TY - JOUR
AU - Li, Tianzuo
AB - Abstract In clinic, perioperative neurocognitive disorder is becoming a common complication of surgery in old patients. Neuroinflammation and blood–brain barrier (BBB) disruption are important contributors for cognitive impairment. Atorvastatin, as a strong HMG-CoA reductase inhibitor, has been widely used in clinic. However, it remains unclear whether atorvastatin could prevent anesthesia and surgery-induced BBB disruption and cognitive injury by its anti-inflammatory property. In this study, aged C57BL/6J mice were used to address this question. Initially, the mice were subject to atorvastatin treatment for 7 days (10 mg/kg). After a simple laparotomy under 1.5% isoflurane anesthesia, Morris water maze was performed to assess spatial learning and memory. Western blot analysis, immunohistochemistry, and enzyme-linked immunosorbent assay were used to examine the inflammatory response, BBB integrity, and cell apoptosis. Terminal-deoxynucleotidyl transferase mediated nick end labeling assay was used to assess cell apoptosis. The fluorescein sodium and transmission electron microscopy were used to detect the permeability and structure of BBB. The results showed that anesthesia and surgery significantly injured hippocampal-dependent learning and memory, which was ameliorated by atorvastatin. Atorvastatin could also reverse the surgery-induced increase of systemic and hippocampal cytokines, including IL-1β, TNF-α, and IL-6, accompanied by inhibiting the nuclear factor kappa-B (NF-κB) pathway and Nucleotide-Binding Oligomerization Domain, or Leucine Rich Repeat and Pyrin Domain Containing 3 (NLRP3) inflammasome activation, as well as hippocampal neuronal apoptosis. In addition, surgery triggered an increase of BBB permeability, paralleled by a decrease of the ZO-1, occludin, and Claudin 5 proteins in the hippocampus. However, atorvastatin treatment could protect the BBB integrity from the impact of surgery, by up-regulating the expressions of ZO-1, occludin, and Claudin 5. These findings suggest that atorvastatin exhibits neuroprotective effects on cognition in aged mice undergoing surgery. neuroinflammation, surgery, blood–brain barrier, atorvastatin, perioperative neurocognitive disorder Introduction Many studies have shown that anesthesia and surgery can induce perioperative neurocognitive disorders (PNDs), with symptoms of memory, attention, and concentration injury as well as disorientation [1–3]. PND is more likely to occur in the elderly patients, which leads to the increase of the cost, complications, and even mortality [4,5]. Furthermore, patients with PND will be more at risk for mild cognitive impairment and dementia [6,7]. However, the exact mechanisms remain unclear. The blood–brain barrier (BBB) is a critical structure for preventing the central nervous system from exogenous pathogens and toxin-induced injury, which is mainly composed of blood vessels and glial cells [8]. BBB disruption often leads to brain injury, cognitive dysfunction, and neurodegenerative disorders, such as ischemia reperfusion injury and Alzheimer’s disease [9,10]. Tight junctions (TJs) are the typical structure of the BBB, which are composed of occluding, claudins, and Zonula ocluudens (ZO) proteins [11]. Any factors, such as ischemic injury, oxidative stress, as well as inflammation response would change the levels of these proteins and damage the BBB integrity [12–15]. Xie et al. [16] reported that surgery could increase the BBB permeability, which further resulted in the neuroinflammation and cognitive impairment. The measures to protect the BBB and cognition against the anesthesia and surgery are getting more and more attention. Atorvastatin, an HMG-CoA reductase inhibitor, is widely used in clinical practice because of its lipid-lowering effect. Several studies reported that atorvastatin could improve neurobehavioral impairment of the rat/mouse models with stroke and Alzheimer’s disease, through the potential anti-inflammatory effects [17–20]. However, the effects of atorvastatin on the BBB permeability and cognition in the elderly patients undergoing surgery remain to be investigated. Thus, in this study, we aimed to explore the protective role of atorvastatin in the acute inflammatory responses, BBB damage, and cognitive impairment in the aged mice after anesthesia and surgery. Furthermore, we also discussed the inhibitory effects of atorvastatin on the surgery-induced NF-κB pathway and NLRP3 inflammasome activation. Materials and Methods Animals C57BL/6 mice aged 20 months (male, weighing 38–44 g; Beijing Vital River Laboratory Animal Technology Co., Ltd., Beijing, China) were used in this study. Before the study, all the pups were adaptively reared in a room with 12/12 h light/dark cycle at a humidity of 55%–60% and temperature of 23 ± 2°C. The mice were randomly divided into the four groups with 16 mice in each group: (i) control group: intragastric administration (i.g.) with 0.9% normal saline for 7 days, (ii) atorvastatin group: intragastric administration with atorvastatin (10 mg kg−1 d−1) for 7 days; (iii) surgery group: gavage with 0.9% normal saline for 7 days, then underwent a simple laparotomy under 1.5% isoflurane anesthesia for 2 h; and (iv) atorvastatin + surgery group: gavage with atorvastatin (10 mg kg−1 d−1) for 7 days, followed by a simple laparotomy under 1.5% isoflurane anesthesia for 2 h. All non-surgery groups also received 100% oxygen for 2 h. The dose of atorvastatin was selected according to previous studies and our preliminary work [21,22]. The whole design of this study was showed in Fig. 1. Figure 1. Open in new tabDownload slide The experimental design of this study Before anesthesia and surgery, saline solution or atorvastatin (10 mg kg−1 d−1) was administered intragastrically for 7 days (day 1 to day 7). On the eighth day, anesthesia and surgery were applied. Twenty-four hours after the surgery, the open field was performed. Then, the MWM was started from day 10 to day 15, with five consecutive days of acquisition training and probe trial. After the behavior tests, the mice were sacrificed for further biochemical analyses. Figure 1. Open in new tabDownload slide The experimental design of this study Before anesthesia and surgery, saline solution or atorvastatin (10 mg kg−1 d−1) was administered intragastrically for 7 days (day 1 to day 7). On the eighth day, anesthesia and surgery were applied. Twenty-four hours after the surgery, the open field was performed. Then, the MWM was started from day 10 to day 15, with five consecutive days of acquisition training and probe trial. After the behavior tests, the mice were sacrificed for further biochemical analyses. All the procedures in this study were approved by the Institutional Animal Care and Use Committee of Beijing Shijitan Hospital, Capital Medical University. The procedures were performed in accordance with the principles outlined in the National Institutes of Health Guide for the Care and Use of Laboratory Animals, USA. Adequate measures were taken to minimize the discomfort of animals. Surgery procedures The mice were all anesthetized with isoflurane in a chamber filled with 1.5% isoflurane and 100% O2 at 1.5 l/min for 2 h. A Datex-Ohmeda ULTSV analyzer (Madison, USA) was used to monitor the isoflurane concentration. Under isoflurane anesthesia, mice in the surgery group underwent a simple laparotomy. A longitudinal midline incision was made from the xiphoid to the pubic symphysis of the mice. The skin, the abdominal muscles, and peritoneum were successively spliced. Then, the incision was sutured layer by layer using 5–0 Vicryl thread. Compound lidocaine cream (2.5% lidocaine and 2.5% prilocaine) was applied to the surgical incision to ameliorate postoperative pain. After recovery of the mice from anesthesia and surgery, the mice were returned to their home cage containing food and water. All operations have been reported in previous studies [16,23]. Neither the 1.5% isoflurane nor the surgery could influence the blood gas and blood pressure of the mice in our preliminary study as well as previous studies [1,16]. In addition, compound lidocaine cream was used to treat the pain. During the anesthesia procedure, the temperature of the mouse was maintained at 37 ± 0.5°C. After all the interventions, open field and Morris water maze (MWM) tests were performed, and finally, the mice were euthanized to detect the expression of related proteins in the hippocampus. Behavior studies Open field tests One day after anesthesia and surgery, all the mice were placed in the center area of a chamber (50 cm × 50 cm × 40 cm) with inner walls painted white. They were left for 5 min, and the trajectory was observed using a video tracking system (XR-XZ301; Shanghai Softmaze Information Technology Co, Ltd., Shanghai, China). After each test, 75% alcohol was used to eliminate the odor of the previous mouse. The entire distance of the trajectory and the duration for which the mice remained in the central area were recorded and analyzed. MWM test MWM test is able to reflect spatial training and memory of mice. The water maze was a circular tank with a diameter of 120 cm and a depth of 50 cm, which included four quadrants, marked as quadrant I, II, III, and IV. A platform was placed in the center of the quadrant III, and 1 cm below the water surface, which was the target quadrant. The MWM test contains two parts: acquisition training and probe trial. Twenty-four hours after the open field test, the mice underwent training for five consecutive days. All the mice were trained to find the hidden platform in the four trials each day. The mice were given 60 s to find the platform and another 10 s for staying on the platform. The escape latency and mean speed were recorded. The mice were guided to stay on the platform for 10 s, for those that could not find the platform within 60 s. After training, the probe trial was started. The platform was removed, and the mice were placed in quadrant I to swim for 60 s. The number of crossings of the platform, the time spent in quadrant III (the target quadrant), as well as the trajectory were recorded. Western blot analysis After the behavioral tests, the hippocampus was isolated and homogenized with RIPA and PMSF lysis buffer (Solarbio Science & Technology Co., Ltd., Shanghai, China). The homogenate was then centrifuged at 12,000 rpm for 20 min at 4°C. The protein concentration of the collected supernatant was detected using a BCA Protein Assay kit (Zhongshan Jinqiao Institute of Biotechnology, Beijing, China). Protein samples (20 µg total protein from each sample) were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then transferred to polyvinylidene difluoride membranes (Millipore, Billerica, USA). The protein bands on the membranes were detected by incubation with primary antibodies, including anti-NF-κB p65 (1:1000; Invitrogen, Grand Island, USA), anti-NLRP3 (1:1000; Cell Signaling Technology, Beverly, USA), anti-caspase-1 (1:500; Servicebio Technology Co., Ltd., Wuhan, China), anti- ZO-1 (1:1000; Millipore), anti-occludin (1:500; Santa Cruz Biotech, Santa Cruz, USA), anti-Claudin 5 (1:500; Santa Cruz Biotech), anti-caspase-3 (1:1000; Millipore), and anti-glyceraldehyde-3-phosphate dehydrogenase (GAPDH; 1:10,000; Abcam, Cambridge, UK) antibodies, followed by further incubation with horseradish peroxidase (HRP)-conjugated antibody and final visualization using an enhanced chemiluminescence kit (Santa Cruz Biotech). Protein bands were standardized against the GAPDH band from the same samples and quantified using the Gel-Pro Analyzer software (Version 3.1). Immunohistochemistry Immunohistochemistry (IHC) was performed as previously described [24,25]. Paraffin sections were successively deparaffinized and hydrated according to the following steps: 10-min wash with xylene twice, followed by 5, 10, 10, and 10-min washes with different concentrations of ethanol (100%, 95%, 85%, and 70%) and then three 5-min wash with phosphate buffered saline (PBS) at room temperature. Antigen retrieval was achieved by boiling the sections in a microwave oven. The sections were boiled for 10 min in 10 mM sodium citrate to retrieve the antigen, then washed with PBS three times and treated with 3% H2O2-methanol for 15 min. Finally, the sections were incubated with antibodies, including anti-NF-κB p65 (1:1000; Invitrogen), anti-NLRP3 (1:1000; Cell Signaling Technology), anti-occludin (1:500; Santa Cruz Biotech), anti-ZO-1 (1:1000; Millipore), and anti-Claudin 5 (1:500; Santa Cruz Biotech) antibodies for 2 h. After being washed, the sections were then incubated with the HRP-conjugated secondary antibody for 30 min. The typical morphology of the positive cells showed brownish-yellow cytoplasm. The numbers of NF-κB p65, NLRP3, ZO-1, occludin, and Claudin 5 immunoreactive cells in the CA1 region of the hippocampus were counted and analyzed under the microscope at 400× magnification. Transmission electron microscopy The protocol for transmission electron microscopy was performed as previously described [26]. After the mice were sacrificed, the hippocampi were isolated and immersed in glutaraldehyde. Then, a transmission electronic microscope (JEM-1230; Jeol, Tokyo, Japan) was used to visualize and capture the images of ultra-microstructures. Enzyme-linked immunosorbent assays Blood (2 ml) and hippocampus samples (30 mg) were collected after behavioral tests. Concentrations of IL-1β, IL-6, and TNF-α in the serum and in the hippocampus were measured using the corresponding enzyme-linked immunosorbent assay (ELISA) kits (Servicebio Technology Co., Ltd) according to the manufacturer’s instructions. Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling (TUNEL) staining A TUNEL kit (Roche Applied Science, Penzberg, Germany) was used to detect cell apoptosis according to the manufacturer’s instructions. Briefly, the hippocampus sections were incubated with a permeabilization solution, then with a TUNEL reaction mixture, and finally with 10 µg/ml Hoechst 33342. In the end, 4,6-diamidino-2-phenylindole were used to stain these sections. Then, the sections were fixed with Fluoromount (SouthernBiotech, Birmingham, USA) and then observed under a fluorescence microscope (Olympus America, Melville, USA). The numbers of apoptotic cells in the hippocampal CA1 region per view were recorded at 400 × magnification. Measurement of BBB permeability BBB permeability was determined using sodium fluorescein dye (NaF, 376 Da; Sigma -Aldrich, St Louis, USA), as reported in previous studies [27,28]. Six mice in each group were intraperitoneally injected with 10 mg of NaF which was dissolved in the sterile saline (0.1 ml) 24 h after the surgery. Then, the peripheral blood was collected 10 min after the circulation of NaF, and 15% trichloroacetic acid (TCA) was used to recover the serum (50 µl). After centrifugation at 10,000 g for 10 min, 30 µl of 5 M NaOH and 7.5% TCA were added into the supernatant. Then mice were anesthetized and the brain tissues were isolated. The brain was also homogenized with 7.5% TCA and centrifuged at 10,000 g for 10 min. The supernatant was collected and mixed with 5 M NaOH. The fluorescence intensity of the supernatant was determined with the Bio-Tek Fluorescence Spectrophotometer (Bio-Tek Instruments, Wonooski, USA) at an excitation wavelength of 485 nm and an emission wavelength of 530 nm. The NaF content in the samples was calculated according to the standards (125 to 4000 µg/ml). The NaF uptake into the brain issues were presented as: (µg of fluorescence brain/mg of tissue)/(µg of fluorescence serum/ml of blood). Statistical analysis All the data obtained were shown as the mean ± SD and analyzed using the SPSS19.0 software package. Two-way repeated analysis of variance (ANOVA) was used to analyze escape latency in the training period of MWM tests among groups. One-way ANOVA was used to compare other behavior tests, protein levels, and BBB permeability of the hippocampus mentioned above, followed with Bonferroni’s tests. A value of P<0.05 was considered statistically significant. Results Atorvastatin prevented neurocognitive impairment induced by anesthesia and surgery in aged mice Open field tests were performed first to assess the locomotor activity of the aged mice. Compared with the control group, surgery did not affect the locomotor activity of the aged mice, which was assessed by the total distance (P>0.05; Fig. 2A) and time spent in the center (P>0.05; Fig. 2B). Atorvastatin treatment did not affect the locomotor activity of the aged mice (P>0.05; Fig. 2A,B). Figure 2. Open in new tabDownload slide Atorvastatin prevented surgery-induced spatial learning and memory impairment in aged mice (A) The total distance of the aged mice in the open field among the four groups. (B) The time spent in the center area of the open field in the four groups. (C) The escape latency of the mice in the acquisition training for five days. (D) The time spent in the target quadrant (quadrant I). (E) The number of platform crossings. (F) Representative trajectories of the mice in the probe trial. Data are shown as the mean ± SD (n = 10 per group). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin +surgery versus surgery group. Figure 2. Open in new tabDownload slide Atorvastatin prevented surgery-induced spatial learning and memory impairment in aged mice (A) The total distance of the aged mice in the open field among the four groups. (B) The time spent in the center area of the open field in the four groups. (C) The escape latency of the mice in the acquisition training for five days. (D) The time spent in the target quadrant (quadrant I). (E) The number of platform crossings. (F) Representative trajectories of the mice in the probe trial. Data are shown as the mean ± SD (n = 10 per group). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin +surgery versus surgery group. The MWM tests were used to assess spatial learning and memory. A long escape latency was observed on the fifth day of the training test (F = 11.894, P<0.01; Fig. 2C) in mice subjected to surgery. Meanwhile, decreased target quadrant time (F = 9.390, P<0.01; Fig. 2D) and reduced cross-platform times (F = 11.535, P<0.01; Fig. 2E) were observed in the probe trial in mice subjected to surgery. However, changes in the escape latency in the training test (P<0.05; Fig. 2C), in the target quadrant time (P<0.05; Fig. 2D), and in the crossing-platform times (P<0.05; Fig. 2E) were all counteracted by atorvastatin pretreatment. These results indicated that surgery resulted in cognitive impairment in the aged mice, while atorvastatin treatment, at a dose of 10 mg/kg, had a therapeutic effect on isoflurane and surgery-induced cognitive impairment. Atorvastatin did not affect spatial learning or memory in aged mice without anesthesia and surgery (P>0.05; Fig. 2). Atorvastatin attenuated anesthesia and surgery-induced severe inflammatory response The levels of IL-1β, IL-6, and TNF-α in the hippocampus and serum were detected by ELISA. Compared the control group, surgery increased both the hippocampal levels of IL-1β (F = 15.865, P<0.01; Fig. 3A), IL-6 (F = 47.708, P<0.01; Fig. 3B), TNF-α (F = 60.166, P<0.01; Fig. 3C) and their serum levels (FIL-1β = 34.048, P<0.01, Fig. 3A; FIL-6 = 44.695, P<0.01, Fig. 3B; FTNF-α = 18.369, P<0.01, Fig. 3C). However, administration of atorvastatin at 10 mg kg−1 d−1 significantly ameliorated the hippocampal and serum levels of IL-1β (P<0.05; Fig. 3A), IL-6 (P<0.05; Fig. 3B), as well as TNF-α (P<0.05; Fig. 3C). Figure 3. Open in new tabDownload slide Atorvastatin inhibited the hippocampal and serum levels of IL-1β, TNF-α, and IL-6 induced by surgery (A) The levels of IL-1β in the hippocampus and serum. (B) The levels of IL-6 in the hippocampus and serum. (C) The levels of TNF-α in the hippocampus and serum. Data are shown as the mean ± SD (n = 10). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin +surgery versus surgery group. Figure 3. Open in new tabDownload slide Atorvastatin inhibited the hippocampal and serum levels of IL-1β, TNF-α, and IL-6 induced by surgery (A) The levels of IL-1β in the hippocampus and serum. (B) The levels of IL-6 in the hippocampus and serum. (C) The levels of TNF-α in the hippocampus and serum. Data are shown as the mean ± SD (n = 10). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin +surgery versus surgery group. Atorvastatin inhibited surgery-induced activation of NF-κB and NLRP3 inflammasome in the hippocampus To further investigate whether the early neuroprotective actions of atorvastatin were associated with inhibition of the NF-κB pathway and NLRP3 inflammasome, we performed IHC staining and western blot analysis (Fig. 4). IHC staining results showed that anesthesia and surgery induced a significant increase in the number of NF-κB p65 positive cells (F = 21.499, P<0.01; Fig. 4A–E) and NLRP3 positive cells (F = 22.278, P<0.01; Fig. 4H–L) in the hippocampal CA1 region. Western blot analysis results demonstrated that anesthesia and surgery induced a significant increase in the hippocampal levels of phospho-NF-κB p65 (F = 63.123, P<0.01; Fig. 4F,G), NLRP3 (F = 72.714, P<0.01; Fig. 4M,N), and cleaved caspase-1 (F = 73.975, P<0.01; Fig. 4M,O), indicating the activation of the NF-κB and NLRP3 inflammasomes. Atorvastatin pretreatment attenuated the surgery-induced excessive activation of the NF-κB and NLRP3 inflammasomes in the hippocampus (P<0.05; Fig. 4). However, atorvastatin did not affect the activation of the NF-κB and NLRP3 inflammasome in aged mice without anesthesia and surgery (P>0.05; Fig. 4). Figure 4. Open in new tabDownload slide Atorvastatin ameliorated the activation of the NF-κB and NLRP3 inflammasome after surgery (A–D) Representative images of the NF-κB p65 IHC staining in the CA1 region of the hippocampus. Cells with the brownish-yellow cytoplasm were positive for NF-κB. Scale bar: 50 µm. (E) The number of the NF-κB-positive cells in the CA1 region of the hippocampus. (F,G) Western blot analysis and quantitative analysis of the expressions of the NF-κB p65 and phosphor-NF-κB p65 in the hippocampal tissues. (H–K) Representative images of the NLRP3 IHC staining in the CA1 region of the hippocampus. Cells with the brownish-yellow cytoplasm were positive for NLRP3. Scale bar: 50 µm. (L) The number of the NF-κB-positive cells in the CA1 region of the hippocampus. (M–O) Western blot analysis and quantitative analysis of the expressions of the NLRP3 and cleaved caspase-1 in the hippocampal tissues. Data are shown as the mean ± SD (n = 10). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin + surgery versus surgery group. Figure 4. Open in new tabDownload slide Atorvastatin ameliorated the activation of the NF-κB and NLRP3 inflammasome after surgery (A–D) Representative images of the NF-κB p65 IHC staining in the CA1 region of the hippocampus. Cells with the brownish-yellow cytoplasm were positive for NF-κB. Scale bar: 50 µm. (E) The number of the NF-κB-positive cells in the CA1 region of the hippocampus. (F,G) Western blot analysis and quantitative analysis of the expressions of the NF-κB p65 and phosphor-NF-κB p65 in the hippocampal tissues. (H–K) Representative images of the NLRP3 IHC staining in the CA1 region of the hippocampus. Cells with the brownish-yellow cytoplasm were positive for NLRP3. Scale bar: 50 µm. (L) The number of the NF-κB-positive cells in the CA1 region of the hippocampus. (M–O) Western blot analysis and quantitative analysis of the expressions of the NLRP3 and cleaved caspase-1 in the hippocampal tissues. Data are shown as the mean ± SD (n = 10). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin + surgery versus surgery group. Atorvastatin reduced cellular apoptosis and BBB permeability of aged mice after surgery TUNEL staining was performed to examine the morphology of apoptotic cells in the hippocampus. Caspase-3 is the executor of cellular apoptosis and reflects the degree of apoptosis. Compared with those of the control group, both the number of apoptotic cells (F = 39.494, P<0.001; Fig. 5A–E) and the expression of cleaved caspase-3 (F = 65.267, P<0.01; Fig. 5F,G) were significantly increased in the hippocampus of the mice subjected surgery. However, atorvastatin significantly inhibited cell apoptosis (P<0.01; Fig. 5A–E) and the activation of caspase-3 (P<0.01; Fig. 5F,G) induced by surgery but did not affect those in the control group mice (P>0.05; Fig. 5). Figure 5. Open in new tabDownload slide Atorvastatin reduced cell apoptosis and BBB permeability of the aged mice after surgery (A–D) Representative images of the TUNEL staining in the hippocampal CA1 region. Scale bar: 50 µm. Cells with brownish-yellow cytoplasm without nucleus are apoptotic cells. (E) The number of the apoptotic cells in the hippocampal CA1 region. (F,G) Western blot analysis and quantitative analysis of the expression of cleaved caspase-3 in the hippocampus. (H) The relative ratio of the NaF uptake of the hippocampus to the control group. (I–L) The morphology of TJs in the hippocampus among different groups revealed by transmission electron microscopy. Scale bar: 1 μm. Data are shown as the mean ± SD (n = 6–10). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin + surgery versus surgery group. Figure 5. Open in new tabDownload slide Atorvastatin reduced cell apoptosis and BBB permeability of the aged mice after surgery (A–D) Representative images of the TUNEL staining in the hippocampal CA1 region. Scale bar: 50 µm. Cells with brownish-yellow cytoplasm without nucleus are apoptotic cells. (E) The number of the apoptotic cells in the hippocampal CA1 region. (F,G) Western blot analysis and quantitative analysis of the expression of cleaved caspase-3 in the hippocampus. (H) The relative ratio of the NaF uptake of the hippocampus to the control group. (I–L) The morphology of TJs in the hippocampus among different groups revealed by transmission electron microscopy. Scale bar: 1 μm. Data are shown as the mean ± SD (n = 6–10). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin + surgery versus surgery group. Sodium fluorescein dye (NaF; 376 Da) was used to detect BBB permeability. It was found that uptake of the sodium fluorescein dye was significantly increased in the mice exposed to surgery compared to that in the control group mice (F = 54.227, P<0.01; Fig. 5H), indicating higher permeability of BBB in mice subjected to surgery. Furthermore, the ultrastructure of the BBB was examined by transmission electron microscopy. The results showed that in the surgery group, the capillary basement membrane, and tight connection structure were fuzzy and discontinuous, with swelling endothelial cells, while the structures of BBB in the control group mice were clearly normal (Fig. 5I–L). Atorvastatin prevented the TJs of the BBB from the damage induced by the surgery BBB permeability was significantly increased in the mice exposed to surgery, as mentioned above. The TJ is a critical part of the BBB. Thus, we further evaluated the expressions of TJ-related proteins, including occludin, ZO-1, and Claudin 5 by IHC staining and western blot analysis. Surgery significantly reduced the number of occludin positive cells (F = 23.298, P<0.01; Fig. 6A–E), ZO-1 positive cells (F = 29.358, P<0.01; Fig. 6F–J), and Claudin 5 positive cells (F = 79.040, P<0.01; Fig. 6K–O) in the BBB. Surgery also decreased the protein expression levels of occludin (F = 78.527, P<0.01; Fig. 6P,Q), ZO-1 (F = 24.087, P<0.01; Fig. 6P,R), and Claudin5 (F = 55.983, P<0.01; Fig. 6P,S) in the hippocampus. However, all changes in the three proteins induced by the surgery could be inhibited by atorvastatin treatment (P<0.05; Fig. 6). Figure 6. Open in new tabDownload slide Atorvastatin prevented the TJs of the BBB from the damage induced by the surgery (A–E) Representative images of the occludin immunohistochemical (IHC) staining and quantification of the occluding-positive cells in the hippocampal CA1 region. (F–J) Representative images of the ZO-1 IHC staining and quantification of the ZO-1-positive cells in the hippocampal CA1 region. (K–O) Representative images of the Claudin5 IHC staining and quantification of the claudin5-positive cells in the hippocampal CA1 region. Cells with the brownish-yellow cytoplasm were positive for occluding, ZO-1, and claudin 5. Scale bar: 50 µm. (P–S) Western blot analysis and quantitative analysis of the expressions of occluding, ZO-1 and Claudin 5 in the hippocampus. Data are shown as the mean ± SD (n = 6–10). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin + surgery versus surgery group. Figure 6. Open in new tabDownload slide Atorvastatin prevented the TJs of the BBB from the damage induced by the surgery (A–E) Representative images of the occludin immunohistochemical (IHC) staining and quantification of the occluding-positive cells in the hippocampal CA1 region. (F–J) Representative images of the ZO-1 IHC staining and quantification of the ZO-1-positive cells in the hippocampal CA1 region. (K–O) Representative images of the Claudin5 IHC staining and quantification of the claudin5-positive cells in the hippocampal CA1 region. Cells with the brownish-yellow cytoplasm were positive for occluding, ZO-1, and claudin 5. Scale bar: 50 µm. (P–S) Western blot analysis and quantitative analysis of the expressions of occluding, ZO-1 and Claudin 5 in the hippocampus. Data are shown as the mean ± SD (n = 6–10). *P<0.05 and **P<0.01: control versus surgery group; #P<0.05 and ##P<0.01: atorvastatin + surgery versus surgery group. Discussion Accumulating evidence suggests that elderly patients are prone to PND after surgery and anesthesia [29–31]. In our study, the results showed that atorvastatin treatment could attenuate the hippocampus-related learning and memory performance in the acute phase of anesthesia and surgery. Our primary findings include: (i) atorvastatin treatment ameliorates early cognition impairment; (ii) atorvastatin treatment reduces the systemic inflammation response and release of cytokines; (iii) atorvastatin treatment inhibits surgery-induced BBB disruption and cellular apoptosis in the hippocampus; and (iv) atorvastatin treatment suppresses surgery-induced activation of the NF-κB pathway and NLRP3 inflammasome. Increasing evidence also suggests that excessive inflammation contributes to BBB disruption and neuronal damage [1,32]. Anesthesia and surgery induce excessive inflammation via excessive microglial activation and further promote the secretion of inflammatory mediators such as IL-1β and TNF-α [2,33,34]. In the present study, we found that a simple abdominal surgery could increase both the plasma and hippocampal levels of IL-1β, IL-6, and TNF-α in the aged mice, while atorvastatin could inhibit the surgery-induced inflammation. The results also indicated that there is a certain relationship between peripheral inflammatory response and central inflammatory response after surgery. The BBB, which consists of blood vessels with endothelial cells, basement membrane, pericytes, etc., prevents pathogenic microorganisms and other macromolecules from blood to the brain parenchyma [35]. Several studies reported that BBB disruption is associated with cognitive dysfunction, Alzheimer’s disease, and so on [36,37]. In the present study, sodium fluorescein and transmission electron microscopy were used to detect the BBB permeability and ultrastructure. The results showed that the BBB permeability was increased in the aged mice exposed to surgery, with swelling of endothelial cells and disruption of basement membrane, which is consistent with Xie’s report [16]. Thus, we considered that peripheral inflammation induced by surgery contributed to neurobehavioral impairment through a compromised BBB. Furthermore, atorvastatin treatment was found to attenuate surgery-induced BBB damage by inhibiting inflammatory responses. The barrier function is mainly accomplished by the TJ complex between endothelial cells [11]. Thus, we further investigated the changes in the TJ. TJs include occludin, Claudin family, and junctional adhesive molecules [38,39]. Occludin and Claudin-5 are typical members, attaching to the cytoskeleton through ZO-1. The levels of these proteins have also been proven to be negatively associated with the permeability of BBB [40,41]. In this study, IHC and western blot analysis showed that the expressions of occludin, Claudin-5, and ZO-1 were decreased in the hippocampus after surgery. Meanwhile, transmission electron microscopy showed swollen endothelial cells of the BBB after surgery. However, all these changes were inhibited by atorvastatin treatment, which further proved the protective effects of atorvastatin on the BBB integrity. Our results implied that peripheral inflammation could induce BBB dysfunction and activate central inflammatory response. The IL-1β, IL-6, and TNF-α released by peripheral monocytes may bind to their corresponding receptors on BBB microvascular endothelial cells, which inhibits the synthesis and expression of the TJ-related proteins [42]. Some other studies reported that inflammation induces BBB disruption partly by promoting the expression of MMP-9 and the degradation of the basement membrane [43,44]. In this study, we proposed that surgery may induce excessive activation and release of cytokines which accumulate in the blood vessel endothelium, damage the endothelial cell, and magnify an inflammatory cascade. The excessive inflammatory response further aggravates the injury of endothelial cells, degradation of basement membrane, and damage of TJs, leading to neuroinflammation and cognition disorders. However, the specific interaction between inflammation and BBB remains unclear. We will perform in vitro experiments to discuss the mechanisms in the future. In addition, we further investigated the related signal pathways that regulate neuroinflammation and explored the potential mechanisms for the neuroprotective effects of atorvastatin. Previous studies have revealed the effects of NF-κB pathway on post-operative inflammation, which promote the maturation and release of cytokines, including IL-1β, IL-6, and TNF-α, as well as induce cell apoptosis [2,33,34]. Furthermore, IL-1β is a critical pro-inflammatory mediator in the inflammatory cascades. Recent studies indicated that, besides NF-κB, NLRP3 inflammasome-medicated caspase-1 activation is also an important pathway for IL-1β production [45,46]. NLRP3 inflammasome can be activated by NF-κB and noxious stimuli [45,47]. Thus, the NF-κB pathway and NLRP-3 inflammasome were detected in this study. In this study, we provided new evidence that atorvastatin treatment could inhibit the activation of NF-κB pathway, the NLRP3/caspase-1 inflammasome, and further decrease the expressions of IL-1β, IL-6, and TNF-α. NLRP3 inflammasome activation is partly regulated by the NF-κB pathway; therefore, we propose that the anti-inflammatory effects of atorvastatin after surgery may be associated with the inhibition of NF-κB-mediated NLRP3 inflammasome activation. With regard to PND, prevention makes more sense than clinical treatment. Atorvastatin, a member of the statins, is widely used as a cholesterol-lowering drug which has many pharmacological properties, such as antioxidative, and anti-inflammatory, in other animal models of diseases [48–50]. However, whether atorvastatin plays a neuroprotective role in surgery-induced cognitive dysfunction of aged brain as well as the related mechanism is still unclear. Based on previous studies [18,49,51], we selected pre-treatment intervention for atorvastatin rather than post-operative treatment in this study. Our results showed that atorvastatin intervention could significantly attenuate cognition impairment by inhibiting the release of cytokines, disrupting the BBB, and activating the NF-κB pathway and NLRP-3 inflammasome. Nevertheless, this study has some limitations. First, in this study, the behavior tests were performed one day after anesthesia and surgery, to mimic the condition that patients might have difficulty learning new things after surgery in a short period of time. However, the protective function of atorvastatin in long-term PND remains unclear, which needs to be further investigated. Second, in this study, we preliminarily explored the related inflammatory mechanism for PND and the neuroprotective effects of atorvastatin. In a follow-up study, inhibitors of the NF-κB pathway and NLRP3 inflammasome will be used to explore the underlying mechanisms, the defined cellular sources, as well as the link between neuroinflammation and BBB disruption of aged brain exposed to surgery. Additionally, the safety of atorvastatin therapy for PND was not evaluated in this study, and there may be other potential mechanisms for its neuroprotective effects, which require further exploration. In summary, the data obtained from this study suggested that atorvastatin treatment could attenuate the activation of the NF-κB pathway and the NLRP3 inflammasome, inhibit BBB disruption, reduce neuronal apoptosis, and finally improve the neurobehavioral outcomes in the acute phase of PND (Fig. 7). Thus, atorvastatin may be a potential therapeutic candidate for patients with PND. Figure 7. Open in new tabDownload slide A schematic diagram of the potential mechanisms Atorvastatin treatment attenuates inflammatory responses by limiting the activation of the NF-κB and NLRP3 inflammasome, thereby inhibits BBB disruption and reduces cellular apoptosis, resulting in improved neurobehavioral outcomes in the acute phase of PND. Figure 7. Open in new tabDownload slide A schematic diagram of the potential mechanisms Atorvastatin treatment attenuates inflammatory responses by limiting the activation of the NF-κB and NLRP3 inflammasome, thereby inhibits BBB disruption and reduces cellular apoptosis, resulting in improved neurobehavioral outcomes in the acute phase of PND. Acknowledgement We would like to thank the Central Laboratory of Beijing Shijitan Hospital, Capital Medical University (Beijing, China) for its technical support in the experiments. Funding This work was supported by the grant from the National Natural Science Foundation of China (No. 81571037 to T.L.). Conflict of Interest The authors declare that they have no conflict of interest. References 1. Zhan G , Hua D, Huang N, Wang Y, Li S, Zhou Z, Yang N, et al. Anesthesia and surgery induce cognitive dysfunction in elderly male mice: the role of gut microbiota . Aging 2019 , 11 : 1778 – 1790 . doi: 10.18632/aging.101871 Google Scholar Crossref Search ADS PubMed WorldCat 2. Xu Z , Dong Y, Wang H, Culley DJ, Marcantonio ER, Crosby G, Tanzi RE, et al. Age-dependent postoperative cognitive impairment and Alzheimer-related neuropathology in mice . Sci Rep 2014 , 4 : 3766. doi: 10.1038/srep03766 Google Scholar OpenURL Placeholder Text WorldCat Crossref 3. Li RL , Zhang ZZ, Peng M, Wu Y, Zhang JJ, Wang CY, Wang YL. Postoperative impairment of cognitive function in old mice: a possible role for neuroinflammation mediated by HMGB1, S100B, and RAGE . J Surg Res 2013 , 185 : 815 – 824 . doi: 10.1016/j.jss.2013.06.043 Google Scholar Crossref Search ADS PubMed WorldCat 4. Deiner S , Silverstein JH. Postoperative delirium and cognitive dysfunction . Br J Anaesth 2009 , 103 Suppl(Suppl1): i41 – i46 . doi: 10.1093/bja/aep291 Google Scholar OpenURL Placeholder Text WorldCat Crossref 5. Amado L , Perrie H, Scribante J, Ben-Israel K. Preoperative cognitive dysfunction in older elective noncardiac surgical patients in South Africa . Br J Anaesth 2020 , 125 : 275 – 281 . doi: 10.1016/j.bja.2020.04.072 Google Scholar Crossref Search ADS PubMed WorldCat 6. Sprung J , Roberts R, Weingarten T, Nunes Cavalcante A, Knopman D, Petersen R, Hanson A, et al. Postoperative delirium in elderly patients is associated with subsequent cognitive impairment . Br J Anaesth 2017 , 119 : 316 – 323 . doi: 10.1093/bja/aex130 Google Scholar Crossref Search ADS PubMed WorldCat 7. Watne L , Torbergsen A, Conroy S, Engedal K, Frihagen F, Hjorthaug G, Juliebo V, et al. The effect of a pre- and postoperative orthogeriatric service on cognitive function in patients with hip fracture: randomized controlled trial (Oslo Orthogeriatric Trial) . BMC Med 2014 , 12 : 63. doi: 10.1186/1741-7015-12-63 Google Scholar OpenURL Placeholder Text WorldCat Crossref 8. Zhao Z , Nelson A, Betsholtz C, Zlokovic B. Establishment and dysfunction of the blood-brain barrier . Cell 2015 , 163 : 1064 – 1078 . doi: 10.1016/j.cell.2015.10.067 Google Scholar Crossref Search ADS PubMed WorldCat 9. Costea L , Mészáros Á, Bauer H, Bauer HC, Traweger A, Wilhelm I, Farkas AE, et al. The blood-brain barrier and its intercellular junctions in age-related brain disorders . Int J Mol Sci 2019 , 20 : 5472. Google Scholar OpenURL Placeholder Text WorldCat 10. Kumar V , Lee JD, Coulson EJ, Woodruff TM. A validated quantitative method for the assessment of neuroprotective barrier impairment in neurodegenerative disease models . J Neurochem 2020 , 00 : 1 – 11 . doi: 10.1111/jnc.15119 Google Scholar OpenURL Placeholder Text WorldCat Crossref 11. Wolburg H , Lippoldt A. Tight junctions of the blood-brain barrier: development, composition and regulation . Vasc Pharmacol 2002 , 38 : 323 – 337 . doi: 10.1016/S1537-1891(02)00200-8 Google Scholar Crossref Search ADS WorldCat 12. Ismail H , Shakkour Z, Tabet M, Abdelhady S, Kobaisi A, Abedi R, Nasrallah L, et al. Traumatic brain injury: oxidative stress and novel anti-oxidants such as mitoquinone and edaravone . Antioxidants (Basel, Switzerland) 2020 , 9 : 943. Google Scholar OpenURL Placeholder Text WorldCat 13. Lee B , Hyun S, Jung Y. Yuzu and Hesperidin ameliorate blood-brain barrier disruption during hypoxia via antioxidant activity . Antioxidants (Basel, Switzerland) 2020 , 9 : 843. Google Scholar OpenURL Placeholder Text WorldCat 14. Furutama D , Matsuda S, Yamawaki Y, Hatano S, Okanobu A, Memida T, Oue H, et al. IL-6 induced by periodontal inflammation causes neuroinflammation and disrupts the blood-brain barrier . Brain Sci 2020 , 10 : 679. Google Scholar OpenURL Placeholder Text WorldCat 15. Propson N , Roy E, Litvinchuk A, Köhl J, Zheng H. Endothelial C3a receptor mediates vascular inflammation and BBB permeability during aging . J Clin Invest 2021 , 131 : e140966. Google Scholar OpenURL Placeholder Text WorldCat 16. Yang S , Gu C, Mandeville ET, Dong Y, Esposito E, Zhang Y, Yang G, et al. Anesthesia and surgery impair blood-brain barrier and cognitive function in mice . Front Immunol 2017 , 8 : 902. doi: 10.3389/fimmu.2017.00902 Google Scholar OpenURL Placeholder Text WorldCat Crossref 17. Barthold D , Joyce G, Diaz Brinton R, Wharton W, Kehoe PG, Zissimopoulos J. Association of combination statin and antihypertensive therapy with reduced Alzheimer’s disease and related dementia risk . PLoS One 2020 , 15 : e0229541. doi: 10.1371/journal.pone.0229541 Google Scholar OpenURL Placeholder Text WorldCat Crossref 18. Zhang YY , Fan YC, Wang M, Wang D, Li XH. Atorvastatin attenuates the production of IL-1β, IL-6, and TNF-α in the hippocampus of an amyloid β1-42-induced rat model of Alzheimer’s disease . Clin Interv Aging 2013 , 8 : 103 – 110 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 19. Kurata T , Miyazaki K, Morimoto N, Kawai H, Ohta Y, Ikeda Y, Abe K. Atorvastatin and pitavastatin reduce oxidative stress and improve IR/LDL-R signals in Alzheimer’s disease . Neurol Res 2013 , 35 : 193 – 205 . doi: 10.1179/1743132812Y.0000000127 Google Scholar Crossref Search ADS PubMed WorldCat 20. Vizcaychipi MP , Watts HR, O’Dea KP, Lloyd DG, Penn JW, Wan Y, Pac-Soo C, et al. The therapeutic potential of atorvastatin in a mouse model of postoperative cognitive decline . Ann Surg 2014 , 259 : 1235 – 1244 . doi: 10.1097/SLA.0000000000000257 Google Scholar Crossref Search ADS PubMed WorldCat 21. Martins W , Dos Santos V, Dos Santos A, Vandresen-Filho S, Dal-Cim T, De Oliveira K, Mendes-de-aguiar C, et al. Atorvastatin prevents cognitive deficits induced by intracerebroventricular amyloid-β1-40 administration in mice: involvement of glutamatergic and antioxidant systems . Neurotox Res 2015 , 28 : 32 – 42 . doi: 10.1007/s12640-015-9527-y Google Scholar Crossref Search ADS PubMed WorldCat 22. Yadollah-Damavandi S , Sharifi Z, Arani H, Jangholi E, Karimi A, Parsa Y, Movassaghi S. Atorvastatin prevent the neuron loss in the hippocampal dentate gyrus region through its anti-oxidant and anti-apoptotic activities . CNS Neurol Disord Drug Targets 2020 (E-pub Ahead of Print). doi: 10.2174/1871527319666200922160627 Google Scholar OpenURL Placeholder Text WorldCat Crossref 23. Wan Y , Xu J, Meng F, Bao Y, Ge Y, Lobo N, Vizcaychipi MP, et al. Cognitive decline following major surgery is associated with gliosis, β-amyloid accumulation, and τ phosphorylation in old mice . Crit Care Med 2010 , 38 : 2190 – 2198 . doi: 10.1097/CCM.0b013e3181f17bcb Google Scholar Crossref Search ADS PubMed WorldCat 24. Zheng B , Lai R, Li J, Zuo Z. Critical role of P2X7 receptors in the neuroinflammation and cognitive dysfunction after surgery . Brain Behav Immun 2017 , 61 : 365 – 374 . doi: 10.1016/j.bbi.2017.01.005 Google Scholar Crossref Search ADS PubMed WorldCat 25. Fan YX , Du LW, Fu Q, Zhou ZQ, Zhang JY, Li GM, Wu J. Inhibiting the NLRP3 inflammasome with MCC950 ameliorates isoflurane-induced pyroptosis and cognitive impairment in aged mice . Front Cell Neurosci 2018 , 12 : 426. doi: 10.3389/fncel.2018.00426 Google Scholar OpenURL Placeholder Text WorldCat Crossref 26. Zhou Y , Huang X, Zhao T, Qiao M, Zhao X, Zhao M, Xu L, et al. Hypoxia augments LPS-induced inflammation and triggers high altitude cerebral edema in mice . Brain Behav Immun 2017 , 64 : 266 – 275 . doi: 10.1016/j.bbi.2017.04.013 Google Scholar Crossref Search ADS PubMed WorldCat 27. Phares TW , Fabis MJ, Brimer CM, Kean RB, Hooper DC. A peroxynitrite-dependent pathway is responsible for blood-brain barrier permeability changes during a central nervous system inflammatory response: TNF-alpha is neither necessary nor sufficient . J Immunol (Baltimore, MD) 1950 , 2007 : 7334 – 7343 . Google Scholar OpenURL Placeholder Text WorldCat 28. Li F , Wang Y, Yu L, Cao S, Wang K, Yuan J, Wang C, et al. Viral infection of the central nervous system and neuroinflammation precede blood-brain barrier disruption during Japanese encephalitis virus infection . J Virol 2015 , 89 : 5602 – 5614 . doi: 10.1128/JVI.00143-15 Google Scholar Crossref Search ADS PubMed WorldCat 29. Zhang C , Zhang Y, Shen Y, Zhao G, Xie Z, Dong Y. Anesthesia/surgery induces cognitive impairment in female Alzheimer’s disease transgenic mice . J Alzheimer’s Dis 2017 , 57 : 505 – 518 . doi: 10.3233/JAD-161268 Google Scholar Crossref Search ADS WorldCat 30. Zhang X , Dong H, Li N, Zhang S, Sun J, Zhang S, Qian Y. Activated brain mast cells contribute to postoperative cognitive dysfunction by evoking microglia activation and neuronal apoptosis . J Neuroinflamm 2016 , 13 : 127. doi: 10.1186/s12974-016-0592-9 Google Scholar OpenURL Placeholder Text WorldCat Crossref 31. Zhang Z , Ji M, Liao Y, Yang J, Gao J. Endotoxin tolerance induced by lipopolysaccharide preconditioning protects against surgery-induced cognitive impairment in aging mice . Mol Med Rep 2018 , 17 : 3845 – 3852 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 32. Jiang Y , Gao H, Yuan H, Xu H, Tian M, Du G, Xie W. Amelioration of postoperative cognitive dysfunction in mice by mesenchymal stem cell-conditioned medium treatments is associated with reduced inflammation, oxidative stress and increased BDNF expression in brain tissues . Neurosci Lett 2019 , 709 : 134372. doi: 10.1016/j.neulet.2019.134372 Google Scholar OpenURL Placeholder Text WorldCat Crossref 33. Almahozi A , Radhi M, Alzayer S, Kamal A. Effects of memantine in a mouse model of postoperative cognitive dysfunction . Behav Sci (Basel, Switzerland) 2019 , 9 : 24. Google Scholar OpenURL Placeholder Text WorldCat 34. Wang P , Velagapudi R, Kong C, Rodriguiz RM, Wetsel WC, Yang T, Berger M, et al. Neurovascular and immune mechanisms that regulate postoperative delirium superimposed on dementia . Alzheimer’s Dement 2020 , 16 : 734 – 749 . doi: 10.1002/alz.12064 Google Scholar Crossref Search ADS WorldCat 35. Poovaiah N , Davoudi Z, Peng H, Schlichtmann B, Mallapragada S, Narasimhan B, Wang Q. Treatment of neurodegenerative disorders through the blood-brain barrier using nanocarriers . Nanoscale 2018 , 10 : 16962 – 16983 . doi: 10.1039/C8NR04073G Google Scholar Crossref Search ADS PubMed WorldCat 36. Posada-Duque R , Cardona-Gómez G. CDK5 targeting as a therapy for recovering neurovascular unit integrity in Alzheimer’s disease . J Alzheimer’s Dis 2020 , Pre-press: 1 – 21 . Google Scholar OpenURL Placeholder Text WorldCat 37. Tran C , George A, Teskey G, Gordon G. Seizures elevate gliovascular unit Ca2+ and cause sustained vasoconstriction . JCI Insight 2020 , 5 : e136469. Google Scholar OpenURL Placeholder Text WorldCat 38. Zenaro E , Piacentino G, Constantin G. The blood-brain barrier in Alzheimer’s disease . Neurobiol Dis 2017 , 107 : 41 – 56 . Google Scholar Crossref Search ADS PubMed WorldCat 39. Kovacs ZI , Kim S, Jikaria N, Qureshi F, Milo B, Lewis BK, Bresler M, et al. Disrupting the blood-brain barrier by focused ultrasound induces sterile inflammation . Proc Natl Acad Sci USA 2017 , 114 : E75 – E84 . doi: 10.1073/pnas.1614777114 Google Scholar Crossref Search ADS PubMed WorldCat 40. Katt ME , Mayo LN, Ellis SE, Mahairaki V, Rothstein JD, Cheng L, Searson PC. The role of mutations associated with familial neurodegenerative disorders on blood-brain barrier function in an iPSC model . Fluids Barriers CNS 2019 , 16 : 20. doi: 10.1186/s12987-019-0139-4 Google Scholar OpenURL Placeholder Text WorldCat Crossref 41. Wong KH , Riaz MK, Xie Y, Zhang X, Liu Q, Chen H, Bian Z, et al. Review of current strategies for delivering Alzheimer’s disease drugs across the blood-brain barrier . Int J Mol Sci 2019 , 20 : 381. Google Scholar OpenURL Placeholder Text WorldCat 42. Tsuge M , Yasui K, Ichiyawa T, Saito Y, Nagaoka Y, Yashiro M, Yamashita N, et al. Increase of tumor necrosis factor-alpha in the blood induces early activation of matrix metalloproteinase-9 in the brain . Microbiol Immunol 2010 , 54 : 417 – 424 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 43. Al-Sadi R , Guo S, Ye D, Dokladny K, Alhmoud T, Ereifej L, Said H, et al. Mechanism of IL-1β modulation of intestinal epithelial barrier involves p38 kinase and activating transcription factor-2 activation . J Immunol (Baltimore, MD) 1950 , 2013 : 6596 – 6606 . Google Scholar OpenURL Placeholder Text WorldCat 44. Al-Sadi R , Guo S, Ye D, Rawat M, Ma T. TNF-α modulation of intestinal tight junction permeability is mediated by NIK/IKK-α axis activation of the canonical NF-κB pathway . Am J Pathol 2016 , 186 : 1151 – 1165 . doi: 10.1016/j.ajpath.2015.12.016 Google Scholar Crossref Search ADS PubMed WorldCat 45. Wei P , Yang F, Zheng Q, Tang W, Li J. The potential role of the NLRP3 inflammasome activation as a link between mitochondria ROS generation and neuroinflammation in postoperative cognitive dysfunction . Front Cell Neurosci 2019 , 13 : 73. doi: 10.3389/fncel.2019.00073 Google Scholar OpenURL Placeholder Text WorldCat Crossref 46. Ye JS , Chen L, Lu YY, Lei SQ, Peng M, Xia ZY. Honokiol-mediated mitophagy ameliorates postoperative cognitive impairment induced by surgery/sevoflurane via inhibiting the activation of NLRP3 inflammasome in the hippocampus . Oxid Med Cell Longev 2019 , 2019 : 8639618. doi: 10.1155/2019/8639618 Google Scholar OpenURL Placeholder Text WorldCat Crossref 47. Xiong C , Liu J, Lin D, Zhang J, Terrando N, Wu A. Complement activation contributes to perioperative neurocognitive disorders in mice . J Neuroinflamm 2018 , 15 : 254. doi: 10.1186/s12974-018-1292-4 Google Scholar OpenURL Placeholder Text WorldCat Crossref 48. Butterfield DA , Barone E, Di Domenico F, Cenini G, Sultana R, Murphy MP, Mancuso C, et al. Atorvastatin treatment in a dog preclinical model of Alzheimer’s disease leads to up-regulation of haem oxygenase-1 and is associated with reduced oxidative stress in brain . Int J Neuropsychopharmacol 2012 , 15 : 981 – 987 . doi: 10.1017/S1461145711001118 Google Scholar Crossref Search ADS PubMed WorldCat 49. Zhao L , Chen T, Wang C, Li G, Zhi W, Yin J, Wan Q, et al. Atorvastatin in improvement of cognitive impairments caused by amyloid β in mice: involvement of inflammatory reaction . BMC Neurol 2016 , 16 : 18.doi: 10.1186/s12883-016-0533-3 Google Scholar OpenURL Placeholder Text WorldCat Crossref 50. Zhao L , Zhao Q, Zhou Y, Zhao Y, Wan Q. Atorvastatin may correct dyslipidemia in adult patients at risk for Alzheimer’s disease through an anti-inflammatory pathway . CNS Neurol Disord Drug Targets 2016 , 15 : 80 – 85 . doi: 10.2174/1871527315999160111160143 Google Scholar Crossref Search ADS PubMed WorldCat 51. Atar S , Ye Y, Lin Y, Freeberg SY, Nishi SP, Rosanio S, Huang MH, et al. Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2 . Am J Physiol Heart Circ Physiol 2006 , 290 : H1960 – H1968 . doi: 10.1152/ajpheart.01137.2005 Google Scholar Crossref Search ADS PubMed WorldCat Author notes † Pengfei Liu, Quansheng Gao and Lei Guan contributed equally to this work. © The Author(s) 2021. Published by Oxford University Press on behalf of the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Atorvastatin attenuates surgery-induced BBB disruption and cognitive impairment partly by suppressing NF-κB pathway and NLRP3 inflammasome activation in aged mice
JF - Acta Biochimica et Biophysica Sinica
DO - 10.1093/abbs/gmab022
DA - 2021-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/atorvastatin-attenuates-surgery-induced-bbb-disruption-and-cognitive-V8O7frB7zn
SP - 1
EP - 1
VL - Advance Article
IS - 
DP - DeepDyve
ER -