A new mechanism of POCD caused by sevoflurane in mice: cognitive impairment induced by cross-dysfunction of iron and glucose metabolism

Abstract

Sevoflurane (Sev) is a commonly used anesthetic in hospitals that can cause neurotoxicity. Postoperative cognitive dysfunction (POCD) is a common clinical problem induced by some anesthetics. However, the exact mechanism of neurotoxicity induced by Sev is unclear. Here we studied a new mechanism of POCD induced by Sev. We treated 15-month-old mice with 2% Sev for 6 hours, and we had found that Sev causes POCD. Using isobaric tags for relative and absolute quantitation (iTRAQ), we found that the transporter and the metabolism of carbohydrates and inorganic ions were involved in the cognitive impairment induced by Sev. Using synchrotron radiation micro-X-ray fluorescence (μ-XRF), we showed that Sev caused the iron overload in the brain of 15-month-old mice. Subsequently, excessive iron led to oxidative stress and impaired mitochondrial function that further led to glucose metabolism disorder and reduced ATP production by regulating the expression of key enzyme genes or proteins including G6Pase, Pck1, and Cs. Meanwhile, Sev also inhibited the oxygen consumption rate and glucose absorption by downregulating the expression of glucose transporter 1 in cerebral vascular endothelial cells. The cross-dysfunction of iron and glucose metabolism caused the apoptosis in the cortex and hippocampus through Bcl2/Bax pathway. In conclusion, the data here showed a new mechanism that Sev caused apoptosis by cross-dysregulation of iron and glucose metabolism and induced energy stress in mice. Maintaining iron and glucose metabolism homeostasis may play an important role in cognitive impairment induced by Sev.

Sevoflurane Effects on Neuronal Energy Metabolism Correlate with Activity States While Mitochondrial Function Remains Intact

“…Mitochondrial dysfunction has been described for both anesthetics using multiple experimental approaches [ 12 , 30 , 32 , 45 , 53 , 54 , 55 ]. In particular, direct inhibition of mitochondrial complexes I, II, and III by volatile anesthetics have been involved in presynaptic modulation, mitochondrial depolarization, decreased ATP production, and preconditioning [ 13 , 14 , 56 , 57 ].…”

“…Conversely, mitochondrial impairment was induced by sevoflurane in different neonatal, aged, and Alzheimer’s disease animal models. Among others, mechanisms involved were mitophagy inhibition [ 30 ], lower oxidative phosphorylation [ 31 ], iron/glucose metabolism-derangement [ 32 ], and mitochondrial depolarization via complex-V inhibition [ 33 ].…”

Transient neuroinflammation following surgery contributes to long-lasting cognitive decline in elderly rats via dysfunction of synaptic NMDA receptor

“…Accumulating clinical evidences also showed that PNDs could occur irrespective of the anesthetic technique used, suggesting that surgery may play a prominent role in the development of postoperative cognitive deficits [ 86 – 88 ]. However, some studies reported that sevoflurane alone could induce cognitive decline in aged animals [ 89 , 90 ]. Possible reason for this discrepancy is the different duration of general anesthetics used.…”

“…Possible reason for this discrepancy is the different duration of general anesthetics used. The animals that exposed to 2% sevoflurane for 5–6 h exhibited impaired cognitive function [ 89 , 90 ]. While the use of general anesthetics no more than 1 h neither induce peripheral or centrally proinflammatory cytokine or NMDARs changes [ 10 , 35 , 63 , 85 , 91 ], nor lead to postoperative cognitive dysfunction [ 10 , 35 , 63 , 85 ].…”

Neuroinflammation as the Underlying Mechanism of Postoperative Cognitive Dysfunction and Therapeutic Strategies

“…Animal experiments have also proven that the occurrence and development of POCD were related to the choice of anesthetics, such as the intravenous anesthetics etomidate and propofol, and the inhaled anesthetic, sevoflurane, all of which have become common induction drugs for constructing animal models of POCD in the field of basic research. Increased attention has been focused on specific induction mechanisms, such as early neuroinflammation, nerve cell death, and sevoflurane-induced cross dysfunction of iron and sugar metabolism in mouse brain cells, which led to apoptosis, along with the corresponding diagnosis and treatment strategies ( Cui et al, 2018 ; Li D. et al, 2020 ; Ge et al, 2021 ; Liu et al, 2021 ). The results of various studies on the effects of different anesthesia methods and anesthetics on postoperative cognitive function have been different, even contradictory, and the reasons for the conflicting results are still inconclusive.…”