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Phosphorylation of Tau Could Induce Postoperative Cognitive Dysfunction of Propofol-Anesthetized Rats

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Phosphorylation of Tau Could Induce Postoperative Cognitive Dysfunction of Propofol-Anesthetized Rats European Review for Medical and Pharmacological Sciences 2017; 21: 3577-3585 Hyperphosphorylation of protein Tau in hippocampus may cause cognitive dysfunction of propofol-anesthetized rats H.-B. ZHENG1, Y.-T. FU2,3, G. WANG4, L.-H. SUN1, Y.-Y. FAN1, T.-W. YANG1 1Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China 2Department of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Changchun, China 3Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, China 4Department of Anesthesiology, Jilin Provence People’s Hospital, Changchun, China Abstract. – OBJECTIVE: We aimed to explore anesthesia or several weeks or months after sur- the effect of hyperphosphorylation of Tau on gery. It is one of the postoperative complica- cognitive function of propofol-anesthetized rats. tions of central nervous system and belongs to MATERIALS AND METHODS: Thirty 2-month- mild neurocognition disturbance, which is often old male Wistar rats weighing 180-220 g were ran- manifested as decreased cognitive abilities, im- domly divided into 3 groups (n=10): group of treat- ing with saline (C group), group of treating with paired memory, personality changes, and men- propofol for 1 hour (P1) and 24 h (P24 group). The tal disorders. In severe conditions patients may cognitive function of rats was tested by Morris wa- even experience dementia1,2. Most patients can ter maze before and 1 h or 24 h after drug admin- self-recover from POCD and generally return istration. The rats were then sacrificed. The pro- to normal within 3 months after surgery. Howe- tein and mRNA expression levels of GSK-3β, total ver, there are still some patients faced with and phosphorylated Tau, cyclin D1, p27kip1 and long-term or permanent cognitive impairment. c-caspase 3 in hippocampus were determined by Western blot and reverse transcriptase-poly- Therefore, POCD has a great destructive effect merase chain reaction (RT-PCR), respectively. on patients’ postoperative recovery and quality RESULTS: Compared with group C, the incuba- of life3,4. At present, it is generally believed that tion period of P1 group and P24 group was pro- POCD is induced by surgery or anesthesia and longed, and the target quadrant retention time formed by a variety of factors. It may be related was shortened (p<0.05). There was no statistical to many factors such as age, type of surgery, difference between P1 and P24 group (p>0.05). anesthetic methods, drugs, hypoxia, hypoten- Immunohistochemistry showed that compared 5 6,7 with group C, p-Tau in hippocampus of P1 group sion, and education level . Researches have and P24 group was highly expressed, with sta- demonstrated that elderly patients over 60 are tistical difference (p<0.05). Western blot and more likely to suffer from cognitive impair- RT-PCR showed that protein and mRNA expres- ment after receiving surgery, while a higher sions of GSK-3β, phosphorylated Tau, cyclin D1 level of education plays a protective role in and c-caspase 3 in hippocampus of P1 and P24 postoperative cognitive function. The relation- groups were up-regulated (p<0.05). CONCLUSIONS: Propofol-induced cognitive ship between anesthetic methods and POCD 8 dysfunction in rats may be related to the hy- remains controversial so far. Literature review perphosphorylation of Tau that causes neuro- shows that spinal anesthesia does not reduce nal cells to re-enter the cell cycle, thus leading the prevalence of POCD compared to general to apoptosis. anesthesia. In recent years, numerous papers9-11 have shown that general anesthetics are one of Key Words: Propofol, Anesthesia, Cognitive function, Tau protein. the definitive factors that affect postoperative cognitive function. Tau protein is a highly soluble microtubu- Introduction le-associated protein which is mainly found in central nervous cells. Tau mainly combi- Postoperative cognitive dysfunction (POCD) nes with tubulin to promote its polymeriza- refers to cognitive decline that occurs during tion to form microtubules, which are impor- Corresponding Author: Yantao Fu, MD; e-mail: [email protected] 3577 H.-B. Zheng, Y.-T. Fu, G. Wang, L.-H. Sun, Y.-Y. Fan, T.-W. Yang tant structures that maintain the integrity of Morris Water Maze Test the neural cytoskeleton and the transport of substances in axons17. When Tau protein is ab- Positioning Navigation Training normally phosphorylated, glycosylated or ubi- (Acquired Training) quitinated, it loses its stabilizing effect on the Rats were put into the water pool with their microtubules, while can make the nerve fibers heads toward the water in a random position lose their normal biological functions. Neuro- (east, west, south and north). The time each rat fibrillary tangles caused by abnormally pho- used to find the platform was recorded as the sphorylated Tau protein are considered to be time to escape from the incubation period. If a one of the major pathogenesis of Alzheimer’s rat failed to find a platform within 60 s, it could disease (AD) or protein-related diseases. In- to be guided to the platform where it was kept for vestigations18-20 have shown that general ane- 10 s, and the time (escape latency) was recorded sthetics can cause abnormal phosphorylation as 60 s. Each rat was trained four times a day of Tau protein in the hippocampus, which is (four quadrants in each of the east, west, south, closely related to degenerative changes in cen- and north) and trained for 5 consecutive days. tral nervous system21,22, suggesting that the This study was approved by the Animal Ethics abnormal phosphorylation of Tau protein cau- Committee of Jilin University Animal Center.. sed by general anesthetics is one of the major causes of POCD. Nykanen et al23 suggested Space Exploration Training that activation of GABAA receptor could indu- After the positioning navigation training, the ce the activation of cyclin-dependent kinase 5 platform was removed, and the rats were placed (Cdk5) and reduce the binding of Tau protein into the water from the target quadrant. The time to protein phosphatases-2A (PP2A), which may that the rat stayed in the target quadrant within change the degree of phosphorylation of Tau 60 s and the number of times it entered the pla- protein. However, whether the high level of tform area were recorded. Tau protein phosphorylation after activation of GABAA receptors can be reversed or reduced Dosage Administration by its antagonists or inverse agonists, has not C Group: tail vein injection of normal saline been elucidated yet. (3.0 mL/kg); P1 Group: tail vein injection of pro- In this study, rats were anesthetized with pofol (30 mg/kg); P24 group: tail vein injection propofol to observe the expression levels of of propofol (30 mg/kg). Propofol was injected phosphorylated Tau (p-Tau) and total protein slowly at 15 mg/kg via the tail vein until the Tau (Tau-5) in the hippocampus. We aimed at rat’s righting reflex disappeared, followed by exploring the effects of Tau hyperphosphoryla- injection for 30 min at a speed of 30 mg/kg/h. tion on cognitive function of propofol-anesthe- The total amount was 30 mg/kg. Rats were kept tized rats. with their spontaneous breathing when admini- stered with drug. After awaking from the ane- sthesia, rats were placed in the cage alone and allowed to free drink. Materials and Methods Quadratic Behavioral Testing Experimental Animals and Grouping (Morris Water Maze Test) 30 healthy male adult Wistar rats of speci- In group C, the secondary water maze was trai- fic-pathogen-free (SPF) grade, with a weight of ned 1 h after injection of saline. In the P1 group, 180-220 g, were selected in our experiment. 5 the second water maze training was performed 1 rats were put in one cage, with quiet breeding h after the injection of propofol. In the P24 group, environment, 12 h lighting/12 h darkness, 22- the second water maze training was performed 24 24°C of room temperature, 55% of humidity, hours after the injection of propofol. free drinking water, and daily replacement lit- ter. Using a random number table method, they Immunohistochemical Staining were randomly divided into 3 groups (n = 10): The tissue slides were subjected to normal saline group (C group), 1 h of propofol-anesthe- gradients of ethanol, washed with phospha- tized group (P1 group), and 24 h of propofol-a- te-buffered saline (PBS) for 3 times, and incu- nesthetized group (P24 group). bated with phosphor-Thr231 polyclonal antibody 3578 Phosphorylation of Tau could induce postoperative cognitive dysfunction of propofol-anesthetized rats and Tau-5 monoclonal antibody in a 4°C freezer 17 (SPSS Inc., Chicago, IL, USA). Measured for 24 hours. On the next day, the slices were data were expressed as mean±standard devia- washed 3 times with PBS and incubated with the tion. Paired t-test was used to compare beha- secondary antibody for 10 min at room tempera- vioral test data within the group. Differences ture. After that, the slices underwent a series of between groups were analyzed using factorial staining such as diaminobenzidine (DAB) colo- variance analysis. p<0.05 was considered stati- ration, hematoxylin counterstaining and sealed stically significant. with gum. Under the microscope, the positive cells stained by the phosphor-Thr231 antibody showed brownish yellow cell nucleus. Three sli- Results ces were randomly selected from each specimen. 6 random fields with non-overlapped fields in the Behavioral Tests hippocampal CAI region in each slice were se- There was no statistically significant differen- lected for capturing images under an inverted ce in the number of incubation periods and the microscope. number of access to the original platform in each group, (Figure 1A-1C). After drug administra- Western Blot Analysis tion, both of P1 and P24 group showed prolonged Expression level of GSK-3β, total Tau (Tau- incubation period and shortened target quadrant 5), phosphorylated Tau (phosphorylated-Thr231 retention time compared with those before tre- site, phosphor-Thr231), cyclin D1, p27kip1, and atment (p<0.05), (Figure 1B).
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