Anesthetic Properties of the Ketone Bodies β-Hydroxybutyric Acid and Acetone

Yang, Luyi; Zhao, Jing; Milutinovic, Pavle S.; Brosnan, Robert J; Eger, Edmond I.; Sonner, James M.

doi:10.1213/01.ane.0000278127.68312.dc

Cited by 43 publications

(41 citation statements)

References 19 publications

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“…Nevertheless, research investigating the utilization of ketones is limited in AD; one study indicated a modest increase in SCOT expression (catabolizes ketone bodies into Acetyl-CoA and generates ATP), while the expression of HADHA and SCHAD (enzymes involved in fatty acid oxidation and ketogenesis) was significantly increased 3x in TgAD brain [46]. Although many studies reported the neuroprotective effect of ketogenic diets [47], the continued accumulation of 3-hydroxybutyric acid from non-dietary sources could diminish the interfacial viscosity of membrane lipids and modulate ion channels and thus disturb higher brain function [48, 49]. Furthermore, our findings shown that cognitive impairment was associated with serine level aberrations after chronic stress.…”

Section: Discussionmentioning

confidence: 99%

Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

Han

Wang

Geng³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Stress response is determined by the brain, and the brain is a sensitive target for stress. Our previous experiments have confirmed that once the stress response is beyond the tolerable limit of the brain, particularly that of the hippocampus, it will have deleterious effects on hippocampal structure and function; however, the metabolic mechanisms for this are not well understood. Methods: Here, we used morris water maze, elisa and gas chromatography-time of flight/mass spectrometry to observe the changes in cognition, neuropathology and metabolomics in the hippocampus of APP/PS1 mice and wild-type (C57) mice caused by chronic unpredictable mild stress (CUMS), we also further explored the correlation between cognition and metabolomics. Results: We found that 4 weeks of CUMS aggravated cognitive impairment and increased amyloid-β deposition in APP/PS1 mice, but did not affect C57 mice. Under non-stress conditions, compared with C57 mice, there were 8 different metabolites in APP/PS1 mice. However, following CUMS, 3 different metabolites were changed compared with untreated C57 mice. Compared to APP/PS1 mice, there were 7 different metabolites in APP/PS1+CUMS mice. Among these alterations, 3-hydroxybutyric acid, valine, serine, beta-alanine and o-phosphorylethanolamine, which are involved in sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism. Conclusion: The results indicate that APP/PS1 mice are more vulnerable to stress than C57 mice, and the metabolic mechanisms of stress-related cognitive impairment in APP/PS1 mice are related to multiple pathways and networks, including sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism.

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Section: Discussionmentioning

confidence: 99%

Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

Han

Wang

Geng³

et al. 2017

Cell Physiol Biochem

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“…However, as KB had historically been viewed as metabolic substrates and not direct modulators of synaptic function, it was therefore not surprising that investigators found that clinically relevant (i.e., low millimolar) concentrations of BHB and ACA did not affect GABA A receptors, ionotropic glutamate receptors, or voltage-gated sodium channels in normal rodent hippocampus [30, 31]. From this point, the hunt for novel potential mechanisms commenced and to date has yielded a few very intriguing candidates.…”

Section: Molecular Targets Of Ketone Body Actionmentioning

confidence: 99%

Ketone Bodies as Anti-Seizure Agents

Simeone

Rho

2017

Neurochem Res

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There is growing evidence that ketone bodies (KB)—derived from fatty acid oxidation and produced during fasting or consumption of high-fat diets—can exert broad neuroprotective effects. With respect to epilepsy, KB (such as β-hydroxybutyrate or BHB, acetoacetate and acetone) have been shown to block acutely induced and spontaneous recurrent seizures in various animal models. Although the mechanisms underlying the anti-seizure effects of KB have not been fully elucidated, recent experimental studies have invoked ketone-mediated effects on both inhibitory (e.g., GABAergic, purinergic and ATP-sensitive potassium channels) and excitatory (e.g., vesicular glutamate transporters) neurotransmission, as well as mitochondrial targets (e.g., respiratory chain and mitochondrial permeability transition). Moreover, BHB appears to exert both epigenetic (i.e., inhibition of histone deacetylases or HDACs) and anti-inflammatory (i.e., peripheral modulation of hydroxycarboxylic acid receptor and inhibition of the NOD-like receptor protein 3 or NRLP3 inflammasome) activity. While the latter two effects of BHB have yet to be directly linked to ictogenesis and/or epileptogenesis, parallel lines of evidence indicate that HDAC inhibition and a reduction in neuroinflammation alone or collectively can block seizure activity. Nevertheless, the notion that KB are themselves anti-seizure agents requires clinical validation, as prior studies have not revealed a clear correlation between blood ketone levels and seizure control. Notwithstanding this limitation, there is growing evidence that KB are more than just cellular fuels, and can exert profound biochemical, cellular and epigenetic changes favoring an overall attenuation in brain network excitability.

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“…Whole cell currents were studied with a -80 mV holding potential using standard 2-electrode voltage clamping techniques. Methods for measuring whole-cell GABA A receptor currents have been described [5,[11][12][13] . Briefly, pairs of identical concentrations of the phenyl compound were prepared in glass syringes containing frog ringer's (FR) solution (115 mmol/l NaCl, 2.5 mmol/l KCl, 1.8 mmol/l CaCl 2 , and 10 mmol/l HEPES in 18.2 MΩ H 2 O, filtered and adjusted to pH 7.4) or FR + agonist (FR-GABA; FR plus 20-40 μmol/l, GABA, equal to an EC [10][11][12][13][14][15][16][17][18][19][20].…”

Section: Methodsmentioning

confidence: 99%

GABA<sub>A</sub> Receptor Modulation by Phenyl Ring Compounds Is Associated with a Water Solubility Cut-Off Value

Brosnan

Pham²

2016

Pharmacology

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Background: The modulation of N-methyl-D-aspartate receptors is associated with a molar water solubility cut-off effect of approximately 1.1 mmol/l and hence are unaffected by significantly less soluble compounds. However, compounds with this molar water solubility are still able to modulate γ-aminobutyric acid type A (GABA_A) receptors. We hypothesized that GABA_A receptor modulation by phenolic compounds would exhibit cut-off at a molar water solubility value less than 1.1 mmol/l. Methods: GABA_A receptors consisting of human α₁ and rat β₂ and γ_2s subunits were expressed in Xenopus laevis oocytes, and drug responses were measured using standard 2-electrode voltage clamp techniques. Twenty substituted phenols and benzenes of similar size and molecular volume were studied at saturated aqueous concentrations. Reversible and statistically significant change in GABA_A receptor current that was 10% or greater in magnitude from the baseline response defined a positive drug effect. Results: All phenyl ring compounds with a molar water solubility value equal to or greater than 0.46 mmol/l positively modulated GABA_A receptor currents. No compounds with a molar water solubility value equal to or less than 0.10 mmol/l had any effect on GABA_A receptor currents. Saturated solutions of phenols with 2,6-dimethyl and 2,6-diisopropyl substituents also caused channel opening in the absence of GABA. Conclusions: The molar water solubility cut-off for GABA_A receptor modulation by phenyl ring compounds lies between 0.10 and 0.46 mmol/l. Data suggest that hydrocarbons, perhaps including inhaled anesthetics, might modulate GABA_A receptors by displacing water from one or more low-affinity amphipathic binding sites to induce conformational changes that increase ion conductance.

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Anesthetic Properties of the Ketone Bodies β-Hydroxybutyric Acid and Acetone

Cited by 43 publications

References 19 publications

Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

Ketone Bodies as Anti-Seizure Agents

GABA<sub>A</sub> Receptor Modulation by Phenyl Ring Compounds Is Associated with a Water Solubility Cut-Off Value

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