|Year : 2022 | Volume
| Issue : 2 | Page : 87-92
Electroacupuncture relieves postoperative cognitive dysfunction in elderly rats via regulating amp-activated protein kinase autophagy signaling
Cong Niu1, Meihua Zhu1, Jiamin Zhang1, Chenye Zhang1, Weiqian Tian2
1 Department of Anesthesiology, The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
2 Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
|Date of Submission||17-Dec-2021|
|Date of Decision||10-Feb-2022|
|Date of Acceptance||05-Mar-2022|
|Date of Web Publication||28-Apr-2022|
Dr. Weiqian Tian
Department of Anesthesiology, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155, Hanzhong Road, Qinhuai District, Nanjing, Jiangsu 210004
Source of Support: None, Conflict of Interest: None
Postoperative cognitive dysfunction (POCD) is a common complication after surgery in elderly patients. Electroacupuncture (EA) has been reported to relieve POCD in animal models, but the mechanism remains fully elucidated. The objective of this work was to clarify whether EA could alleviate POCD via regulating autophagy. In this study, aged rats were assigned into 4 groups: control, surgery (rats underwent exploratory laparotomy to induce POCD), EA + S (rats received EA pre-stimulation before surgery), and EA + S + Chloroquine (CQ) (rats were intraperitoneally injected with CQ before EA stimulation and then underwent surgery). The cognitive function of rats was assessed by Morris Water Maze (MWM) test after surgery, and autophagy in hippocampal tissues of rats was evaluated by western blotting and transmission electron microscope. Results indicated that the MWM test revealed that rats showed reduced platform crossing and increased total swimming distance after surgery. However, this impaired spatial memory was improved by EA and EA plus CQ pre-treatment. Besides, the surgery caused an increased expression in LC3II, Beclin-1, AMP-activated protein kinase (AMPK), and p-AMPK in hippocampal tissues of rats, while EA and EA plus CQ pre-treatment also reversed this effect. In addition, the surgery-induced increased amount of autophagic vesicles in hippocampal tissues of rats was reduced by EA and EA plus CQ pre-treatment. In conclusion, EA pre-stimulation could effectively attenuate cognitive impairment in aged rats with POCD via inhibiting AMPK signaling-mediated autophagy.
Keywords: Autophagy, electroacupuncture, postoperative cognitive dysfunction
|How to cite this article:|
Niu C, Zhu M, Zhang J, Zhang C, Tian W. Electroacupuncture relieves postoperative cognitive dysfunction in elderly rats via regulating amp-activated protein kinase autophagy signaling. Chin J Physiol 2022;65:87-92
|How to cite this URL:|
Niu C, Zhu M, Zhang J, Zhang C, Tian W. Electroacupuncture relieves postoperative cognitive dysfunction in elderly rats via regulating amp-activated protein kinase autophagy signaling. Chin J Physiol [serial online] 2022 [cited 2022 Jul 1];65:87-92. Available from: https://www.cjphysiology.org/text.asp?2022/65/2/87/344166
| Introduction|| |
Postoperative cognitive dysfunction (POCD) is a common disorder after surgery, which seriously threatens the quality of life of patients, especially the elderly. POCD is a complication characterized by an impairment affecting memory, orientation, attention, consciousness, and judgment, accompanied by a range of negative outcomes, such as mood and personality changes that occurs after surgery. Accumulating evidence reveals that approximately one-quarter of older adults who undergo major surgery experience identifiable cognitive decline, with 50% of these patients will suffer a permanent functional impairment. Although the best treatment for POCD is prevention, early identification, and management of potential perioperative risk factors, there is still a lack of effective treatment for POCD that has already occurred.
Acupuncture is a conventional therapeutic technique in Traditional Chinese Medicine. So far, acupuncture has been developed for thousands of years and has made many contributions to health and medical treatment. Electroacupuncture (EA) is an electrically driven acupuncture, in which a needle inserted into an acupoint is connected to a trace pulse current with the purpose of generating electric and needling stimulation. In recent years, accumulating studies reported the beneficial role of EA in preventing cognitive impairment in animal models through multiple mechanisms. For instance, Liu et al. found that EA could relieve propofol-induced cognitive impairment in Sprague–Dawley (SD) rats through an opioid receptor-independent mechanism. In aged POCD rats, EA was demonstrated to alleviate cognitive dysfunction via increasing α7-nicotinic acetylcholine receptors expression and suppressing inflammatory pathways. Besides, the consistent result was observed by another study, which reported that EA reduced astrocyte number and oxidative stress in aged rats with surgery-induced cognitive dysfunction. All these studies indicated the potential therapeutic value of EA for treating POCD, but the underlying mechanisms remain to be totally understood.
Although the pathogenesis and therapeutic mechanisms of POCD have not yet been completely elucidated, neuroinflammation, oxidative stress, and autophagy disorder have been proposed as the underlying biological basis of POCD. Autophagy is a fundamental lysosomal process that degrades long-lived or misfolded proteins and damaged organelles and has been found to regulate aging-related diseases including Alzheimer's disease (AD), stroke, and POCD., LC3II is an important substance involved in capturing organelles in the process of autophagy, and LC3II/LC3I has become a gold indicator for detecting autophagy. Beclin-1 is another key protein involved in the autophagy process, which is widely used as quantitative index of autophagy activity. It is generally well known that autophagy can be regulated by AMP-activated protein kinase (AMPK) and autophagy is promoted after AMPK being phosphorylated, which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis., Importantly, EA has been implicated to ameliorate cerebral ischemia-reperfusion injury via inhibiting autophagy.,, However, whether EA exerted its protective effect against POCD via regulating autophagy has not been elucidated.
The aim of the present study was to investigate the effect of EA preconditioning on relieving cognitive impairment in a POCD rat model induced by abdominal exploratory laparotomy, as well as clarifying whether autophagy signaling was involved in this effect.
| Materials and Methods|| |
Animals and grouping
Animal experiments in this study were approved by the Ethics Committee of the Second Affiliated Hospital of the Nanjing University of Chinese Medicine (IACUC-20210510-18). The elderly (20–22 months aged) male SD rats were housed in standard cages in a 12 h light/dark cycle with controlled temperature and humidity and can be access to water and food freely. All experimental rats were acclimated for 3 days before conducting experiments. Rats were randomly assigned into 4 groups (n = 5 per group): Control, Surgery, EA + S (EA + Surgery) and EA + S + Chloroquine (CQ). CQ was used as an inhibitor of autophagy. Rats in the surgery group underwent abdominal exploratory laparotomy; rats in EA + S group received 5 days EA pre-stimulation and then underwent exploratory laparotomy; rats in EA + S + CQ group was intraperitoneally injected with 25 mg/kg CQ (MedChemExpress; #HY-17589A) before EA stimulation every day and then underwent exploratory laparotomy.
Rats in EA + S and EA + S + CQ were pre-stimulated with EA once a day for 5 days before surgery. EA stimulation was applied to the Governor Vessel acupoints of “Dazhui” (GV14) and “Baihui” (GV20) as described previously. The “Dazhui” point was stabbed obliquely and the “Baihui” point was stabbed flat to a depth of about 0.7 inch. EA treatment is a pattern of sparse to dense wave alternating stimulation pulses, with repeats of dense wave: 6.25 Hz, 1.0 mA, time 2.08 s; sparse wave: 3.85 Hz, 1.0 mA, time 1.28 s, and each EA treatment lasted for 30 min, according to the previous study.
The abdominal exploratory laparotomy was performed to induce cognitive dysfunction in elderly rats. After completing the 5 days EA pre-stimulation or not, the rats were fasted on the night of the 5th day, and exploratory laparotomy was performed on the 6th day. Briefly, the rats were anesthetized by intraperitoneal injection of 5% chloral hydrate at a dose of 0.5 ml/100 g, and then an incision with a length of about 3–5 cm was made in the midline of the rat's abdomen. After opening the abdominal wall of rats, a probe was inserted into the abdominal cavity to probe the liver, spleen, stomach, left kidney, right kidney, small intestine, and colon in turn. The wound was sutured with silk and covered with a sterile dressing, the incision was infiltrated with 0.25% ropivacaine to relieve the surgery-associated pain. The rats were returned to their original cages after they were fully awake, free to eat and drink, and disinfected with iodophor every day after the operation. The rats in the control group were injected with chloral hydrate only, and no laparotomy was performed.
Morris water maze
All rats were subjected to the MWM experiment for 5 consecutive days prior to surgery. The experiments were performed in a dark room with constant temperature. The water maze was circular, 150 cm in diameter and 30 cm in height, filled with 25 cm depth of water at a constant temperature of 24°C–26°C. A transparent platform was placed 1.5 cm below the central water surface in one quadrant (the water maze was divided into four quadrants: NE, SE, SW, and NW), and before each swimming experiment, rats were placed on the platform for 30 s in a randomized order, and then placed gently into the water from a prerandomized entry point. All rats were trained as above 3 times a day, and after the third swim, they were returned to the cage and placed under an electric heater for 10 min. The rats were subjected to an inverted water maze experiment 3 days after surgery, in which the transparent platform was placed in the center of the quadrant opposite to the preoperative one and hidden under the water surface, and received 3 consecutive swimming sessions as before. The swimming process of the rats was recorded by a camera placed directly above the water maze, and the water maze software system could analyze the number of times crossing the platform area (platform crossing) and the total swimming distance (total distance), which reflected the learning memory ability of the animals. After the last MWM experiment, the rats were executed by intraperitoneal injection of 5% chloral hydrate 0.5 ml/100 g and cervical dislocation, and the hippocampal tissue was isolated from the brain on ice.
The total protein from isolated hippocampal tissues was homogenized using radio-immunoprecipitation assay buffer (Sigma) and the protein concentration of each sample was determined by a bicinchoninic acid protein kit (Thermo Fisher). Equal amount of the protein samples was resolved in 12% SDS-PAGE and then transferred to the polyvinylidene difluoride membrane. Nonspecific bindings to the membrane were blocked with 5% nonfat milk at room temperature. After that, the membranes were probed with primary antibodies overnight at 4°C, followed by being incubated for 2 h at room temperature with secondary horseradish peroxidase-conjugated secondary antibody (goat anti-rabbit Immunoglobulin G; Abcam; 1:10,000). Immunoreactivity was visualized using Super Signals West Pico (Thermo Fisher) and the expression of target proteins was quantified by Image J software normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Primary antibodies utilized in this study included LC3 (ProteinTech; 1:5000), Beclin-1 (ProteinTech; 1:5000), AMPK (AMPK; Abcam; 1:5000), phosphorylated (p)-AMPK (Abcam; 1:5000), and GAPDH (Abcam; 1:10,000).
Transmission electron microscope
The isolated hippocampal tissues were embedded in Epon after being dehydrated with a graded series of ethanol. The thin sections were stained with 2% uranyl acetate and lead citrate. The transmission electron microscope (TEM) was carried out using a HITACHI, H-7500 TEM (HITACHI, Japan).
All data has been confirmed to be normally distributed by using the Shapiro–Wilk normality test. The groups were compared by one-way ANOVA using GraphPad Prism software (GraphPad, version 8.0). All of the data were shown as the mean ± standard deviation, and the difference was considered statistically significant when P < 0.05.
| Results|| |
Electroacupuncture and electroacupuncture + autophagy inhibitor attenuates cognitive dysfunction of aged rats following surgery
The rat model of POCD was established by abdominal exploratory laparotomy in elderly male rats and then MWM was performed to evaluate the spatial memory of rats. [Figure 1]a illustrates the representative trace graphs of rats in each group in the MWM test. Results showed that, when compared with the control group, rats in the surgery group showed significantly decreased platform crossing [Figure 1]b and increased total swimming distance [Figure 1]c, indicating the impairment in spatial memory. On the contrary, rats in EA + S and EA + S + CQ group exerted considerably enhanced platform crossing and decreased total swimming distance [Figure 1]b and [Figure 1]c. These data revealed that the exploratory laparotomy caused a cognitive dysfunction in aged rats and this cognitive impairment was alleviated by EA preconditioning with autophagy inhibition or not.
|Figure 1: Electroacupuncture attenuates cognitive dysfunction of aged rats following surgery. (a) Representative trace graphs of rats in each group in MWM test. (b and c) The platform crossing and total swimming distance of rats in each group in MWM test. Sample number (n) = 5. ***P < 0.001 versus control; #P < 0.05, ##P < 0.01 and ###P < 0.001 versus surgery. EA: Electroacupuncture; S: Surgery; CQ: Chloroquine; MWM: Morris Water Maze.|
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Electroacupuncture reduces the expression of LC3 II, Beclin-1, and AMP-activated protein kinase in hippocampal tissues of aged rats with postoperative cognitive dysfunction
Next, to clarify the effect of EA pre-stimulation on autophagy signaling, the expression of proteins involved in AMPK-mediated autophagy signaling in hippocampal tissues of rats was assessed. As shown in [Figure 2], the surgery operation caused a significant increase in the expression of LC3II, Beclin-1, AMPK, and p-AMPK in hippocampal tissues of aged rats, revealing the occurrence of autophagy. Whereas, these proteins' expression in the surgery group was remarkably reduced by EA pre-stimulation and EA + CQ pre-treatment [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d, [Figure 2]e. The above results demonstrated the induction of autophagy caused by POCD, which was inhibited by EA pre-stimulation.
|Figure 2: Electroacupuncture reduces the expression of LC3 II, Beclin-1 and AMP-activated protein kinase in hippocampal tissues of aged rats with postoperative cognitive dysfunction. (a-e) The expression of proteins involved in autophagy in the hippocampal tissues of rats in each group was measured by western blotting. Sample number (n) =5. ***P < 0.001 versus control; #P < 0.05, ##P < 0.01 and ###P < 0.001 versus surgery. EA: Electroacupuncture, S: Surgery, CQ: Chloroquine.|
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Electroacupuncture inhibits autophagy in hippocampal tissues of aged rats with postoperative cognitive dysfunction
Finally, the formation of autophagic vesicles in hippocampal tissues of rats was measured by ultra-structural analysis using TEM. As illustrated in [Figure 3], there was an obvious more amount of autophagic vesicles in the hippocampal tissues of rats in the surgery group than that in the control group. However, upon EA and EA + CQ pre-treatment, the amount of autophagic vesicles in rats who underwent surgery was markedly reduced, suggesting that EA preconditioning could effectively inhibit autophagy in the hippocampal tissues of rats with POCD.
|Figure 3: Electroacupuncture inhibits autophagy in hippocampal tissues of aged rats with postoperative cognitive dysfunction. The amount of autophagic vesicles in the hippocampal tissues of rats in each group was observed by transmission electron microscope (magnification ×5000 and ×10,000). Sample number (n) = 5. EA: Electroacupuncture, S: Surgery, CQ: Chloroquine.|
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| Discussion|| |
It is well known that the incidence of POCD is high in elderly patients. In the present study, our results revealed that EA pre-stimulation effectively improved the cognitive function of aged rats with POCD. Moreover, we found that the molecular mechanisms underlying the effectiveness of EA may be related to the inhibition of AMPK signaling-mediated autophagy.
The exploratory abdominal surgery in aged animals is known to produce memory impairments and is widely employed to establish the POCD model. In this study, the MWM test showed that the surgery-induced learning and memory dysfunction in rats, as manifested by decreased platform crossing and increased total swimming distance. This result was consistent with previous studies, indicating the establishment of POCD model using aged rats., Furthermore, we found that the pre-stimulation of EA significantly improved the spatial memory of rats, suggesting that EA effectively alleviated POCD in aged rats. In the past decade, acupuncture, as one of the complementary alternative medicine techniques, has shown clinically neuroprotective effects in patients with cognitive impairment.,,, A random controlled trial in AD patients showed that acupuncture was safe, well tolerated and effective in improving the cognitive function and global clinical status of AD. Another clinical trial revealed that acupuncture could improve cognitive function in patients with mild cognitive impairment via increasing connectivity between cognition-related regions. In addition, the effectiveness of EA for cognitive improvement in AD and POCD animals models was also been confirmed. For example, in the AD rat model, EA exerted effective effect on improving cognitive deficits. EA attenuated cognition impairment via anti-neuroinflammation in an AD animal model. In the aged rat POCD model, EA was reported to alleviate POCD by inhibiting hippocampal neuroinflammation. Taken together, the results from this study and others supported the effectiveness of EA in protecting against cognitive impairment.
Autophagy disorders have been largely studied and are closely related to a variety of neurodegenerative diseases including POCD, which is characterized by cognitive impairment., Autophagy is a cleaning process by which cells remove damaged macromolecules and organelles through the formation of autophagosome, thereby maintaining cellular homeostasis. While decreased immune function in the aging brain, combined with attacks from “dangerous challenges” such as surgery, can lead to changes in important pathways that regulate autophagy in microglia, resulting in a variety of aging phenotypes. In animal models, autophagy has been reported to play a role in cognitive dysfunction, but the specific effect was controversial. Some studies reported that autophagy played a protective effect against POCD and inhibition of autophagy increased the severity of cognitive impairment,,, while other studies reported the opposite results.,, In the present study, we found that rats with POCD exerted enhanced expression of LC3II, Beclin-1, AMPK and p-AMPK along with increased formation of autophagic vesicles in hippocampal tissues. LC3II and Beclin-1 are known to be the autophagic markers and AMPK is widely accepted to promote autophagy upon being phosphorylated. Therefore, our results demonstrated the occurrence of autophagy in hippocampal tissues of rats with POCD. We also showed that EA-pre-treatment significantly inhibited autophagy induced by surgery in rats. Intriguingly, EA or acupuncture has been reported to inhibit autophagy, thereby ameliorating brain injury in rats. For example, a recent study showed that EA pre-treatment exerted a neuroprotective effect against cerebral ischemia-reperfusion injury via suppressing autophagy. Consistently, EA was demonstrated to relieve central poststroke pain by inhibiting autophagy in the hippocampus. We, therefore, speculated that EA may exert its protective effect against POCD via inhibiting excessive autophagy in hippocampal tissues of rats. CQ, an inhibitor of autophagy, can inactivate autophagosome-lysosome fusion, thus causing the accumulation of autophagosomes in cell. It has been reported that CQ treatment can elevate the mean number of platform crossings in water maze experiment of rats with cognitive deﬁcits induced by multi-walled carbon nanotubes. Compelling evidence indicates that CQ significantly reduces the time to identify the platform in the MWM experiment in a rat model of traumatic brain injury. In this study, CQ was used to treat rats every day before EA pre-stimulation. We then revealed that the presence of CQ further enhanced the effect of EA on improving cognitive function and inhibiting autophagy of the POCD rat model. However, the usage of CQ could not confirm the involvement of autophagy in the actions of EA, future work using autophagy activators to explore whether activation of autophagy could reverse the effect of EA on POCD will be performed. Additionally, since EA was applied at Governor Vessel, it is also possible the improvement of POCD comes from the recovery in motor activities. More comprehensive research will be carried out in future experiments.
| Conclusion|| |
The current work showed that EA could alleviate POCD in aged rats, and the potential mechanism may relate to inhibition of the AMPK-mediated autophagy in hippocampal tissues. Future studies to investigate other pathways involved in autophagy are necessary to confirm this mechanism.
Financial support and sponsorship
This work was supported by the Hospital-level Project of the Second Affiliated Hospital of Nanjing University of Traditional Chinese Medicine (SEZ202111).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]