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Mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction in aged rats.

ABSTRACT: Postoperative cognitive dysfunction (POCD) is frequently observed in elderly patients following anesthesia, but its pathophysiological mechanisms have not been fully elucidated. Sevoflurane was reported to repress autophagy in aged rat neurons; however, the role of mitophagy, which is crucial for the control of mitochondrial quality and neuronal health, in sevoflurane-induced POCD in aged rats remains undetermined. Therefore, this study investigated whether mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction. We found sevoflurane treatment inhibited mitochondrial respiration and mitophagic flux, changes in mitochondria morphology, impaired lysosomal acidification, and increased Tomm20 and deceased LAMP1 accumulation were observed in H4 cell and aged rat models. Rapamycin counteracted ROS induced by sevoflurane, restored mitophagy and improved mitochondrial function. Furthermore, rapamycin ameliorated the cognitive deficits observed in aged rats given sevoflurane anesthesia as determined by the Morris water maze test; this improvement was associated with an increased number of dendritic spines and pyramidal neurons. Overexpression of PARK2, but not mutant PARK2 lacking enzyme activity, in H4 cells decreased ROS and Tomm20 accumulation and reversed mitophagy dysfunction after sevoflurane treatment. These findings suggest that mitophagy dysfunction could be a mechanism underlying sevoflurane-induced POCD and that activating mitophagy may provide a new strategy to rescue cognitive deficits.

SUBMITTER: Chen Y

PROVIDER: S-EPMC7521530 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction in aged rats.

Chen Yeru Y Zhang Piao P Lin Xianyi X Zhang Huan H Miao Jiamin J Zhou Youfa Y Chen Gang G

Aging 20200909 17

Postoperative cognitive dysfunction (POCD) is frequently observed in elderly patients following anesthesia, but its pathophysiological mechanisms have not been fully elucidated. Sevoflurane was reported to repress autophagy in aged rat neurons; however, the role of mitophagy, which is crucial for the control of mitochondrial quality and neuronal health, in sevoflurane-induced POCD in aged rats remains undetermined. Therefore, this study investigated whether mitophagy impairment is involved in se ...[more]

PMID: 32903215

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Project description:Sevo?urane, a commonly used anesthetic agent has been confirmed to induce cognitive impairment in aged rats. Normobaric hyperoxia preconditioning has been demonstrated to induce neuroprotection in rats. The present study aimed to determine whether normobaric hyperoxia preconditioning could ameliorate cognitive deficit induced by sevoflurane and the possible mechanism by which it may exert its effect. A total of 66, 20-month-old male Sprague-Dawley rats were randomly divided into 3 groups (n=22 each): Rats in the control (C) and sevoflurane anesthesia (S) groups received no normobaric hyperoxia preconditioning before sevoflurane exposure, rats in the normobaric hyperoxia pretreatment (HO) group received normobaric hyperoxia preconditioning before sevoflurane exposure (95% oxygen for 4 continuous h daily for 6 consecutive days). The anesthesia rats (S and HO groups), were exposed to 2.5% sevoflurane for 5 h, while the sham anesthesia rats (C group) were exposed to no sevoflurane. The neurobehavioral assessment was performed using a Morris water maze test, the expressions of the apoptosis proteins were determined using western blot analysis, and the apoptosis rate and cytosolic calcium concentration were measured by flow cytometry. Normobaric hyperoxia preconditioning improved prolonged escape latency and raised the number of platform crossings induced by sevoflurane in the Morris water maze test, increased the level of bcl-2 protein, and decreased the level of bax and active caspase-3 protein, the apoptosis rate and cytosolic calcium concentration in the hippocampus 24 h after sevoflurane exposure. The findings of the present study may imply that normobaric hyperoxia preconditioning attenuates sevoflurane-induced spatial learning and memory impairment, and this effect may be partly related to apoptosis inhibition in the hippocampus. In conclusion, normobaric hyperoxia preconditioning may be a promising strategy against sevoflurane-induced cognitive impairment by inhibiting the hippocampal neuron apoptosis.

Dataset Information

Mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction in aged rats.

Publications

Mitophagy impairment is involved in sevoflurane-induced cognitive dysfunction in aged rats.

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