Decreased PSD95 expression in medial prefrontal cortex (mPFC) was associated with cognitive impairment induced by sevoflurane anesthesia

Abstract

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.

Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating caspase-3/cleaved-poly (ADP-ribose) polymerase pathway

“…For instance, Zhang et al (8) reported that inhalation of Sevoflurane exposure in postnatal rats induced long-term cognitive impairment through upregulating caspase-3/cleaved-poly (ADP-ribose) polymerase pathway sevoflurane may reduce synaptotagmin-1 protein levels in the hippocampus, which then reduced the efficiency of synaptic transmission, thus resulting in memory impairment in rats. In one of our previous studies, decreased PSD95 expression in the medial prefrontal cortex was also observed in mice with cognitive impairment induced by sevoflurane (9). Furthermore, Xiong et al (10) reported that the CREB signaling pathway was inhibited in aged rats following exposure to sevoflurane.…”

“…Behavioral experiments. As described in our previous study (9), three tests were conducted in sequence, including the elevated plus-maze (EPM), O-maze and Y-maze. For each behavioral test, the movement tracks of experimental rats were recorded by a video-tracking software (Any-Maze version 5.1; Stoelting Co., Wood Dale, IL, USA) and analyzed by an additional researcher who was blinded to the experimental protocols.…”

“…All the test were performed during the dark phase (active period of rats) between 1 a.m. and 4 p.m. The experimental details of EPM test, O-maze and Y-maze were as described in previous studies (9,(17)(18)(19). Briefly, the EPM and O-maze tests were used to assess the anxiety-like behavior in rodents, while the Y-maze test was used to investigate the immediate spatial working memory (a pattern of manifestation of cognitive function) of rodents.…”

“…Total RNA was extracted from the hippocampal tissues using a standard TRIzol reagent (catalogue no. 15596026; Thermo Fisher Scientific, Inc., Waltham, MA, USA) as described previously (9). In brief, after the tissue was homogenized, 0.3 ml TRIzol was added to each sample.…”

Difficulties in Understanding Postoperative Cognitive Dysfunction

“…The possible mechanisms of POCD investigated included platelet activation (17), oxidative stress (18), cholinergic function impairment (19,20), impairment of synaptic integrity (2,21), similar mechanisms of Alzheimer's disease (AD) such as beta-amyloid accumulation (22,23) and tau phosphorylation (24), and immune response and inflammation related mechanisms such as the bone marrow-derived macrophages recruitment in hippocampal area (25) and the recent popular surgery-induced neuroinflammation (12,26,27) (Table 2).…”