Stereoisomers of beta-hydroxybutyrate and dibenzylamine

Ketone bodies,Methodology — Tags: , , , , — 8:53 am

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

On the mechanisms of brain protection by ketones

Dementia,Excitatory GABA,Ketogenic diet,Ketone bodies,Neuroprotectors — Tags: , , , , , , , , — 8:17 am

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).

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

Maturity levels determine energy substrate use

Brain metabolism,Glucose,Ketone bodies — Tags: , , , — 8:05 am

The newborns are not created equal.

Physiological effects of ketone bodies

Applications,Ketogenic diet,Ketone bodies — Tags: , , , , , , — 8:33 am

See References in this post

Anticonvulsant action of the ketogenig diet

Ketogenic diet,Ketone bodies,Theories — Tags: , , , , — 8:31 am

Anticonvulsant action of the ketogenig diet

HYPOTHESES:

Ketogenic diet reduces seizures by:

a) promoting inhibitory action of GABA

b) reducing cellular consequences of energy deficiency by supplying an alternative and 40 % more efficient fuel

c) eliminating damaging consequences of excessive glycolysis

Question: what does work in this case — ketone bodies or glycolysis exclusion?


Is ketosis natural?

Ketogenic diet,Ketone bodies,Ketosis, ketogenesis,Methodology — Tags: , , , — 8:29 am

“Repeat after me three times, ketones are not evil, ketones are not evil, ketones are not evil… OK, now that we have gotten that out of the way…”

– Jeffrey Paul Krabb, MD

In general medical literature, ketosis is often defined as abnormally high levels of ketone bodies in the blood.

Meanwhile, ketosis — but not ketoacidosis! — naturally occurs:

  • Every morning after the night fast
  • During fasting and calorie restriction
  • After intensive prolonged exercise
  • As a result of a diet significantly higher in fat comparing tha in carbohydrates
  • Early in ontogenesis

Major sources of energy for the brain

Energy Substrates,Glucose,Ketone bodies,Lactate — Tags: , , — 8:08 am

The use of energy substrates by the brain depend on species, age, and physiological conditions

Exceptional energy demands of the brain and energy substrates

Energy Homeostasis,Ketone bodies,Lactate,Pyruvate — Tags: , , — 7:59 am
  • In addition to glucose, other substrates must be considered along with fuel interactions, metabolic challenges, and cerebral maturation. (1)
  • Ketone bodies are major metabolic fuels of the brain of the suckling rat under normal conditions. (2)
  • Ketone bodies can represent about 30–70% of the total energy metabolism balance of the immature rat brain.(3)
  • Lactate is an important metabolic substrate for the brain…and plays a crucial role in brain development… Once the onset of suckling takes place, however, ketone bodies become the major fuel for brain development.(4)
  • 70% of the cerebral metabolic requirements were met by lactate in animals aged 6 days. At 15 days of age, glucose, 3-hydroxybutyrate, and lactate supply 58%, 19%, and 23% of the brain’s fuel requirement, respectively.(5)

Sources:
1. Prins, M. L. (2008) J Cereb Blood Flow Metab, 28, 1-16.
2. Hawkins, R. A., Williamson, D. H. and Krebs, H. A. (1971) Biochem J, 122, 13-18.
3. Nehlig, A. (2004) Prostaglandins Leukot Essent Fatty Acids, 70, 265-275.
4. Medina, J. M. and Tabernero, A. (2005) J Neurosci Res, 79, 2-10.
5. Dombrowski, G. J., Jr., Swiatek, K. R. and Chao, K. L. (1989) Neurochem Res, 14, 667-675.

Ketosis dynamics in human newborns

Ketone bodies — Tags: — 8:42 am
Blood glucose concentration falls rapidly after birth, reaching its minimal level by 1 h of age and then rising to stabilize by 3 h of age even without feeding. During the first 8 h, newborns have low plasma ketone body concentrations despite adequate levels of precursor free fatty acids
Newborn brain potentially can utilize ketone bodies at a rate that is up to 40-fold greater than that of infant or adult brain
  • Starting from 12 h of age, newborns show high ketone body turnover rates approaching those in adults after several days of fasting
  • By the 6th postnatal day, breast-fed infants have lower blood glucose concentrations than formula-fed newborns but significantly higher ketone body concentrations and lower insulin responses
These findings suggest:
  1. ketogenic properties of breast milk, e.g., lipase content allowing delivery of fatty acids to the liver
  2. anti-ketogenic properties of protein, fat and energy load in the formula-fed infant

Sources: Denne, Kalhan, 1986; Kraus et. al, 1974, Bougneres et al., 1986, Hawdon et al., 1992; Persson B, Settergren, 1972; Stanley et al., 1979; Lucas et al., 198

Ketone bodies dynamics in neonatal rats

Ketone bodies — Tags: — 8:40 am

Related: Dynamics of ketosis in human newborns

  • Ketone bodies are produced from fatty acids in liver mitochondria in response to low availability of carbohydrate fuel (in the blood plus stored as glycogen)
  • Ketone bodies enter the cells by simple diffusion (beta-hydroxybutirate) or are carried by transporters (acetoacetate) thus supplying energy source that is 40% more efficient than glucose

(Glucose enter the cells being carried by transporters that are under the influence of insulin)

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