Role of mTOR-Regulated Autophagy in Synaptic Plasticity Related Proteins Downregulation and the Reference Memory Deficits Induced by Anesthesia/Surgery in Aged Mice.

Postoperative cognitive dysfunction increases mortality and morbidity in perioperative patients and has become a major concern for patients and caregivers. Previous studies demonstrated that synaptic plasticity is closely related to cognitive function, anesthesia and surgery inhibit synaptic function. In central nervous system, autophagy is vital to synaptic plasticity, homeostasis of synapticproteins, synapse elimination, spine pruning, proper axon guidance, and when dysregulated, is associated with behavioral and memory functions disorders. The mammalian target of rapamycin (mTOR) negatively regulates the process of autophagy. This study aimed to explore whether rapamycin can ameliorate anesthesia/surgery-induced cognitive deficits by inhibiting mTOR, activating autophagy and rising synaptic plasticity-related proteins in the hippocampus. Aged C57BL/6J mice were used to establish POCD models with exploratory laparotomy under isoflurane anesthesia. The Morris Water Maze (MWM) was used to measure reference memory after anesthesia and surgery. The levels of mTOR phosphorylation (p-mTOR), Beclin-1 and LC3-II were examined on postoperative days 1, 3 and 7 by western blotting. The levels of synaptophysin (SYN) and postsynaptic density protein 95 (PSD-95) in the hippocampus were also examined by western blotting. Here we showed that anesthesia/surgery impaired reference memory and induced the activation of mTOR, decreased the expression of autophagy-related proteins such as Beclin-1 and LC3-II. A corresponding decline in the expression of neuronal/synaptic, plasticity-related proteins such as SYN and PSD-95 was also observed. Pretreating mice with rapamycin inhibited the activation of mTOR and restored autophagy function, also increased the expression of SYN and PSD-95. Furthermore, anesthesia/surgery-induced learning and memory deficits were also reversed by rapamycin pretreatment. In conclusion, anesthesia/surgery induced mTOR hyperactivation and autophagy impairments, and then reduced the levels of SYN and PSD-95 in the hippocampus. An mTOR inhibitor, rapamycin, ameliorated anesthesia/surgery-related cognitive impairments by inhibiting the mTOR activity, inducing activation of autophagy, enhancing SYN and PSD-95 expression.

Can dexmedetomidine reduce atrial fibrillation after cardiac surgery? A systematic review and meta-analysis.

PURPOSE: Cardiac surgery patients always present with atrial fibrillation (AF) after admission to the intensive care unit, leading to high mortality and lengthy hospitalization. Dexmedetomidine (DEX) is a popular medication used for sedation in the intensive care unit; however, whether it can reduce AF needs to be analyzed. MATERIALS AND METHODS: Three primary databases, Medline, Embase (Ovid SP) and the Cochrane Central Register of Controlled Trials (CENTRAL), were searched. All English language and randomized control designed clinical publications comparing DEX to control medicines for sedation after elective cardiac surgery were included. Two independent colleagues conducted the data extraction and quality assessments. The subgroup analysis was performed according to the medicine used, age, AF history, and whether previous beta-blocker premedication and cardiopulmonary bypass (CPB) were applied. The overall incidence of AF was analyzed. RESULTS: A total of 1,295 patients in nine studies met the selection criteria among 2,587 studies screened from the database. After quantitative synthesis, our results revealed that the DEX group was not associated with a decreased incidence of AF compared with the placebo (risk ratio [RR] 0.76, 95% CI 0.37, 1.55, P=0.44) and morphine groups (RR 0.86, 95% CI 0.56, 1.31, P=0.48). Subgroup analysis also indicated that the DEX vs propofol comparison exhibited no difference: 1) for patients of age >60 years (P=0.69) or ≤60 years (P=0.69); 2) under CPB surgery (P=0.45) or without CPB surgery (P=0.88); 3) with beta-blocker premedication (P=0.32) or without beta-blocker premedication (P=0.90); and 4) with AF history (RR 1.07, 95% CI 0.85, 1.36, P=0.57) or without AF history (P=0.30). CONCLUSION: This meta-analysis revealed that DEX could not reduce the incidence of AF compared to control medicines following cardiac surgery. DEX may have an increased influence on AF occurrence if patients had a history of AF. However, cautious interpretation should be made due to high clinical heterogeneity.

Does dexmedetomidine have an antiarrhythmic effect on cardiac patients? A meta-analysis of randomized controlled trials.

BACKGROUND: Cardiac surgery patients often experience several types of tachyarrhythmias after admission to the intensive care unit (ICU), which increases mortality and morbidity. Dexmedetomidine (DEX) is a popular medicine used for sedation in the ICU, and its other pharmacological characteristics are gradually being uncovered. PURPOSE: To determine whether DEX has an antiarrhythmic effect after cardiac surgery. METHODS: The three primary databases MEDLINE, Embase (OVID SP) and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched, and all English-language and randomized control-designed clinical publications comparing DEX to control medicines for sedation after elective cardiac surgery were included. Two colleagues independently extracted the data and performed other quality assessments. A subgroup analysis was performed according to the different medicines used and whether cardiopulmonary bypass (CPB) was applied. All tachyarrhythmias that occurred in the atria and ventricles were analyzed. RESULTS: A total of 1295 patients in 9 studies met the selection criteria among 2587 studies that were screened. After quantitative synthesis, our results revealed that the DEX group was associated with a lower incidence of ventricular arrhythmia (VA, OR 0.24, 95% CI 0.09-0.64, I2 = 0%, P = 0.005) than the control group. Subgroup analysis did not reveal a significant difference between the DEX and propofol subgroups (OR 0.13, 95% CI 0.03-0.56, I2 = 0%, P = 0.007). Additionally, no difference in the incidence of atrial fibrillation (AF) was observed regardless of the different control medicines (OR 0.82, 95% CI 0.60-1.10, I2 = 25%, P = 0.19) or whether CPB was applied. CONCLUSIONS: This meta-analysis revealed that DEX has an antiarrhythmic effect that decreases the incidence of VA compared to other drugs used for sedation following cardiac surgery. DEX may not have an effect on AF, but cautious interpretation should be exercised due to high heterogeneity.