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October 22, 2019
10/22/2019 7:45:00 AM - 10/22/2019 9:45:00 AM
Room WA2 - Area C
Conflicting Actions of Inhaled Anesthetics, Neurotoxicity and Neuroprotection
Tomohiko Aoe, M.D.,Ph.D., Hiroshi Kokubun, M.D., Hisayo Jin, M.Sc., Mari Komita, M.D., Mitsuo Aono, M.D.
Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan
Disclosures: T. Aoe: None.H. Kokubun: None.H. Jin: None.M. Komita: None.M. Aono: None.
Background) Although there is no significant effect on human healthy children during short-term surgery, laboratory experiments have revealed that inhaled anesthetics induce neuronal damage and cognitive dysfunction in developing brain. On the other hand, neuroprotective action has been reported for inhalational anesthetics. When cells suffer from invasions such as ischemia, hypoxia or toxic substances that disturb protein folding in the endoplasmic reticulum (ER), cells undergo compensatory reactions such as ER stress response and heat shock response, resulting in the production of cytoprotective chaperones like BiP in the ER and HSP70 in the cytosol. Previously, we revealed that exposure to inhalational anesthetics at fetal stage causes neuronal cell death and cognitive dysfunction related to ER stress by using mice expressing a mutant gene of ER chaperone BiP (Komita, M., Jin, H., and Aoe, T. 2013. Anesth. Analg. 117, 1197-1204. Jin H, Komita M and Aoe T 2018. Frontier Neurosci. 12: 753). In this study, we examined the role of ER stress on dual actions of inhaled anesthetics, neurotoxicity and neuroprotection.


Cell experiments;

1, Neuroblastoma cells were exposed to 3% sevoflurane for 5 hours and then cultured under 1% oxygen for 17 hours before collection. 2, Also, after exposure to sevoflurane, the recovery time was set to 12 hours, and then cells were exposed to 1% oxygen. 3, Another condition was also established to suppress the expression of BiP that acts cytoprotectively against ER stress by RNA interference. The expression of CHOP that induces cell death and that of BiP were detected by western blot.

Mouse experiments;

Mutant BiP mice and wild type mice of 1 year old were exposed to 3% sevoflurane for 3 hours, and eight-radial maze experiments for cognitive functions were performed before exposure and 7 days after exposure. Completion time and correct answer rate were analyzed by repeated measures one-way ANOVA. This animal experiment was carried out in accordance with the recommendations of the guidelines for animal experiments of Chiba University. The protocol was approved by the Institutional Animal Care Committee of Chiba University, Chiba, Japan.

Results) Expression of CHOP was increased in cells exposed to hypoxia following sevoflurane challenge than cells with hypoxic exposure alone. On the contrary, 12-hour recovery time after sevoflurane exposure suppress the expression of CHOP by hypoxia and enhances the expression of BiP. However, when expression of BiP was suppressed by RNA interference, the expression of CHOP was increased. In adult wild type mice, cognitive function was significantly improved after exposure to anesthetics. No significant change in cognitive function after exposure was observed in the mutant BiP adult mice.

Discussion) Exposure to inhalational anesthetics attenuates ER functions and induces ER stress response (Anesth. Analg. 117, 1197-1204, 2013). Moderate endoplasmic reticulum stress due to exposure of inhalational anesthetics will enhance cellular function through increased production of ER chaperones like BiP. The recovery time after sevoflurane exposure may enhance neuronal functions against hypoxia, resulting in improved cognitive function. However, in individuals sensitive to ER stress, such as mutant BiP mice and wild type newborn mice, neuroprotective effects were not observed, rather inhalational anesthetics caused neurotoxicity.

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