Abstract: Objective: Though sevoflurane has been widely used as an anesthetic in surgery, recent studies have shown that exposure to sevoflurane alone could lead to postoperative cognitive dysfunction (POCD), of which the mechanisms still remain largely unknown. The medial prefrontal cortex (mPFC) is known to be implicated in various cognitive impairments, including working memory and attentional processes. In the present study, we tried to identify dysregulated gene expression in mPFC and investigate the underlying mechanisms involved in POCD. Methods: Behavioral tests, including elevated plus-maze, O-maze, and Y-maze tests, were performed on Wistar rats exposed to sevoflurane. Whole-genome mRNA profiling of mPFC from Wistar rats after exposure to sevoflurane was carried out. Real-time polymerase chain reaction (PCR) was done to verify the differentially expressed genes. Results: Significant impairment of working memory of rats after exposure to sevoflurane was observed. A total of 119 of 7319 detected mRNAs showed significantly different expression between rats with and without sevoflurane exposure (fold change (FC)>2.0, P<0.05, and false discovery rate (FDR)<0.05), among which 74 mRNAs were down-regulated and 45 mRNAs were up-regulated. Postsynaptic density-95 (PSD95, also named DLG4) showed the most significantly decreased expression in mPFC and further investigation indicated that PSD95 expression level was correlated with spatial working memory performance. Conclusions: Our study revealed that PSD95 might be involved in the mechanism of POCD, which could provide clues for preventing POCD in clinical operations.

七氟烷麻醉诱导的认知功能损伤与内测前额叶皮层中PSD95表达量降低有关

[1]Chen, G., Gong, M., Yan, M., et al., 2013. Sevoflurane induces endoplasmic reticulum stress mediated apoptosis in hippocampal neurons of aging rats. PLoS ONE, 8(2):e57870.

[2]Chen, X., Zhao, M., White, P.F., et al., 2001. The recovery of cognitive function after general anesthesia in elderly patients: a comparison of desflurane and sevoflurane. Anesth. Analg., 93(6):1489-1494.

[3]Chudasama, Y., 2011. Animal models of prefrontal-executive function. Behav. Neurosci., 125(3):327-343.

[4]Clark, L., Cools, R., Robbins, T.W., 2004. The neuropsychology of ventral prefrontal cortex: decision-making and reversal learning. Brain Cogn., 55(1):41-53.

[5]Davidson, R.J., 2002. Anxiety and affective style: role of prefrontal cortex and amygdala. Biol. Psychiatry, 51(1):68-80.

[6]Dong, Y.L., Zhang, G.H., Zhang, B., et al., 2009. The common inhalational anesthetic sevoflurane induces apoptosis and increases β-amyloid protein levels. Arch. Neurol., 66(5):620-631.

[7]Florio, S.K., Loh, C., Huang, S.M., et al., 2009. Disruption of nNOS-PSD95 protein-protein interaction inhibits acute thermal hyperalgesia and chronic mechanical allodynia in rodents. Br. J. Pharmacol., 158(2):494-506.

[8]Goldman-Rakic, P.S., 1995. Architecture of the prefrontal cortex and the central executive. Ann. N. Y. Acad. Sci., 769:71-83.

[9]Gong, M., Chen, G., Zhang, X.M., et al., 2012. Parecoxib mitigates spatial memory impairment induced by sevoflurane anesthesia in aged rats. Acta Anaesthesiol. Scand., 56(5):601-607.

[10]Heo, H., Shin, Y., Cho, W., et al., 2009. Memory improvement in ibotenic acid induced model rats by extracts of Scutellaria baicalensis. J. Ethnopharmacol., 122(1):20-27.

[11]Hu, N., Guo, D., Wang, H., et al., 2014. Involvement of the blood-brain barrier opening in cognitive decline in aged rats following orthopedic surgery and high concentration of sevoflurane inhalation. Brain Res., 1551:13-24.

[12]Hu, Z., Bian, X., Liu, X., et al., 2013. Honokiol protects brain against ischemia-reperfusion injury in rats through disrupting PSD95-nNOS interaction. Brain Res., 1491:204-212.

[13]Ji, M.H., Qiu, L.L., Yang, J.J., et al., 2015. Pre-administration of curcumin prevents neonatal sevoflurane exposure-induced neurobehavioral abnormalities in mice. Neurotoxicology, 46:155-164.

[14]Kambouris, M., Maroun, R.C., Ben-Omran, T., et al., 2014. Mutations in zinc finger 407 [ZNF407] cause a unique autosomal recessive cognitive impairment syndrome. Orphanet J. Rare Dis., 9(1):80.

[15]Kim, E., Niethammer, M., Rothschild, A., et al., 1995. Clustering of Shaker-type K⁺ channels by interaction with a family of membrane-associated guanylate kinases. Nature, 378(6552):85-88.

[16]Li, C., Wong, W.H., 2001. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. PNAS, 98(1):31-36.

[17]Li, S., Murakami, Y., Wang, M., et al., 2006. The effects of chronic valproate and diazepam in a mouse model of posttraumatic stress disorder. Pharmacol. Biochem. Behav., 85(2):324-331.

[18]Liang, G., Ward, C., Peng, J., et al., 2010. Isoflurane causes greater neurodegeneration than an equivalent exposure of sevoflurane in the developing brain of neonatal mice. Anesthesiology, 112(6):1325-1334.

[19]Millar, K., Asbury, A.J., Bowman, A.W., et al., 2006. The effects of brief sevoflurane-nitrous oxide anaesthesia upon children’s postoperative cognition and behaviour. Anaesthesia, 61(6):541-547.

[20]Peng, S., Zhang, Y., Sun, D.P., et al., 2011. The effect of sevoflurane anesthesia on cognitive function and the expression of insulin-like growth factor-1 in CA1 region of hippocampus in old rats. Mol. Biol. Rep., 38(2):1195-1199.

[21]Rinn, J.L., Chang, H.Y., 2012. Genome regulation by long noncoding RNAs. Annu. Rev. Biochem., 81(1):145-166.

[22]Rubino, T., Realini, N., Braida, D., et al., 2009. Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood. Hippocampus, 19(8):763-772.

[23]Satomoto, M., Satoh, Y., Terui, K., et al., 2009. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology, 110(3):628-637.

[24]Seamans, J.K., Lapish, C.C., Durstewitz, D., 2008. Comparing the prefrontal cortex of rats and primates: insights from electrophysiology. Neurotox. Res., 14(2-3):249-262.

[25]Smyth, G.K., 2004. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol., 3(1):1-25.

[26]Sultana, R., Banks, W.A., Butterfield, D.A., 2010. Decreased levels of PSD95 and two associated proteins and increased levels of BCl₂ and caspase 3 in hippocampus from subjects with amnestic mild cognitive impairment: insights into their potential roles for loss of synapses and memory, accumulation of Aβ, and neurodegeneration in a prodromal stage of Alzheimer’s disease. J. Neurosci. Res., 88(3):469-477.

[27]Wang, F., Chang, G., Geng, X., 2014. NGF and TERT co-transfected BMSCs improve the restoration of cognitive impairment in vascular dementia rats. PLoS ONE, 9(6):e98774.

[28]Whitfield, D.R., Vallortigara, J., Alghamdi, A., et al., 2014. Assessment of ZnT3 and PSD95 protein levels in Lewy body dementias and Alzheimer’s disease: association with cognitive impairment. Neurobiol. Aging, 35(12):2836-2844.

[29]Xie, J., Wei, Q., Deng, H., et al., 2014. Negative regulation of GRB10 interacting GYF protein 2 on insulin-like growth factor-1 receptor signaling pathway caused diabetic mice cognitive impairment. PLoS ONE, 9(9):e108559.

[30]Xie, Z.C., Culley, D.J., Dong, Y.L., et al., 2008. The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid β-protein level in vivo. Ann. Neurol., 64(6):618-627.

[31]Xiong, W.X., Zhou, G.X., Wang, B., et al., 2013. Impaired spatial learning and memory after sevoflurane-nitrous oxide anesthesia in aged rats is associated with down-regulated cAMP/CREB signaling. PLoS ONE, 8(11):e79408.

[32]Xu, J., Liu, Z.A., Pei, D.S., et al., 2010. Calcium/calmodulin-dependent kinase II facilitated GluR6 subunit serine phosphorylation through GluR6-PSD95-CaMKII signaling module assembly in cerebral ischemia injury. Brain Res., 1366:197-203.

[33]Zhang, W., Hetzel, A., Shah, B., et al., 2014. Greater physiological and behavioral effects of interrupted stress pattern compared to daily restraint stress in rats. PLoS ONE, 9(7):e102247.

[34]Zhou, H., Li, S., Niu, X., et al., 2013. Protective effect of FTY720 against sevoflurane-induced developmental neurotoxicity in rats. Cell Biochem. Biophys., 67(2):591-598.

[35]List of electronic supplementary materials

[36]Table S1 Dysregulated mRNAs in in medial prefrontal cortex between experimental rats and normal rats