2-deoxy-D-glucose enhances anesthetic effects in mice.
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-carnitine (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 the mice, as evidenced by 2-DG not enhancing isoflurane-induced LORR in the mice pretreated with idebenone. Idebenone (idebenone + saline versus idebenone + 2-DG: P = 0.177, N = 6), but not L-carnitine (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 cells pretreated with idebenone. Finally, isoflurane decreased ATP levels in both cultured cells and mouse brains (β-ATP: P = 0.003, N = 10; β-ATP/phosphocreatine: P = 0.006, N = 10; β-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.
From the *Department of Anesthesia, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China; †Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts; and ‡Anesthesia and Operation Center, Chinese PLA General Hospital, Beijing, China.
Hui
H
Wang
Zhipeng
Z
Xu
Anshi
A
Wu
Yuanlin
Y
Dong
Yiying
Y
Zhang
Yun
Y
Yue
Zhongcong
Z
Xie
D000255:Adenosine Triphosphate / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002331:Carnitine / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology*; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009574:Nitro Compounds / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology
D018685:Anesthetics, Inhalation; D000963:Antimetabolites; D000975:Antioxidants; D009574:Nitro Compounds; D011422:Propionates; D014815:Vitamins; D014451:Ubiquinone; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D007530:Isoflurane; C036619:idebenone; C015392:3-nitropropionic acid; D002331:Carnitine