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.