D-β-Hydroxybutyrate Is Protective in Mouse Models of Huntington's Disease

Lim, Soyeon; Chesser, Adrianne S.; Grima, Jonathan C.; Rappold, Phillip M.; Blum, David; Przedborski, Serge; Tieu, Kim

doi:10.1371/journal.pone.0024620

Cited by 82 publications

(54 citation statements)

References 62 publications

(77 reference statements)

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“…2-DG (1000 mg/kg), 29 3-NP (50 mg/kg), 30 or saline was injected [intraperitoneally (ip)] 5 minutes before isoflurane anesthesia. Idebenone (200 mg/kg) 31 or L-carnitine (100 mg/kg) 32 was injected 15 minutes before isoflurane anesthesia (10 minutes before treatment with 2-DG or 3-NP).…”

Section: Methodsmentioning

confidence: 99%

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

Wang¹,

Xu²,

et al. 2015

Anesthesia &Amp; Analgesia

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Background The mechanisms of general anesthesia by volatile drugs remain largely unknown. Mitochondrial dysfunction and reduction in energy levels have been suggested to be associated with general anesthesia status. 2-Deoxy-d-glucose (2-DG), an analog of glucose, inhibits hexokinase and reduces cellular levels of adenosine triphosphate (ATP). 3-Nitropropionic acid is another compound which can deplete ATP levels. In contrast, idebenone and L-carnitine could rescue deficits of energy. We therefore sought to determine whether 2-DG and/or 3-nitropropionic acid can enhance the anesthetic effects of isoflurane, and whether idebenone and L-carnitine can reverse the actions of 2-DG. Methods C57BL/6J mice (8 months old) received different concentrations of isoflurane with and without the treatments of 2-DG, 3-nitropropionic acid, idebenone, and L-carnitine. Isoflurane-induced loss of righting reflex (LORR) was determined in the mice. ATP levels in H4 human neuroglioma cells were assessed after these treatments. Finally, 31P-magnetic resonance spectroscopy was used to determine the effects of isoflurane on brain ATP levels in the mice. Results 2-DG enhanced isoflurane-induced LORR (P = 0.002, N = 15). 3-nitropropionic acid also enhanced the anesthetic effects of isoflurane (P = 0.005, N = 15). Idebenone (Idebenone + saline versus Idebenone + 2-DG: P = 0.165, N = 15), but not L-cartinine (L-carnitine + saline versus L-carnitine + 2-DG: P < 0.0001, N = 15), inhibited the effects of 2-DG on enhancing isoflurane-induced LORR in mice, as evidenced by 2-DG not enhancing isoflurane-induced LORR in mice pretreated with idebenone. Idebenone (Idebenone + saline versus Idebenone + 2-DG: P = 0.177, N = 6), but not L-cartinine (L-carnitine + saline versus L-carnitine + 2-DG: P = 0.029, N = 6), also mitigated the effects of 2-DG on reducing ATP levels in cells, as evidenced by 2-DG not decreasing ATP levels in the cell pretreated with idebenone. Finally, isoflurane decreased ATP levels in both cultured cells and mouse brains (-ATP: P = 0.003, N = 10; -ATP/phosphocreatine: P = 0.006, N = 10; -ATP/inorganic phosphate: P = 0.001, N = 10). Conclusions These results from our pilot studies have established a system and generated a hypothesis that 2-DG enhances anesthetic effects via reducing energy levels. These findings should promote further studies to investigate anesthesia mechanisms.

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Section: Methodsmentioning

confidence: 99%

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

Wang¹,

Xu²,

et al. 2015

Anesthesia &Amp; Analgesia

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“…Although BHB has previously been shown to have HDACi activity (7,21), the potential for therapeutic application remains speculative. Here, we show that therapeutically relevant levels of BHB are achieved with a KD modeled on protocols that are used show a significant decrease (P < 0.005) in the H3ac/DAPI fluorescence ratio compared with Kmt2d +/+ littermates; this ratio significantly increased (P < 0.05) in Kmt2d +/βGeo mice after 2 wk on the KD (n = 11-14 per group).…”

Section: Discussionmentioning

confidence: 99%

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

Benjamin

Pilarowski

Carosso

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.

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“…For example, the ketogenic diet and β-hydroxybutyrate are used to treat epilepsy 97 , are protective against neurodegenerative diseases 98,99 , and are currently being tested in about 30 clinical trials (https://clinicaltrials.gov). In addition to promoting Kbhb, β-hydroxybutyrate has been reported to repress oxidative stress in mouse kidney by inhibiting HDAC activity and thus enhancing histone Kac 100 .…”

Section: The Function Of Differential Acylationmentioning

confidence: 99%

Metabolic regulation of gene expression through histone acylations

Sabari

Zhang

Allis

et al. 2016

Nat Rev Mol Cell Biol

729

775

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Eight types of short-chain lysine (Lys) acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. Emerging evidence suggest that these histone modifications affect gene expression and are structurally and functionally different from the widely studied histone Lys acetylation. In this review, we discuss the regulation of non-acetyl histone acylation by enzymatic and metabolic mechanisms, acylation “reader” proteins that mediate the effects of different acylations, and their physiological functions, including in signal-dependent gene activation, spermatogenesis, tissue injury and metabolic-induced stress. We propose a model to explain our present understanding of how differential histone acylation is regulated by metabolism of the different acyl-CoA forms, which in turn modulate the regulation of gene expression.

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D-β-Hydroxybutyrate Is Protective in Mouse Models of Huntington's Disease

Cited by 82 publications

References 62 publications

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

2-Deoxy-D-Glucose Enhances Anesthetic Effects in Mice

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

Metabolic regulation of gene expression through histone acylations

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