In the previous post On the mechanisms of brain protection by ketones, I described how a shortage of ketones caused pathological changes in brain cells in brain slices (in vitro, 1) and in whole animals (in vivo, 2) resulting in abnormal (excitatory) behavior of GABA, the principal brain chemical helping to resist hyperactivity. (more…)
Stereoisomers of beta-hydroxybutyrate and dibenzylamine
D-beta-Hydroxybutyrate is a physiologically occurring D-isomer produced by hepatocytes and, to a lesser extent, by astrocytes. It is an alternative source of energy in the brain when glucose supply is depleted
The vast majority of researchers dealing with effects of ketone bodies or, specifically, beta-hydroxybutyrate, use the mixture of D and L isomers, the racemate DL-beta-hydroxybutyrate since the L-form is essentially inactive and, correcting for the actual dosage of D-form in the racemate, effects are safely attributed to the active D-form.
Biological effects of DL-form are abundant in many species, organs, preparations, and conditions. Did I mention that DL form is substantially cheaper than the pure isomers?
An interesting reason can be added to the advantages of using racemate of beta-hydroxybutyrate. It turns out that in the process of separation of the isomers, a non-physiological contaminant, dibenzylamine, remains with the L-form changing it from biologically inactive to biologically VERY active. When left alone, the DL form remained free of dibenzylamine. It’s a good news because we can rest assured that the many effects of DL-beta-hydroxybutyrate remain reliable.
Source: Jong M. Rho, Gail D. Anderson, Sean D. Donevan, and Steve White. Acetoacetate, Acetone, and Dibenzylamine (a Contaminant in L-(+)-b-Hydroxybutyrate) Exhibit Direct Anticonvulsant Actions in Vivo. Epilepsia, 43(4):358-361, 2002
D-beta-Hydroxybutyrate is a physiologically occurring D-isomer produced by hepatocytes and, according to (1), by astrocytes. It is an alternative source of energy in the brain when glucose supply is depleted. The vast majority of researchers dealing with effects of ketone bodies or, specifically, beta-hydroxybutyrate, use the mixture of D and L isomers, the racemate DL-beta-hydroxybutyrate since the L-form is essentially inactive and, correcting for the actual dosage of D-form in the racemate, effects are safely attributed to the active D-form.
Biological effects of DL-form are abundant in many species, organs, preparations, and conditions. Did I mention that DL form is substantially cheaper than the pure isomers?
An interesting reason can be added to the advantages of using racemate of beta-hydroxybutyrate. It turns out that in the process of separation of the isomers, a non-physiological contaminant, dibenzylamine, remains with the L-form changing it from biologically inactive to biologically VERY active. When left alone, the DL form remained free of dibenzylamine. It’s a good news because we can rest assured that the many effects of DL-beta-hydroxybutyrate remain reliable (2).
Sources:
1. Guzman M, Blazquez C. Is there an astrocyte-neuron ketone body shuttle? Trends Endocrinol. Metab. 2001;12:169–173
2. Jong M. Rho, Gail D. Anderson, Sean D. Donevan, and Steve White. Acetoacetate, Acetone, and Dibenzylamine (a Contaminant in L-(+)-b-Hydroxybutyrate) Exhibit Direct Anticonvulsant Actions in Vivo. Epilepsia, 43(4):358-361, 2002
Pyruvate protects neurons against A-beta peptides characteristic for Alzheimer’s
Pyruvate is one of major energy carriers in the brain, it is shown to be protective against damaging consequences of neurotoxins, such as hydrogen peroxide, glutamate, zinc, and copper/cysteine (1). Pyruvate plus another energy substrate, malate, in addition to standard glucose concentrations, protects embryonic neurons in the brain region such as hippocampus and cortex against glutamate excitotoxicity (2). These pyruvate and malate effects promoting neuronal survival were preferential over over glucose suggested that glucose-derived pyruvate from glucose may be limited in neurons studied in vitro, especially under conditions of elevated energy demands. neurons.
Supplementation of glucose-containing culture media with energy substrates, pyruvate plus malate (P/M), protected rat primary neurons from degeneration and death caused by A-beta peptides characteristic for Alzheimer’s disease (3).
Source: Pyruvate Protection Against -Amyloid-Induced Neuronal Death: Role of Mitochondrial Redox State. Gema Alvarez, Milagros Ramos, Francisca Ruiz, Jorgina Satrustegui, and Elena Bogonez. Journal of Neuroscience Research 73:260-269 (2003)
Citations from the source:
- Eimerl and Schramm 1995; Desagher et al., 1997; Ruiz et al., 1998; Sheline et al., 2000; Wang and Cynader, 2001
- Ruiz et al., 1998
- Alvarez et al., 2003
Additional information
Ivanov et al. (2011) supplemented glucose with 5 mM pyruvate in ACSF. Pyruvate induced a strong increase in the NAD(P)H oxidation phase and oxygen consumption during neuronal stimulation suggesting that pyruvate enhances aerobic energy metabolism and synaptic integrity. Effects of pyruvate in the same concentration on normalization of on GABA reversal potential first shown by Y. Zilberter’s group (Holmgren et al., 2010) has been confirmed by Tyzio et al. (2011) although the authors, for some reason measuring pyruvate contents in the blood, not ECF, arrived at the conclusion that the concentration was non-physiological (see discussion here)
References
- 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.
- Tyzio R, Allene C, Nardou R, Picardo M, Yamamoto S, Sivakumaran S, Caiati MD, Rheims S, Minlebaev M, Milh M, Ferre P, Khazipov R, Romette J-L, Lorquin J, Cossart R, Khalilov I, Nehlig A, Cherubini E, Ben-Ari Y. (2011) Depolarizing Actions of GABA in Immature Neurons Depend Neither on Ketone Bodies Nor on Pyruvate. pp 34-45.
On the mechanisms of brain protection by ketones
Neuronal activity in immature neocortical neurons depends on the availability of ketone bodies in ACSF
The provoking findings of Rheims et al. suggest that an important caveat of previous electrophysiological experiments is that they were carried out with artificial cerebrospinal fluid (ACSF) added with energy sources that can only be metabolized through glycolytic pathways (e.g. glucose).
Researchers studied how naturally occurring ketones influenced activity of brain cells during development. They showed that a shortage of ketones caused pathological changes in brain cells resulting in abnormal behavior of GABA, the principal brain chemical helping to resist hyperactivity. It was repeatedly reported earlier that, normally working as a “break pedal”, GABA did not do the job in the immature brain and acted as a “gas pedal” instead. To imagine the devastating consequences, picture a car having two gas pedals and no brakes.
To make things worse, the energy deficit during hyperactivity is usually combined with increased energy demands thus starting a vicious circle — demands/deficit/demands — a well known feature of many neurodegenerative diseases including Alzheimer’s, Parkinson’s, epilepsy, encephalopathies, dementia, or multiple sclerosis. For many of them, the ketogenic diet was shown to be of a significant help. In the new article, the French and UK researchers offered an explanation. When there was enough of ketone bodies, GABA displayed its natural “break” properties and parameters of brain cells were also normal — as it happens in real life, in real animals and babies.
Researchers suggest that sufficient supply of appropriate brain fuels can break the vicious circle and prevent brain’s hyper-excitation. They now look into other natural energy substrates possibly having greater potential as a “diet in a bottle” than the costly ketones while being as efficient as the overly-stringent ketogenic diet.
Source: J Neurochem. 2009 Aug;110(4):1330-8. Epub 2009 Jun 22. 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.
To make things worse, the energy deficit during hyperactivity is usually combined with increased energy demands thus starting a vicious circle — demands/deficit/demands — a well known feature of many neurodegenerative diseases including Alzheimer’s, Parkinson’s, epilepsy, encephalopathies, dementia, or multiple sclerosis. For many of them, the ketogenic diet was shown to be of a significant help. In the new article, the French and UK researchers offered an explanation. When there was enough of ketone bodies, GABA displayed its natural “break” properties and parameters of brain cells were also normal — as it happens in real life, in real animals and babies.
Researchers suggest that sufficient supply of appropriate brain fuels can break the vicious circle and prevent brain’s hyper-excitation. They now look into other natural energy substrates possibly having greater potential as a “diet in a bottle” than the costly ketones while being as efficient as the overly-stringent ketogenic diet.Source: J Neurochem. 2009 Aug;110(4):1330-8. Epub 2009 Jun 22.
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.
http://starturl.com/GAGA-ketones
