et al., 2011, Ruusuvuori et al., 2010 and Kirmse et al., 2010) arrived at the conclusion contradicting to the well known fact about brain energy metabolism in neonates. It seemed indisputable that in the neonatal brain, the use of glucose as an energy substrate is limited due to immaturity of the mechanisms of glucose utilization but the articles in question shed doubts on it. Why is it important to sort out these conflicting research results?

I already wrote about the importance of energy substrates other than glucose for the immature brain and the consequence of ignoring this role in experiments on neonatal brain slices discussing the results of Rheims et al., 2009 and Holmgren et al., 2010.

In 2010, at the meeting of the Society for Neuroscience in San Diego, CA, a poster has been presented announcing in its title: “BHB does not alter GABA signals in neonatal slices: sweet slices are fine, no need to alter conventional ACSF“. Neither poster nor its abstract (Picardo et al., 2010) contained methodical details and they remained unknown until 2011 when an article in the Journal of Neuroscience was published (Tyzio et al., 2011). It became possible to compare the differences in methods, which has been done in due time and published in the Frontiers in Neuroenergetics (Ivanov et al., 2011) — see parts 2-4.

Important is, that Ivanov et al. showed that in immature brain slices, glucose rendered less efficient energy carrier than lactate, BHB, and pyruvate.  Judged by the hallmarks of energy metabolism – oxygen utilization and nicotinamide adenine dinucleotide phosphate or NAD(P)H, neuronal activity robustness was higher in the presence of lactate alone or combined with glucose than with glucose alone. The authors concluded: “We show that in the presence of glucose, lactate is effectively utilized as an energy substrate, causing an  augmentation of oxidative metabolism. Moreover, in the absence of glucose lactate is fully capable of maintaining synaptic function. Therefore, during network activity in neonatal slices, lactate can be  an efficient energy substrate capable of sustaining and enhancing aerobic energy metabolism.”

References

  1. Garcia, A.J., 3rd, Putnam, R.W., and Dean, J.B. (2010). Hyperbaric hyperoxia and normobaric reoxygenation increase excitability and activate oxygen-induced potentiation in CA1 hippocampal neurons. J Appl Physiol 109, 804-819.
  2. Hajos, N., Ellender, T.J., Zemankovics, R., Mann, E.O., Exley, R., Cragg, S.J., Freund, T.F., and Paulsen, O. (2009). Maintaining network activity in submerged hippocampal slices: importance of oxygen supply. Eur J Neurosci 29, 319-327.
  3. Holmgren CD, Mukhtarov M, Malkov AE, Popova IY, Bregestovski P, Zilberter Y (2010) Energy substrate availability as a determinant of neuronal resting potential,GABAsignaling and spontaneous network activity in the neonatal cortex in vitro. J Neurochem 112:900 –912.
  4. Ivanov A, Mukhtarov M, Bregestovski P and Zilberter Y (2011). Lactate effectively covers energy demands during neuronal network activity in neonatal hippocampal slices. Front. Neuroenerg. 3:2.
  5. Kirmse K, Witte OW, Holthoff K. (2010). GABA Depolarizes Immature Neocortical Neurons in the Presence of the Ketone Body β-Hydroxybutyrate. J Neuroscience, 24; 30(47): 16002-16007
  6. Lehninger, A.L. (2005). “Oxydative phosphorylation and photophosphorylation,” in Principles of biochemistry, eds. D.L. Nelson & M.M. Cox. Forth ed: W. H. Freeman), 690-740.
  7. Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y (2009) GABA action in immature neocortical neurons directly depends on the availability of ketone bodies. J Neurochem 110: 1330–1338.
  8. Schurr, A., and Payne, R.S. (2007). Lactate, not pyruvate, is neuronal aerobic glycolysis end product: an in vitro electrophysiological study. Neuroscience 147, 613-619.
  9. Tyzio, R., Allene, C., Nardou, R., Picardo, M.A., Yamamoto, S., Sivakumaran, S., Caiati, M.D., Rheims, S., Minlebaev, M., Milh, M., Ferre, P., Khazipov, R., Romette, J.L., Lorquin, J., Cossart, R., Khalilov, I., Nehlig, A., Cherubini, E., and Ben-Ari, Y. (2011). Depolarizing actions of GABA in immature neurons depend neither on ketone bodies nor on pyruvate. J Neurosci 31, 34-45.

MCT and beta-hydroxybutirate protect cognitive and synaptic functions

Energy Homeostasis,Energy Substrates,Glucose,Ketone bodies,Neuroprotectors — 7:57 am


Medium-Chain Fatty Acids Improve Cognitive Function and Support In Vitro Synaptic Transmission During Acute Hypoglycemia (1)

The brain can use alternative fuels such as monocarboxylic acids, lactate, and ketones to maintain energy homeostasis (2-8). Fasting or hypoglycemia causes adaptive changes in the brain, including an enhanced ability to utilize alternative fuels. The work conducted by joined teams from Yale School of Medicine, State University of New York, Winthrop University Hospital, Long Island, Department of Psychology, State University of New York, and University at Albany studied how alternative energy substrates influenced cognitive and synaptic functions disturbed by hypoglycemia.

Impaired verbal memory, digit symbol coding, digit span backwards, and map searching was observed during insulin-induced hypoglycemia. Medium-chain triglycerides given in a drink produced higher free fatty acids and beta-hydroxybutyrate levels and returned cognitive performance to normal levels without adversely affecting adrenergic or symptomatic responses to hypoglycemia.

1. Diabetes 58:1237–1244, 2009
2. Hasselbalch SG, Knudsen GM, Jakobsen J, Hageman LP, Holm S, Paulson
OB. Brain metabolism during short-term starvation in humans. J Cereb
Blood Flow Metab 1994;14:125–131
3. Maran A, Cranston I, Lomas J, Macdonald I, Amiel SA. Protection by
lactate of cerebral function during hypoglycaemia. Lancet 1994;343:16–20
4. Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J. Effect of hyperketonemia
and hyperlacticacidemia on symptoms, cognitive dysfunction,
and counterregulatory hormone responses during hypoglycemia in normal
humans. Diabetes 1994;43:1311–1317
5. Amiel SA, Archibald HR, Chusney G, Williams AJ, Gale EA. Ketone infusion
lowers hormonal responses to hypoglycaemia: evidence for acute cerebral
utilization of a non-glucose fuel. Clin Sci (Lond) 1991;81:189–194
6. Hawkins RA, Williamson DH, Krebs HA. Ketone-body utilization by adult
and suckling rat brain in vivo. Biochem J 1971;122:13–18
7. Pan JW, Rothman TL, Behar KL, Stein DT, Hetherington HP. Human brain
beta-hydroxybutyrate and lactate increase in fasting-induced ketosis.
J Cereb Blood Flow Metab 2000;20:1502–1507
8. Mason GF, Petersen KF, Lebon V, Rothman DL, Shulman GI. Increased
brain monocarboxylic acid transport and utilization in type 1 diabetes.
Diabetes 2006;55:929–934


Great Controversies in Neurobiogy

Excitatory GABA,Glucose,Ketone bodies,Methodology,Pyruvate — 9:47 am

“They teach us in our institutes that GABA is excitatory in the neonates, should we still believe it?” (Excitatory GABA scandal?)

There was an interesting development in the Department of Neuroscience of the Brown University who published a provocative recommendation to the Neuro 193E Course under the general title “Great Controversies in Neurobiogy.”

Since 80′s it was becoming a firmly established fact that in immature brain, the reversal potential for GABA receptors was more depolarized, making GABA excitatory and producing a special form of electrical activity named the giant depolarizing potentials, GDP, described by Ben-Ari in hippocampal slices of the immature brain.

“This is something which has been widely described in multiple brain regions by many different labs and is pretty much accepted as fact,” wrote the course’s authors. “However,” continues the chapter, “about a year ago, a couple of papers from the Zilberter’s lab (1, 2) have seriously brought this fact into question.”

The matter is, as multiple prior studies showed [as reviewed in 3, BF], the immature brain “is not very good at metabolizing glucose” due to the immaturity of glycolytic mechanisms and instead it relies on brain fuels alternative to glucose, such as ketones, lactate, and/or pyruvate.

“They noted that almost all papers published using brain slices use artificial cerebro-spinal fluid (ACSF) made with pleny of glucose, but no ketones. Which means that any immature slices cut and maintained in this media will likely be metabolically compromised.”

“They show quite convincingly that adding ketone bodies to ACSF used for immature slices actually makes GABA reversal potential more negative, similar to an adult neuron. Thus they suggest that the depolarizing actin of GABA during early development is an experimental artifact of metabolically-compromised brain slices,” concluded the author.

Source: Dept. of Neuroscience, Brown University. Course Neuro 193E. Last edited by Carlos Aizenman-Stern on Aug 24, 2010 15:34

References

  1. GABA Action in Immature Neocortical Neurons Directly Depends on the Availability of Ketone Bodies. Rheims S, Holmgren CD, Chazal G,Mulder J, Harkany T, Zilberter T, Zilberter Y. J Neurochem 2009;110(4):1330–13382.
  2. Energy Substrate Availability as a Determinant of Neuronal Resting Potential, GABA Signaling and Spontaneous Network Activity in the Neonatal Cortex In Vitro. Holmgren CD,MukhtarovM,Malkov AE, Popova IY, Bregestovski P, Zilberter Y. J Neurochem 2010;112(4):900–912
  3. Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis. Trends Pharmacol Sci. 2010 Sep;31(9):394-401. Epub 2010 Jul 14. Zilberter Y, Zilberter T, Bregestovski P.

Energy substrates and neuroprotection: what does what

Epilepsy,Glucose,Ketone bodies,Lactate,Neuroprotectors,Pyruvate — Tags: — 6:05 am

A few interesting articles about glucose, lactate, and pyruvate
and their neuroprotective functions.

J Neurochem. 2010 Feb 15
Chronic in vitro ketosis is neuroprotective but not anticonvulsant.
Marina Samoilova, Michael Weisspapir, Peter Abdelmalik, Alexander A
Velumian, Peter L Carlen

Chronic in vitro treatment with a ketone body, D-beta-hydroxybutyrate
(DbetaHB), protected the cultures against chronic hypoglycemia,
oxygen-glucose deprivation and NMDA-induced excitotoxicity, but failed
to suppress intrinsic and induced seizure-like activity, indicating
improved neuroprotection is not directly translated into seizure
control. However, chronic in vitro ketosis abolished hippocampal
network hyperexcitability following a metabolic insult, hypoxia,
demonstrating for the first time a direct link between metabolic
resistance and better control of excessive, synchronous, abnormal
electrical activity.

Neuroscience. 2007 Jun 7
Lactate, not pyruvate, is neuronal aerobic glycolysis end product: An
in vitro electrophysiological study. A Schurr, R S Payne

We hypothesized that, in the brain, both aerobic and anaerobic
glycolysis terminate with the formation of lactate from pyruvate by the
enzyme lactate dehydrogenase (LDH). If this hypothesis is correct,
lactate must be the mitochondrial substrate for oxidative energy
metabolism via its oxidation to pyruvate, plausibly by a mitochondrial
LDH

Neurosci Res. 2004 Dec;50 (4):467-74
Glycolysis regulates the induction of lactate utilization for synaptic
potentials after hypoxia in the granule cell of guinea pig hippocampus.
Toshihiro Takata, Bo Yang, Takashi Sakurai, Yasuhiro Okada, Koichi
Yokono

Population spikes are not maintained with lactate following hypoxia in
10 mM glucose medium, but are maintained at their original levels with
lactate after exposure to hypoxia in lower concentration (5 mM) of
glucose.

Neurosci Res. 2003 Jul ;46 (3):333-7
Effects of lactate/pyruvate on synaptic plasticity in the hippocampal
dentate gyrus.
Bo Yang, Takashi Sakurai, Toshihiro Takata, Koichi Yokono

Replacement of glucose with lactate and pyruvate maintained population
spikes after transient depression, and supported a similar degree of
paired-pulse facilitation. These results indicate that monocarboxylates
could serve as sufficient substrates LTP but with less efficiency than
glucose.

Neuroscience. 2007 Jun 7
Lactate, not pyruvate, is neuronal aerobic glycolysis end product: An
in vitro electrophysiological study.A Schurr, R S Payne

 

We hypothesized that, in the brain, both aerobic and anaerobic
glycolysis terminate with the formation of lactate from pyruvate by the
enzyme lactate dehydrogenase (LDH). If this hypothesis is correct,
lactate must be the mitochondrial substrate for oxidative energy
metabolism via its oxidation to pyruvate, plausibly by a mitochondrial
LDH


Neurosci Res. 2004 Dec 50 (4):467-74
Glycolysis regulates the induction of lactate utilization for synaptic
potentials after hypoxia in the granule cell of guinea pig
hippocampus.Toshihiro Takata, Bo Yang, Takashi Sakurai, Yasuhiro Okada,
Koichi Yokono

 

Population spikes are not maintained with lactate following hypoxia in
10 mM glucose medium, but are maintained at their original levels with
lactate after exposure to hypoxia in lower concentration (5 mM) of
glucose.

 

The seven effects of ketone bodies making them powerful neuroprotectors

Ketone bodies,Neuroprotectors — Tags: , , , — 9:27 am

There are seven traits allowing ketones to serve as neuroprotectors during brain damage:

  1. they require only three steps to enter the Krebs cycle (footnote a) – compare with 9 steps obligatory for glucose;
  2. they cause  inhibition of glycolysis, thus decreasing free radical formation;
  3. they increase production of ATP (footnote b);
  4. they increase mitochondrial energy efficiency;
  5. they increase antioxidant activity of glutathione peroxidase (footnote c);
  6. they spare pyruvate from processing in the Krebs cycle

Source: Journal of Cerebral Blood Flow & Metabolism (2008) 28, 1–16

Footnotes
a) The Krebs cycle or the citric acid cycle is a metabolic pathway involved in the conversion (“burning”) of carbohydrates, fats and proteins into CO2 and H2O to generate energy in the form that can be used by living organisms.
b) ATP: Adenosine Triphosphate, the ultimate “energy molecule”.
c) Glutathione peroxidase: a powerful scavenger of free radicals.

The astrocyte–neuron ketone body shuttle

Astrocyte–neuron ketone shuttle,Ketone bodies — Tags: , , , , — 6:20 am

In the brain, to each one neurone, there are 9 astrocytes (1). They are surrounded by capillaries and are close to the both blood-brain and blood-cerebrospinal “the first cellular barrier encountered by glucose entering the brain tissue, which makes them a prevalent site of glucose uptake”(2)

Astrocytes interacts with neurons and synapses; they express neurotransmitter receptors and transporters. The delivery of lactate from astrocytes to neurons is enhanced during increased synaptic activity. But astrocytes (according to 2) are also able to process fatty acids for the ketogenesis depending on neuronal energy demands. The ketone bodies and acetoacetate can replace glucose as the major source of brain energy during starvation and in the immature brain. Ketone bodies produced by astrocytes seem to be used together with lactate as substrates for neuronal oxidative metabolism in situations such as enhanced synaptic activity and hypoxia . (more…)

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