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

Glucose versus lactate in immature brain slices

Brain metabolism,Energy Substrates,Ethics in science,Excitatory GABA,Lactate,Methodology,Neurodegenerative diseases,Neuroscience FAQ, Q&A — Tags: — 11:55 am

Related Q&A: “Y Ben-Ari writes that ‘Zilberter and Bregestovski and colleagues’ dealt with ‘ketone body metabolites’. What does ketone body metabolite mean? ”

About this post

1. These quotes were first used by Elly Strammer at F1000.com. After she agreed to remove her post from there, she contacted us suggesting that we use the quotes. We thank Elly for her contribution and for further commenting at the Naturally Selected

2. We received many questions regarding this post, quite a few of them concerned the formatting, which was not helping to clearly understand the issue. Because of that, we updated the post making sure to visually indicate quotes belonging to the arguing sides (according to F1000.com) . Now, remarks related to comments concerning the works of Y. Zilberter et al. are marked as  and remarks by Y. Ben-Ari are marked as 

 ”We demonstrate that in the neonatal brain, Em [membrane potential] and EGABA [reversal potential of GABA-induced anionic currents] strongly depend on composition of the energy substrate pool. Complementing glucose with ketone bodies, pyruvate or lactate resulted in a significant hyperpolarization of both Em and EGABA, and induced a radical shift in the mode of GABAergic synaptic transmission towards network inhibition.” (1)

“The main conclusions of our work are that the inhibitory effect of L-lactate on GDPs is not mediated by mitochondrial energy metabolism, and that glucose at its standard 10 mM concentration is an adequate energy substrate for neonatal neurons in vitro.” (2)

 ”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.” (3)

“Lactate is not an efficient replacement for glucose and, as in vivo glucose is always kept at 4-5mM in the brain even in conditions of severe stress.” (4 a)

“The fact is, in the extracellular fluid (ECF) in the brain, glucose concentration is between 1.9 mM and 0.59 while lactate concentration is between 5.1 mM and 0.78 mM (for review, see [9 in this post]). The question arises: why 10 mM glucose in standard ACSF is adequate but 10 mM lactate is not.” (5)

“Clearly, the suggestions of Zilberter and colleagues rely on wrong assumptions and results that have not been reproduced.” (4 a)

“The effect of weak acids on GABA reversal potential and GDP generation was initially described for 4-5 mM concentrations of BHB [ketone body 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), lactate and propionate (Ruusuvuori et al. 2010).” (6)

“From a clinical perspective, it is interesting to stress that relying on their observations on the positive actions of lactate on metabolism, Zilberter and colleagues have suggested that administration of lactate may be “a novel therapeutic tool to cure Parkinson, Alzheimer, Leigh syndrome and epilepsies” (4a)

 From Brain Fuels: This quotation is taken out of context. The exact piece from (9) reads: “… a growing body of evidence shows that metabolic stress caused by impaired energy homeostasis is a common feature of neurodegenerative disorders (NDDs) such as Alzheimer disease, Leigh syndrome, epilepsy, dementia, multiple sclerosis, neuropathies or ataxias [88] and [89]. We speculate that endogenous ES such as lactate, BHB and pyruvate or their combinations can be efficient in treatingNDD, and would address the cause rather than symptoms. Indeed, the neuroprotective effects of pyruvate have been repeatedly demonstrated in cases of brain ischemia, hypoglycemia, hemorragia, stroke and kainate-inducedepileptic brain damage[90], [91], [92]and [93]. Further research into mechanisms of the effects of ES on fundamental neuronal properties might allow more rapid progress in preventing and managing NDDs.”

The comment made on 29 Jul 2011 (4 b) quoted this paragraph with the references removed thus attributing the text solely to (9).

“Considering the compelling and well-known clinical observation that high lactate level is a classical sign of neuron suffering and severe conditions that require rapid intervention, this suggestion is, to say the least, astonishing.” (4 a)

“The bulk of the evidence suggests that lactate is an important intermediary in numerous metabolic processes, a particularly mobile fuel for aerobic metabolism, and perhaps a mediator of redox state among various compartments both within and between cells. Lactate can no longer be considered the usual suspect for metabolic ‘crimes’, but is instead a central player in cellular, regional and whole body metabolism… we might term the period from the 1930s to approximately the early 1970s the dead-end waste product era.” (7)

” It is curious that Dr Zilberter and colleagues refer to metabolism but have never reported measuring it.” (4 b)

“…Ivanov et al. (2011) simultaneously recorded oxygen tension, NAD(P)H fluorescence transients and local field potentials during electrical stimulation of the hippocampal Schaffer collateral pathway in neonatal brain tissue slices from mice. From the very beginning, the authors took great care to ensure both viability and functionality of their preparations. They convincingly demonstrated that surprisingly high superfusion rates with standard artificial cerebrospinal fluid (ACSF) in the slice chamber are required to ensure adequate oxygenation and complete electrical function in blood-free tissue slices. 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.” (8)

References

  1. Holmgren, C. D., Mukhtarov, M., Malkov, A. E., Popova, I. Y., Bregestovski, P., and Zilberter, Y. (2010). Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity in the neonatal cortex in vitro. J. Neurochem. 112, 900–912.
  2. Ruusuvuori E et al. (2010). Spontaneous network events driven by depolarizing GABA action in neonatal hippocampal slices are not attributable to deficient mitochondrial energy metabolism. J Neurosci. Nov 17; 30(46):15638-42
  3. 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.
  4. Ben-Ari Y.  a) Faculty of 1000, 06 Jan 2011, evaluation,  b) 29 Jul 2011, comment.
  5. Zilberter Y. Faculty of 1000, 19 May 2011 and July 14 2011, comments.
  6. Khakhalin A (May 18, 2011). Questioning the depolarizing effects of GABA during early brain development. J Neurophysiol doi: 0.1152/jn.00293.2011.
  7. Mendel I. Faculty of 1000, 04 Jun 2011, comment (Currently the comment is removed).
  8. Kasischke K (2011) Lactate fuels the neonatal brain. Front. Neuroenerg. 3:4. doi: 10.3389/fnene.2011.00004
  9. Zilberter Y, Zilberter T, Bregestovski P. (2010) Neuronal activity in vitro and the in vivo reality: the role of energy homeostasis. Trends PharmacolSci 31:394–401.

F1000 and the lactate controversy

Ethics in science,Ketosis, ketogenesis,Lactate,Neuroscience FAQ, Q&A — Tags: — 9:11 am

Q&A and FAQ (archived) :: Ongoing Q&A :: Neuroscience Q&A and FAQ

Question: Hi Tanya,

I am fascinated by development at the Faculty of 1000 started by Y. Ben-Ari. I couldn’t contain myself and posted a comment there. However, I felt a little out of place being just a student arguing with a real scientist. So I still have a couple of questions to ask you.

1. Y Ben-Ari writes there that “Zilberter and Bregestovski and colleagues” dealt with “ketone body metabolites”. What does ketone body metabolite mean? From the articles (Rheims et al., 2009; Holmgren et al., 2010) Y. Ben-Ari refers, I could only find beta-hydroxybutyrate and basing on my textbook, I thought that ketone bodies are metabolized in the brain resulting in CO2, HCO3- and acetone.”]

2. Y Ben-ari argues with your statement and here’s his exact words: “Zilberter and colleagues have suggested that administration of lactate may be “a novel therapeutic tool to cure Parkinson, Alzheimer, Leigh syndrome and epilepsies”. What did you mean the “tool to cure”?

Thank you!

Ingrid

Answer: Hi Ingrid,

The phrase “ketone body metabolites” is used very scarcely and I’ll give you exact usage of it, then I’ll explain what you probably know already from your textbook.

From those authors who use this phrase, most of them refer to the work of Miles et al. (1), the accurate quote of which is: “ketone body metabolites (CO2, bicarbonate and acetone)” (1). Fontain et al. (2) mention ketone bodies metabolites listing them as beta-hydroxybutyric acid and acetoacetic acid, which is not exactly accurate since they both are ketone bodies themselves.

Other than that, the phrase has a different meaning, like this: “Fatty acids and their ketone body metabolites may serve as afferent signals to modulate food intake” (3). Clearly, ketone bodies are meant as metabolites of fatty acids, again a textbook information.

A citation from very recent reference (4): “Ketone bodies, as described here, comprise acetoacetic acid (AcAc), D-3-hydroxy-n-butyric acid (3HB), and acetone.” Note that they are ketone bodies, not ketone body metabolites.

Now, from the textbook (5): In muscle and brain, ketone bodies yield ATP + CO2 (p. 905); Acetoacetate  + H2O -> Acetone + HCO3- (p. 920)

None of the the two articles Y Ben-Ari refers to in his evaluation concerns anything other than beta-hydroxybutyrate, not other ketone bodies, not ATP, CO2 or HCO3-, or acetone.

As to your question number 2, text concerning “therapeutic” might be from (6): “Our hypothesis predicts that the adequate delivery of energy substrates may interrupt this pathological spiral of events and provide therapeutic options targeting the cause of pathologies rather than their symptoms”. However, there’s nothing wrong with this statement  even as it’s cited (excluding of course the words “cure”, which I can hardly imaging being in the Zilberter and coauthors’ vocabulary) and many authors describe and discuss metabolic crisis in connection with neurodegenerative diseases.

1. Miles J et al., (1980) Determination of 14C radioactivity in ketone bodies: a new, simplified method and its validation. J Lipid Res, 21, 646-650.

2. Fontaine M et al. (1996) Acylcarnitine removal in a patient with acyl-CoA beta-oxidation deficiency disorder: effect of L-carnitine therapy and starvation Clinica Chimica Acta 252; 109-122

3. Bray GA “A Guide to Obesity and the Metabolic Syndrome: Origins and Treatment” CRC Press, 2011.

4. Sass JO (2011). Inborn errors of ketogenesis and ketone body utilization. J Inherit Metab Dis DOI 10.1007/s10545-011-9324-6

5. Lehninger, A. L. (2005). in Principles of Biochemistry, 4th Edn, eds D. L. Nelson and M. M. Cox (W. H. Freeman),

690–740.

6. Holmgren, C. D., Mukhtarov, M., Malkov, A. E., Popova, I. Y., , P., and Zilberter, Y. 2010). Energy substrate availability as a determinant of neuronal resting potential, GABA signaling and spontaneous network activity n the neonatal cortex in vitro. J. Neurochem. 112, 900–912.

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

The metabolic rate of plasma-borne lactate is a function of brain lactate concentration

Astrocyte–neuron lactate shuttle,Lactate — Tags: , — 5:07 am

In the Journal club section of the Journal of Neuroscience (written exclusively by graduate students or postdoctoral fellows), a review by C. Figley from Johns Hopkins University and Kennedy Krieger Institute, Baltimore, Maryland was recently published, concluding: “…neurons are capable of transporting and metabolizing large quantities of lactate in vivo” and “…cultured neurons might preferentially oxidize lactate as their primary metabolic substrate”

Chase R. Figley. Human Brain: Implications for the Astrocyte-Neuron Lactate Shuttle Hypothesis. J Neuroscience, 2011, 31(13): 4768-4770; doi: 10.1523/​JNEUROSCI.6612-10.2011




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.

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.

 

Lactate shuttle or glia-neuron metabolic cooperation

Astrocyte–neuron lactate shuttle,Lactate,Neuroscience FAQ, Q&A — Tags: — 11:44 am

Original Q&A :: About these Q&A :: Other Q&A

Q: Dr. Zilberter,

I am a little bit confused in the area of what they call shuttles between neurons and glial cells. What the suttles do? I can imagine that something is being delivered FROM glia to neurons, but what goes back and how?

Thank you for you time,

Doug

A: Dear Doug,

First of all, it’s safe to talk about metabolic cooperation between astrocytes and neurons since the lactate shuttle remains a hypotheses having opponents though experimental data supporting it accumulates.

The simplified picture is the following. Glucose (let’s talk about glucose but keep in mind that there are other energy carriers) and oxygen come to the vicinity of neurons and glial cells, astrocytes, in the capillaries, which generally speaking are closer to glia than to neurons. Glucose is being pulled into the cells by transporters, GLUT1 for astrocytes and GLUT3 for neurons. Inside cells, glucose converts into pyruvate, which serves as energy substrate (neuron) or further converts into lactate and with the help of the transporter MCT1 goes outside astrocyte and into the extracellular lactate pool and with the help of another transporter, MCT2, into neurons to be converted into pyruvate and used for energy. The entire chain of the processes are regulated by energy demands corresponding to neuronal activity levels and signals — Na and K pumps, regulatory peptides like VIP. On its side, neurone contribute to the cooperation (shuttle) via synaptic processes and neurotransmitter Glutamate. Please let me know if you need more details about the Glutamate part of the cooperation.

A little bit more of this can be found at: Glucose or lactate as fuels in mature brain: whose primacy?

Tanya Zilberter

Comparison of lactate kinetics in vitro and in vivo is to be done

Astrocyte–neuron lactate shuttle,Lactate,Methodology — Tags: , , — 6:23 am

Glucose is an energy source for both neurons and glia in the adult brain but lactate, one of the monocarboxylic acids, being converted from pyruvate in astrocytes and supplied to neuron (“astrocyte-neurona lactate shuttle“) is an important energy fuel alternative to glucose as well. The role of exogenously added lactate as a viable energy substrate has remained controversial although recent data showed that exogenous lactate might be selectively taken up by neuron in intact rat brain (1) and that lactate works as an energy substrate supporting neuronal activity in presence or absence of glucose in vitro (2, 3) and in vivo (4, 5).

Notwithstanding experimental data supporting the existence of astrocyte-neurona lactate shuttle, the opponents (for contrasting views see 6, 7) basing on mathematical modeling, challenge the very phenomenon, strongly insisting on the following experiments that should be done before jumping to conclusions:

“In this perspective, we suggest that highly relevant experiments to help the experimental-theoretical interaction could be: (i) comparison of lactate kinetics in vitro, in vivo using biosensors, and in vivo using 1H MRS, in the same brain areas, and using various stimulation protocols; (ii) comparison, in vitro and in vivo, of NADH kinetics in astrocytes and neurons, and extracellular lactate and pH kinetics; (iii) this approach would be reinforced if the kinetics of oxygen concentration and intracellular pH and sodium were also measured, using for instance microelectrodes and fluorescent dyes.” (8)

  1. Yamada A, et. al., Lactate is an alternative energy fuel to glucose in neurons under anesthesia. NeuroReport 20:1538–1542, 2009
  2. 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.
  3. Kasischke K (2011). “Lactate fuels the neonatal brain”. Front. Neuroenerg. 3:4.
  4. Wyss M, Jolivet R, Buck A, Magistretti P, and Weber B. (2011). In Vivo Evidence for Lactate as a Neuronal Energy Source. J Neuroscience, 31(20):7477-7485
  5. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, Alberini CM. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell. 2011 Mar 4; 144(5):810-23 Evaluation access here
  6. Korf J. 2006. Is brain lactate metabolized immediately after neuronal activity through the oxidative pathway? J Cereb Blood Flow Metab 26:1584–1586.
  7. Schurr A. 2006. Lactate: The ultimate cerebral oxidative energy substrate? J Cereb Blood Flow Metab 26:142–152.
  8. Aubert AS, Costalat R, Compartmentalization of Brain Energy Metabolism Between Glia and Neurons: Insights from Mathematical Modeling. GLIA 55:1272–1279, 2007
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