Protective Effects of Edaravone in Adult Rats with Surgery and Lipopolysaccharide Administration-Induced Cognitive Function Impairment

<div><p>Postoperative cognitive dysfunction (POCD) is a clinical syndrome characterized by cognitive declines in patients after surgery. Previous studies have suggested that surgery contributed to such impairment. It has been proven that neuroinflammation may exacerbate surgery-induced cognitive impairment in aged rats. The free radical scavenger edaravone has high blood brain barrier permeability, and was demonstrated to effectively remove free radicals from the brain and alleviate the development of POCD in patients undergoing carotid endarterectomy, suggesting its potential role in preventing POCD. For this reason, this study was designed to determine whether edaravone is protective against POCD through its inhibitory effects on inflammatory cytokines and oxidative stress. First, Sprague Dawley adult male rats were administered 3 mg/kg edaravone intraperitoneally after undergoing a unilateral nephrectomy combined with lipopolysaccharide injection. Second, behavioral parameters related to cognitive function were recorded by fear conditioning and Morris Water Maze tests. Last, superoxide dismutase activities and malondialdehyde levels were measured in the hippocampi and prefrontal cortex on postoperative days 3 and 7, and microglial (Iba1) activation, p-Akt and p-mTOR protein expression, and synaptic function (synapsin 1) were also examined 3 and 7 days after surgery. Rats that underwent surgery plus lipopolysaccharide administration showed significant impairments in spatial and working memory, accompanied by significant reductions in hippocampal-dependent and independent fear responses. All impairments were attenuated by treatment with edaravone. Moreover, an abnormal decrease in superoxide dismutase activation, abnormal increase in malondialdehyde levels, significant increase in microglial reactivity, downregulation of p-Akt and p-mTOR protein expression, and a statistically significant decrease in synapsin-1 were observed in the hippocampi and prefrontal cortices of rats at different time points after surgery. All mentioned abnormal changes were totally or partially reversed by edaravone. To our knowledge, few reports have shown greater protective effects of edaravone on POCD induced by surgery plus lipopolysaccharide administration from its anti-oxidative stress and anti-inflammatory effects, as well as maintenance of Akt/mTOR signal pathway activation; these might be closely related to the therapeutic effects of edaravone. Our research demonstrates the potential use of edaravone in the treatment of POCD.</p></div

The schematic outline of the experimental protocol and the timeline of LPS and edaravone administration.

<p>(A)Schematic outline of the experimental protocol. (B) Timeline of LPS and edaravone administration. MWM, Morris water maze; FCS, Fear conditioning test;C-P, sham surgery plus placebo; C-E, sham surgery plus edaravone; S-P, surgery plus placebo; S-E, surgery plus edaravone.</p

Protective Effects of Edaravone in Adult Rats with Surgery and Lipopolysaccharide Administration-Induced Cognitive Function Impairment - Fig 6

Effects of edaravone on protein expression in rats with LPS-induced hippocampal and prefrontal cortical impairment (A) The expression of related protein in the hippocampi on day 3 after surgery. (B) The ratio of p-Akt/Akt in the hippocampi on day 3 after surgery. (C) The ratio of p-mTOR/actin in the hippocampi on day 3 after surgery. (D) The expression of related protein in the prefrontal cortex on postoperative day 3. (E) The ratio of p-Akt/Akt in the prefrontal cortex on postoperative day 3. (F) The ratio of p-mTOR/actin in the prefrontal cortex on postoperative day 3. *PPP <0.05 vs. S-P group. C-P, sham surgery plus placebo; C-E, sham surgery plus edaravone; S-P, surgery plus placebo; S-E, surgery plus edaravone.</p

Case study of a patient with cerebrovascular akcident

<div><p>Postoperative cognitive dysfunction (POCD) is a clinical syndrome characterized by cognitive declines in patients after surgery. Previous studies have suggested that surgery contributed to such impairment. It has been proven that neuroinflammation may exacerbate surgery-induced cognitive impairment in aged rats. The free radical scavenger edaravone has high blood brain barrier permeability, and was demonstrated to effectively remove free radicals from the brain and alleviate the development of POCD in patients undergoing carotid endarterectomy, suggesting its potential role in preventing POCD. For this reason, this study was designed to determine whether edaravone is protective against POCD through its inhibitory effects on inflammatory cytokines and oxidative stress. First, Sprague Dawley adult male rats were administered 3 mg/kg edaravone intraperitoneally after undergoing a unilateral nephrectomy combined with lipopolysaccharide injection. Second, behavioral parameters related to cognitive function were recorded by fear conditioning and Morris Water Maze tests. Last, superoxide dismutase activities and malondialdehyde levels were measured in the hippocampi and prefrontal cortex on postoperative days 3 and 7, and microglial (Iba1) activation, p-Akt and p-mTOR protein expression, and synaptic function (synapsin 1) were also examined 3 and 7 days after surgery. Rats that underwent surgery plus lipopolysaccharide administration showed significant impairments in spatial and working memory, accompanied by significant reductions in hippocampal-dependent and independent fear responses. All impairments were attenuated by treatment with edaravone. Moreover, an abnormal decrease in superoxide dismutase activation, abnormal increase in malondialdehyde levels, significant increase in microglial reactivity, downregulation of p-Akt and p-mTOR protein expression, and a statistically significant decrease in synapsin-1 were observed in the hippocampi and prefrontal cortices of rats at different time points after surgery. All mentioned abnormal changes were totally or partially reversed by edaravone. To our knowledge, few reports have shown greater protective effects of edaravone on POCD induced by surgery plus lipopolysaccharide administration from its anti-oxidative stress and anti-inflammatory effects, as well as maintenance of Akt/mTOR signal pathway activation; these might be closely related to the therapeutic effects of edaravone. Our research demonstrates the potential use of edaravone in the treatment of POCD.</p></div

Additional file 1 of Association between intraoperative mean arterial pressure variability and postoperative delirium after hip fracture surgery: a retrospective cohort study

Additional file 1: Supplementary Figure 1. Receiver operating characteristic curves were used to determine the optimal MAPV cut-off value for predicting POD. Supplementary Table 1. Definitions of postoperative delirium. Supplementary Table 2. Association between MAPV as continuous variables and POD in different models. Supplementary Table 3. Association between MAPV as categories variables and POD in different models. Supplementary Table 4. Multivariable logistic regression analysis for POD in elderly patients with hip fractures (Model PSM)

Tracheobronchial Parameters.

<p>Values are given as mean ±SD. NS = not significant. AP-mcTD: Anteroposterior Midclavicular tracheal diameter; Tr-mcTD: Transverse Midclavicular tracheal diameter; AP-mTD: Anteroposterior Middle tracheal diameter; Tr-mTD: Transverse Middle tracheal diameter; Pe-LBD: Proximal end Left main bronchus internal diameter; M-LBD: Intermedius Left main bronchus internal diameter; Pe-RBD: Proximal end Right main bronchus internal diameter; M-RBD: Intermedius Right main bronchus internal diameter; RUBD: Right upper bronchus internal diameter; Pe-RMBD: Proximal end Right middle bronchus internal diameter; M-RMBD: Intermedius Right middle bronchus internal diameter; TL: Tracheal length; LBL: Left main bronchus length; RBL: Right main bronchus length; RMBL: Right middle bronchus length; LA: Left bronchial angle; RA: Right bronchial angle; RUA: Right upper bronchial angle.</p><p>Tracheobronchial Parameters.</p

Additional file 6 of Development and validation of a risk nomogram for postoperative acute kidney injury in older patients undergoing liver resection: a pilot study

Additional file 6. Sensitivity and specificity values of risk score model

Additional file 2: of MiR-190a potentially ameliorates postoperative cognitive dysfunction by regulating Tiam1

Figure S1. The detailed time line of the euthanization of study animals. According to the protocol, all mice were euthanized before obtaining hippocampal tissue. All mice were deeply anesthetized based on several signs (see Methods part). Then the mice were decapitated 24 h after operation, brains were instantly dissected on ice, and the hippocampal tissues were obtained and stored in liquid nitrogen. Figure S2. Volcano plot of miRNA expression in replication cohort. This dataset (GSE95070) was downloaded from the GEO database. Figure S3. The results of qRT-PCR for technical replication. Expression level of the most significantly mmu-miR-190a-3p was validated by using real-time PCR assay. Reverse transcription reaction was performed with M-MLV Reverse Transcriptase kit (Takara Code: D2639A) based on the manufacturers’ protocol. Figure S4. WGCNA module-based analysis for genes and miRNAs expression data. The genes and miRNAs expression data of GSE73507 were acquired from GEO database. After the filtering process, 13,241 mRNAs and 546 miRNAs from hippocampus tissue of wild type mice (n = 24) were included for WGCNA analysis. Figure S5. KEGG pathway analyses for mmu-miR-190a-3p highly related genes in red module. We refined 169 genes from red module with a highly connected with mmu-miR-190a-3p (Fig. 2b) and used ClueGO (v. 2.3.4) to decipher the pathways and determine their biological functions. (PPTX 118 kb

Additional file 5 of Development and validation of a risk nomogram for postoperative acute kidney injury in older patients undergoing liver resection: a pilot study

Additional file 5. Summary risk score model and sensitivity/specificity values of the predictors for AKI. Abbreviations: AUC, Area under ROC curve; CKD, Chronic kidney disease; NSAIDs, Non-steroidal anti-inflammatory drugs; ROC, Receiver operating characteristic

Additional file 1 of Development and validation of a risk nomogram for postoperative acute kidney injury in older patients undergoing liver resection: a pilot study

Additional file 1. Patient characteristics and perioperative variables stratified by AKI. Notes: “Vasopressors” in vasoactive agents include ephedrine, epinephrine, dopamine, norepinephrine, and phenylephrine. “Vasodilators” in vasoactive agents include urapidil and nicardipine. Nephrotoxic antibiotics refers to aminoglycoside and sulfonamide antibiotics. Continuous data are shown as medians (quartiles) and compared using Wilcoxon rank-sum test. Categorical variables are shown as frequencies (percentages) and compared using chi-squared test or Fisher’s exact test as appropriate. Abbreviations: AKI, Acute kidney injury; ASA PS: American Society of Anesthesiologists physical score; BMI, Body mass index; CI, Confidential interval; CKD, Chronic kidney disease; eGFR, estimated glomerular filtration rate; LOS, Length of hospital stay; MAP, Mean arterial pressure; NSAIDs, Non-steroidal anti-inflammatory drugs; OR, Odds ratio