Electroacupuncture pretreatment protects against anesthesia/surgery-induced cognitive decline by activating CREB via the ERK/MAPK pathway in the hippocampal CA1 region in aged rats.

Effective preventive measures against postoperative cognitive dysfunction in older adults are urgently needed. In this study, we investigated the effect of electroacupuncture (EA) on anesthesia and surgery-induced cognitive decline in aged rats by RNA-seq analysis, behavioral testing, Golgi-Cox staining, dendritic spine analysis, immunofluorescence assay and western blot analysis. EA ameliorated anesthesia and surgery induced-cognitive decline. RNA-seq analysis identified numerous differentially-expressed genes, including 353 upregulated genes and 563 downregulated genes, after pretreatment with EA in aged rats with postoperative cognitive dysfunction. To examine the role of CREB in EA, we injected adeno-associated virus (AAV) into the CA1 region of the hippocampus bilaterally into the aged rats to downregulate the transcription factor. EA improved synaptic plasticity, structurally and functionally, by activating the MAPK/ERK/CREB signaling pathway in aged rats. Together, our findings suggest that EA protects against anesthesia and surgery-induced cognitive decline in aged rats by activating the MAPK/ERK/CREB signaling pathway and enhancing hippocampal synaptic plasticity.

[Effects of electroacupuncture pretreatment on long-term postoperative cognitive dysfunction and neuron-inflammation in aged rats].

OBJECTIVE: To observe the effects of electroacupuncture pretreatment on postoperative cognitive dysfunction (POCD), neuronal apoptosis and neuron-inflammation in aged rats. METHODS: Thirty-six male SD rats aged 20 months were randomly divided into sham operation group, model group and electroacupuncture (EA) group, with 12 rats in each group. The POCD rats model was prepared by internal fixation of left tibial fracture. Five days before modeling, EA stimulation (2 Hz/15 Hz, 1 mA, 30 min) was applied to "Zusanli" (ST36), "Hegu" (LI4) and "Neiguan" (PC6) on the unaffected side of rats in the EA group, once a day for consecutive 5 d. The learning and memory abilities of rats were evaluated by water maze test 31-35 days after operation. The apoptosis of hippocampal neurons was observed by Tunel/NeuN double staining. The expressions of high mobility group protein B1 (HMGB1) and phosphorylated (p)-nuclear factor (NF)-κB in microglia cells in hippocampal dentate gyrus were detected by immunofluorescence staining. The expression levels of interleukin (IL)-6 and IL-1ß in the hippocampus were detected by Western blot. RESULTS: Compared with the sham operation group, the escape latency was prolonged (P<0.05); the frequency of crossing the original platform, ratio of the swimming distance and the time in the target quadrant of the Morris water maze were significantly decreased (P<0.05); the apoptosis rate of hippocampal neurons was significantly increased (P<0.05); the expressions of HMGB1 and p-NF-κB in microglia cells in the dentate gyrus and the expression levels of IL-6 and IL-1ß in hippocampus were increased (P<0.05) in the model group. Compared with the model group, the results of the above indexes were all opposite (P<0.05) in the EA group. CONCLUSION: EA preconditioning can regulate hippocampal inflammatory response, alleviate neuronal apoptosis rate and long-term cognitive dysfunction in aged rats with POCD, the mechanisms may be related to the inhibition of microglia HMGB1/NF-κB pathway in hippocampal dentate gyrus.

Electro-Acupuncture Pretreatment Ameliorates Anesthesia and Surgery-Induced Cognitive Dysfunction Via Inhibiting Mitochondrial Injury and nEuroapoptosis in Aged Rats.

Postoperative cognitive dysfunction (POCD) remains one of the most common complications following anesthesia and surgery (AS) in the elderly population. Calcium-mediated mitochondrial injury has been proved to induce cognitive impairment in a variety of neurologic diseases. In the current study we determined whether electro-acupuncture (EA) pretreatment ameliorated AS-induced POCD in aged rats, as well as the underlying mechanism. Eighty SD rats (18 months, male) were randomly assigned into four groups (n = 20): C, C + EA, POCD and EA + POCD. Rats in Group POCD and EA + POCD were subjected to exploratory laparotomy under sevoflurane anesthesia. Rats of Group C + EA and EA + POCD received a 5-day EA stimulation at Hegu, Neiguan and Zusanli acupoints before AS. At 3rd day after AS, open field test along with Morris water maze test were employed to examine the cognitive function of aged rats. Then hippocampal tissues were stripped and hippocampal neuronal amount, expression level of cleaved caspase-9 level, cytochrome c (Cyt C), cleaved caspase-3 level, Bcl-2, Bax, ROS expression level, apoptosis rate, mitochondrial membrane potential (MMP), cytosolic calcium concentration ([Ca2+]c), opening level of mitochondrial permeability transition pore (mPTP) and ultrastructure of hippocampal neurons were detected separately. EA pretreatment inhibited AS-induced cognitive dysfunction. Furthermore, EA pretreatment decreased level of [Ca2+]c, MMP, mPTP, ROS and hippocampal mitochondrial disruption and enhanced neuronal amount. In addition, EA pretreatment notably reduced the AS-induced increased level of cleaved caspase-9, cleaved caspase-3 and expression of Cyt c, Bax/Bcl-2 ratio, as well as neuronal apoptosis rate in aged rats. EA pretreatment ameliorates AS-induced POCD in aged rats, the potential mechanism may be associated with inhibiting calcium overload and ameliorating mitochondrial injury and neuroapoptosis in hippocampal neurons.

Electroacupuncture Pretreatment Ameliorates Anesthesia and Surgery-Induced Cognitive Dysfunction via Activation of an α7-nAChR Signal in Aged Rats.

OBJECTIVE: Postoperative cognitive dysfunction (POCD) after anesthesia and surgery (AS) is a common complication in the elderly population. A cholinergic-dependent signal, the alpha7-nicotinic acetylcholine receptor (α7-nAChR), has been suggested to regulate cognitive processes in a variety of neurologic diseases. In the current study, we determined whether electroacupuncture (EA) pretreatment ameliorates AS-induced POCD in aged rats, as well as the underlying mechanism. METHODS: Male Sprague-Dawley rats (20 months old) were randomly assigned to the following 5 groups (n=12): vehicle; POCD (tibial fracture surgery); EA plus POCD; EA plus POCD and alpha-bungarotoxin (α-BGT); and POCD plus α-BGT groups. Alpha-bungarotoxin (1 µg/kg), a selective antagonist of α7-nAChR, was administrated via intraperitoneal injection before EA. Thirty days post-AS, the Morris water maze and a novel objective recognition test were used to evaluate cognitive function. Neuronal amount, apoptosis, microglial activation, percentage of high mobility group box 1 (HMGB1)- and nuclear factor-κB (NF-κB)-positive microglia, and levels of HMGB-1 downstream factors, including NF-κB, interleukin-6 (IL-6), and IL-1ß, were detected by Nissl staining, immunofluorescence, and Western blot assays. RESULTS: EA pretreatment significantly increased crossing platform times and elevated the time with a novel object, restored the quantity of neurons, decreased TUNEL-positive neurons, alleviated activation of microglia, downregulated expression of HMGB1 and NF-κB in the microglia, and reduced levels of phosphor-NF-κB, IL-6, and IL-1ß 35 days after AS, while α-BGT partially reversed these changes. CONCLUSION: EA pretreatment improved AS-induced POCD in aged rats, and the underlying mechanism may be associated with inhibition of HMGB1-NF-κB via an α7-nAChR signal in the microglia.

Effects of Transcutaneous Electrical Acupoint Stimulation on Postoperative Cognitive Decline in Elderly Patients: A Pilot Study.

BACKGROUND: Postoperative cognitive decline (POCD) in the old ages seriously delays the rapid recovery. Here, we aimed to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS) against POCD in elderly patients undergoing laparoscopic radical colon cancer surgery, as well as the potential mechanism. METHODS: A prospective, single-center, parallel-group, randomized trial was designed. A total of 100 patients (age ≥65 years) undergoing laparoscopic radical resection of colon cancer were involved and randomly divided into TEAS (Group T) and control (Group C) groups. The patients in Group T were performed with percutaneous acupoint electrical stimulation in bilateral Hegu, Neiguan and Zusanli points from 30 minutes before anesthesia induction to the end of surgery. A Z-score based on Mini-Mental State Exam (MMSE) was used to assess the incidence of POCD. The levels of serum IL-6, hs-CRP, CGRP at 0 min before TEAS (T0), 1 h after beginning of surgery (T1) and the end of surgery (T2) were evaluated. RESULTS: Our data showed that the cumulative duration of POCD on postoperative day 2 and 3 in Group T was significantly decreased compared to Group C (P < 0.05). Compared with T0, the levels of serum IL-6, hs-CRP, and CGRP in both Group T and C were statistically elevated at T1 and T2 (P < 0.05). Moreover, the levels of serum IL-6 and hs-CRP were decreased, but the level of CGRP was increased in Group T compared to Group C at T1 and T2 (P < 0.05). CONCLUSION: TEAS is associated with a lower cumulative duration of POCD in elderly patients undergoing laparoscopic radical colon cancer surgery, which may be related to the regulation of inflammatory factors and neuropeptides interacted with gut-brain axis.

Concomitant memantine and Lactobacillus plantarum treatment attenuates cognitive impairments in APP/PS1 mice.

Trimethylamine-N-oxide (TMAO) is a gut microbial metabolite that promotes Alzheimer's disease (AD) progression. Given that probiotics can alleviate AD symptoms by inhibiting the synthesis of TMAO, here we investigated the correlation between TMAO and cognitive deterioration by measuring TMAO levels in the plasma of choline-treated APP/PS1 mice (an AD mouse model) with and without probiotic treatments. We found that declines in L.plantarum in the gut were associated with cognitive impairment. Moreover, 12-weeks of treatment with memantine plus L. plantarum ameliorated cognitive deterioration, decreased Αß levels in the hippocampus, and protected neuronal integrity and plasticity. These effects were accompanied by reductions in TMAO synthesis and neuroinflammation. These experiments demonstrate that L. plantarum augments the beneficial therapeutic effects of memantine treatment in APP/PS1 mice by remodeling the intestinal microbiota, inhibiting the synthesis of TMAO, and reducing clusterin levels. Our results thus highlight intestinal microbiota as a potential therapeutic target to decrease the risk of AD.

Effect of transcutaneous electrical acupoint stimulation on the EC50 of remifentanil suppressing responses to tracheal extubation in elderly patients.

Transcutaneous electrical acupoint stimulation (TEAS) is a emerging treatment which combines transcutaneous electrical nerve stimulation with traditional acupoint therapy. The present study was aimed to evaluate the effect of TEAS on the effective concentration (EC50) of remifentanil suppressing tracheal extubation response in elderly patients.Fifty-three patients undergoing spine surgery were randomly divided into 2 groups: control group (group C, n = 26) and transcutaneous electrical acupoint stimulation group (group TEAS, n = 27). The EC50 values for remifentanil TCI were determined using sequential method and probit analysis.The remifentanil EC50 of that suppressed responses to extubation during anesthetic emergence was 1.20 ng/mL in group TEAS, a value that was significantly lower than the 1.64 ng/mL needed by patients in group C.The TEAS can enhance the efficacy of remifentanil on suppressing responses to tracheal extubation in elderly patients, the EC50 of remifentanil can reduce approximately 27% compared with group C.

Transcutaneous electrical acupoint stimulation for prevention of postoperative delirium in geriatric patients with silent lacunar infarction: a preliminary study.

PURPOSE: This study aims to investigate the effect of transcutaneous electrical acupoint stimulation (TEAS) on postoperative delirium (POD) in elderly patients with silent lacunar infarct and preliminarily to determine the relationship among TEAS, blood-brain barrier (BBB), neuroinflammation, and POD. PATIENTS AND METHODS: Sixty-four-old patients with silent lacunar infarct were randomly divided into two groups: group TEAS and control group (group C). Patients in the group TEAS received TEAS (disperse-dense waves; frequency, 2/100 Hz) on acupoints Hegu and Neiguan of both sides starting from 30 minutes before induction of anesthesia until the end of surgery, and the intensity was the maximum current that could be tolerated. In group C, electrodes were placed on the same acupoints before anesthesia induction, but no current was given. At 0 minute before the treatment of TEAS, 30 minutes after skin incision, and after completion of surgery (T1-3), blood samples were extracted to detect the concentration of serum tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9), and S100ß. We assessed patients for delirium and coma twice daily in the first 3 postoperative days using the Confusion Assessment Method for the intensive care unit and the Richmond Agitation-Sedation Scale. RESULTS: This study preliminarily suggests that TEAS can reduce the development of POD in elderly patients with silent lacunar infarction (6.3% vs 25.0%; P=0.039). Compared with the baseline value at T1, the serum concentrations of IL-6, TNF-α, MMP-9, and S100ß were significantly increased at T2-3 in both the groups (P<0.05). Compared with group TEAS, serum levels of TNF-α and IL-6 were higher at T2-3 and serum levels of MMP-9 and S100ß were higher at T3 in group C (P<0.05). The intraoperative anesthetic consumptions were less in group TEAS than group C. CONCLUSION: TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduce the neuroinflammation by lowering the permeability of BBB.

Effects of preconditioning of electro-acupuncture on postoperative cognitive dysfunction in elderly: A prospective, randomized, controlled trial.

Electro-acupuncture is a burgeoning treatment using the needle inserting into the body acupoints and the low-frequency pulse current being electrified by an electric acupuncture machine. This study was designed to evaluate the effects of preconditioning of electro-acupuncture on postoperative cognitive dysfunction in elderly.Ninety patients scheduled spine surgery were randomly assigned into 2 groups using a random number table: control group (group C) and electro-acupuncture group (group EA). In group EA, electro-acupuncture was applied on Baihui, Dazhui, and Zusanli acupoints 30 minutes before anesthesia. At 0 minute before treatment of electro-acupuncture, 1 hour after skin incision and surgery completed (T1-3), blood samples were taken for detection of interleukin (IL)-6, IL-10, and S100ß by enzyme-linked immunosorbent assay. The total dose of remifentanil and propofol during surgery were recorded. Mini-Mental State Examination was applied to evaluate the cognitive function of patients at 1 day before surgery and 7th and 30th day after surgery.The results showed that compared with group C, score of MMSE increased after surgery, the serum concentration of IL-6, IL-10, and S100ß decreased at 1 hour after skin incision, and surgery completed in group EA. Moreover, the total dose of remifentanil and propofol reduced during surgery in group EA.The present study suggests that preconditioning of electro-acupuncture could improve the postoperative cognitive function, and the reduction of inflammatory reaction and brain injury may be involved in the mechanism.

Effects of nimodipine on postoperative delirium in elderly under general anesthesia: A prospective, randomized, controlled clinical trial.

Nimodipine is a clinical commonly used calcium antagonistscan lowering the apoptosis rate of hippocampal neuron to reduce the incidence of postoperative cognitive dysfunction (POCD). This study was designed to evaluate the effects of nimodipine on postoperative delirium in elderly under general anesthesia.Sixty patients shceduced spine surgery under general anesthesia were randomly assigned into 2 groups using a random number table: control group (Group C) and nimodipine group (Group N). In Group N, nimodipine 7.5 µg/(kg × h) was injected continually 30 minutes before anesthesia induction, while the equal volume of normal saline was given in Group C. At 0 minute before injection, 0 minute after tracheal intubation, 1 hour after skin incision and surgery completed (T1-4), blood samples were taken from the radial artery and jugular bulb for blood gas analysis. Cerebral oxygen metabolism-related indicators were calculated at the same time. Concentration of S100ß and glial fibrillary acidic protein (GFAP) were tested by ELISA. The incidence of postoperative delirium within 7 days after surgery was recorded.Cerebral oxygen metabolism-related indicators fluctuationed in the normal range in 2 groups at different time points and the difference were not statistically significant. Compared with Group C, S100ß and GFAP decreased and incidence of postoperative delirium reduced at T3-4 in Group N, the difference was statistically significant (P<.05).The present study suggests that nimodipine can reduce the development of postoperative delirium in elderly patients under general anesthesia, the reduction of brain injury and improvement of cerebral oxygen metabolism may be involved in the mechanism.