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.

[Retracted] Involvement of Mitochondrial Dynamics and Mitophagy in Sevoflurane‐Induced Cell Toxicity

“…Exposure of mouse cerebral cortex in the postnatal day (P) P6, P7, and P8 to sevoflurane for 2 hours causes cognitive deficiency, decrease of MMP, and ATP concentration [ 39 ]. Sevoflurane inhibits the respiration of mitochondria in human neuroglioma cells [ 40 ]. And the mitochondrial respiratory function of neonatal mice is more severely suppressed by sevoflurane to compare with the old one [ 41 ].…”

“…The increase of reactive oxygen species (ROS) level is observed by most of the experiments as a result of MMP decrease and the inhibition of mitochondrial respiratory [ 31 – 33 , 39 , 40 , 42 ]. Moe et al first reported that sevoflurane treatment slowly increased the synaptosomal Ca 2+ level [ 36 ].…”

“…Moe et al first reported that sevoflurane treatment slowly increased the synaptosomal Ca 2+ level [ 36 ]. Following researchers proved that sevoflurane treatment would induce an increment of cytosolic Ca 2+ in cultured pheochromocytoma neurosecretory cells and rat hippocampal neurons [ 33 , 40 ]. Some think that the increased Ca 2+ is from the endoplasmic reticulum (ER), for the Ca 2+ level in ER is decreased following the sevoflurane treatment [ 43 ].…”

“…Following the study of Amrock et al, some researches focus on the expression changes of mitochondrial fission and fusion proteins. These researches found that sevoflurane induces the upregulation of Drp1 and Fis1 and the downregulation of Mfn2 and Opa1 [ 26 , 27 , 40 , 73 ]. It seems that sevoflurane could disturb the balance of mitochondrial dynamics through promoting mitochondrial fission and suppressing mitochondrial fusion, thereby inducing the damage of neural cells.…”

Apoptosis inhibition is involved in improvement of sevoflurane‑induced cognitive impairment following normobaric hyperoxia preconditioning in aged rats

“…Especially volatile anesthetics, one class of the most widely used drugs since the 19th century for general anesthesia is often mentioned as a possible cause of POCD ( 7 ). For instance, isoflurane ( 8 ), sevoflurane ( 9 ) and desflurane ( 10 ), which are commonly used in clinic, have been found to cause cognitive impairment. Previous studies have provided evidence of neurotoxicity caused by volatile anesthetics ( 11-13 ), and the safety of these anesthetic agents has come under scrutiny ( 14 ).…”