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

Wang, Hui; Xu, Zhipeng; Wu, Anshi; Dong, Yuanlin; Zhang, Yiying; Yue, Yun; Xie, Zhongcong

doi:10.1213/ane.0000000000000520

Cited by 15 publications

(9 citation statements)

References 51 publications

(61 reference statements)

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“…A previous study based on 13 C magnetic resonance spectroscopy in vivo proposed that lactate, a product of glycogenolysis, might be used as an alternative metabolic substrate under thiopental anesthesia [56]. Here, we found increased GP activity in the CTX, THAL, and STRIAT after isoflurane exposure for 2 h, indicating that isoflurane has an energy metabolism pattern similar to that of thiopental anesthesia to some degree.…”

Section: Discussionsupporting

confidence: 68%

“…It has been revealed that mutations in complex I of mitochondria increase the sensitivity of Caenorhabditis elegans to volatile anesthetics [9][10][11][12]. Recently, emerging evidence has indicated that a reduction in cellular adenosine triphosphate (ATP) levels is associated with a delay in isoflurane-induced loss of the righting reflex (LORR) in mice [13], suggesting that changes in available cerebral energy might regulate anesthetic effects [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice

et al. 2020

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General anesthesia severely affects the metabolites in the brain. Glycogen, principally stored in astrocytes and providing the short-term delivery of substrates to neurons, has been implicated as an affected molecule. However, whether glycogen plays a pivotal role in modulating anesthesia–arousal remains unclear. Here, we demonstrated that isoflurane-anesthetized mice exhibited dynamic changes in the glycogen levels in various brain regions. Glycogen synthase (GS) and glycogen phosphorylase (GP), key enzymes of glycogen metabolism, showed increased activity after isoflurane exposure. Upon blocking glycogenolysis with 1,4-dideoxy-1,4-imino-D-arabinitol (DAB), a GP antagonist, we found a prolonged time of emergence from anesthesia and an enhanced δ frequency in the EEG (electroencephalogram). In addition, augmented expression of glycogenolysis genes in glycogen phosphorylase, brain (Pygb) knock-in (PygbH11/H11) mice resulted in delayed induction of anesthesia, a shortened emergence time, and a lower ratio of EEG-δ. Our findings revealed a role of brain glycogen in regulating anesthesia–arousal, providing a potential target for modulating anesthesia.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice

et al. 2020

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“…To our best knowledge, this is the first report that describes such an effect of a volatile anesthetic, see also (Miro et al 1999 ). A recent in vivo study showed that isoflurane anesthesia decreased ATP levels in mouse brain (Wang et al 2015 ). Together, these data lead us to postulate that isoflurane acts outside the mitochondrion to reduce the supply of pyruvate, which is the main mitochondrial substrate in brain.…”

Section: Discussionmentioning

confidence: 99%

Increased mitochondrial ATP production capacity in brain of healthy mice and a mouse model of isolated complex I deficiency after isoflurane anesthesia

Manjeri

Rodenburg

Blanchet

et al. 2015

J of Inher Metab Disea

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We reported before that the minimal alveolar concentration (MAC) of isoflurane is decreased in complex I-deficient mice lacking the NDUFS4 subunit of the respiratory chain (RC) (1.55 and 0.81 % at postnatal (PN) 22–25 days and 1.68 and 0.65 % at PN 31–34 days for wildtype (WT) and CI-deficient KO, respectively). A more severe respiratory depression was caused by 1.0 MAC isoflurane in KO mice (respiratory rate values of 86 and 45 at PN 22–25 days and 69 and 29 at PN 31–34 days for anesthetized WT and KO, respectively). Here, we address the idea that isoflurane anesthesia causes a much larger decrease in brain mitochondrial ATP production in KO mice thus explaining their increased sensitivity to this anesthetic. Brains from WT and KO mice of the above study were removed immediately after MAC determination at PN 31–34 days and a mitochondria-enriched fraction was prepared. Aliquots were used for measurement of maximal ATP production in the presence of pyruvate, malate, ADP and creatine and, after freeze-thawing, the maximal activity of the individual RC complexes in the presence of complex-specific substrates. CI activity was dramatically decreased in KO, whereas ATP production was decreased by only 26 % (p < 0.05). The activities of CII, CIII, and CIV were the same for WT and KO. Isoflurane anesthesia decreased the activity of CI by 30 % (p < 0.001) in WT. In sharp contrast, it increased the activity of CII by 37 % (p < 0.001) and 50 % (p < 0.001) and that of CIII by 37 % (p < 0.001) and 40 % (p < 0.001) in WT and KO, respectively, whereas it tended to increase that of CIV in both WT and KO. Isoflurane anesthesia increased ATP production by 52 and 69 % in WT (p < 0.05) and KO (p < 0.01), respectively. Together these findings indicate that isoflurane anesthesia interferes positively rather than negatively with the ability of CI-deficient mice brain mitochondria to convert their main substrate pyruvate into ATP.

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“…In fact, there is some evidence that idebenone can not only upregulate mitochondrial copy numbers [ 72 ] but also affect the expression of respiratory complexes in vivo [ 60 ], which could counteract mitochondrial dysfunction to some extent. These effects alone, however, cannot easily explain the idebenone-dependent normalisation of mitochondrial function under a variety of pathological conditions such as oxidative damage [ 45 , 61 ], kinase inhibitors [ 73 ], mitochondrial toxins [ 33 , 34 , 68 , 74 ], the presence of metabolic toxins [ 75 ], hypoxia and reperfusion [ 21 , 49 , 61 ], amyloid-beta 1-40 peptide [ 76 ] and different genetic defects [ 60 , 70 , 77 ].…”

Section: Does Idebenone Improve Mitochondrial Function and Metabolismmentioning

confidence: 99%

Idebenone: When an antioxidant is not an antioxidant

et al. 2021

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Idebenone is a well described drug that was initially developed against dementia. The current literature widely portrays this molecule as a potent antioxidant and CoQ 10 analogue. While numerous papers seem to support this view, a closer look indicates that the pharmacokinetics of idebenone do not support these claims. A major discrepancy between achievable tissue levels, especially in target tissues such as the brain, and doses required to show the proposed effects, significantly questions our current understanding. This review explains how this has happened and highlights the discrepancies in the current literature. More importantly, based on some recent discoveries, a new framework is presented that can explain the mode of action of this molecule and can align formerly contradictory results. Finally, this new appreciation of the molecular activities of idebenone provides a rational approach to test idebenone in novel indications that might have not been considered previously for this drug.

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

Cited by 15 publications

References 51 publications

Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice

Dynamic Variations in Brain Glycogen are Involved in Modulating Isoflurane Anesthesia in Mice

Increased mitochondrial ATP production capacity in brain of healthy mice and a mouse model of isolated complex I deficiency after isoflurane anesthesia

Idebenone: When an antioxidant is not an antioxidant

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