Xuechao Hao

Propofol inhibits inflammatory cytokine-mediated glutamate uptake dysfunction to alleviate learning/memory impairment in depressed rats undergoing electroconvulsive shock.

Electroconvulsive therapy (ECT) is an effective treatment for major depression, but can result in memory impairment. Several studies have shown that anesthetic propofol can alleviate the impairment of memory induced by ECT. However, the underlying molecular mechanisms remain unclear. We aimed to investigate the effects of propofol and electroconvulsive shock (ECS, analog of ECT in animals) on hippocampal inflammatory cytokines and glutamate uptake in depressed rats. The chronic unpredictable mild stress (CUMS) procedure was adopted to establish a model of depression. Sixty adult Sprague-Dawley rats were randomly divided into 5 groups with the following assignments (n=12 for each group): group C: control group without treatment; group D: CUMS+sham ECS; group DE: CUMS+ECS; group DP: CUMS+propofol (80 mg/kg, i.p.); group DPE: CUMS+propofol (80 mg/kg, i.p.)+ECS. Sucrose preference test and Morris water maze were used to assess behavioral changes. Hippocampal glutamate levels were measured with high performance liquid chromatography and the expression levels of IL-1β, TNF-α, GLAST and GLT-1 was quantificational analyzed by real time PCR or Western Blotting. The results demonstrated that ECS increased the levels of IL-1β and TNF-α, down-regulated the expression of GLT-1, GLAST expression remains stable, heightened the concentration of glutamate in the hippocampus and aggravated learning and memory impairment of depressed rats. Propofol suppressed IL-1β and TNF-α production, up-regulated the expression of GLT-1, decreased the concentration of glutamate in the hippocampus and attenuated the impairment of learning and memory induced by ECS. Propofol alleviate the learning and memory impairment induced by ECS could be partly attributed to its anti-inflammatory effects. This article is part of a Special Issue entitled Brain and Memory.

Nerve Growth Factor Protects the Ischemic Heart via Attenuation of the Endoplasmic Reticulum Stress Induced Apoptosis by Activation of Phosphatidylinositol 3-Kinase

Background: Increased expression of nerve growth factor (NGF) has been found in the myocardium suffered from ischemia and reperfusion (I/R). The pro-survival activity of NGF on ischemic heart has been supposed to be mediated by phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Endoplasmic reticulum (ER) stress, which is activated initially as a defensive response to eliminate the accumulated unfolded proteins, has shown a critical involvement in the ischemia induced myocardial apoptosis. This study was aimed to investigate whether NGF induced heart protection against I/R injury includes a mechanism of attenuation of ER stress-induced myocardial apoptosis by activation of PI3K/Akt pathway. Methods: Isolated adult rat hearts were perfused with a Langendörff perfusion system. Hearts in the Sham group were subjected to 225 min of continuous Krebs-Henseleit buffer (KHB) perfusion without ischemia. Hearts in I/R group were perfused with KHB for a 75-min of equilibration period followed by 30 min of global ischemia and 120 min of KHB reperfusion. Hearts in the NGF group accepted 45 min of euilibration perfusion and 30 min of NGF pretreatment (with a final concentration of 100 ng/ml in the KHB) before 30 min of global ischemia and 120 min of reperfusion. Hearts in K252a and LY294002 groups were pretreated with either a TrkA inhibitor, K252a or a phosphatidyl inositol 3-kinase inhibitor, LY294002 for 30 min before NGF (100 ng/ml) administration. Cardiac hemodynamics were measured from the beginning of the perfusion. Cardiac enzymes and cardiac troponin I (cTnI) were assayed before ischemia and at the end of reperfusion. Myocardial apoptosis rate was measured by TUNEL staining, and expression of glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, total- and phospho-(Ser473)-Akt were assessed by Western blot analyses. Results: NGF pretreatment significantly improved the recovery of post-ischemia cardiac hemodynamics. Reduced creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) activity and cTnI levels, as well as decreased myocardial apoptosis ratio were observed in the NGF group. The improvement of NGF on recovery of cardiac function and alleviation of myocardial injury were completely abolished by K252a or LY294002. GRP78, caspase-12 and CHOP were highly expressed in ischemic myocardium, while NGF significantly inhibited the overexpression of these proteins which were involved in ER stress-induced myocardial apoptosis. NGF pretreatment also induced phosphorylation of Akt. When the activation of PI3K/Akt pathway is blocked by LY294002, the NGF induced suppression of the apoptosis-related proteins expression was reversed. Conclusions: NGF pretreatment may protect the ischemic heart via inhibition of the ER stress-induced apoptosis; this pro-survival effect is mediated by PI3K/Akt pathway.

Ketamine-mediated alleviation of electroconvulsive shock-induced memory impairment is associated with the regulation of neuroinflammation and soluble amyloid-beta peptide in depressive-like rats.

Electroconvulsive therapy (ECT) is an effective treatment for depression, but can result in memory deficits. This study aimed to determine whether ketamine could alleviate electroconvulsive shock (ECS, an analog of ECT in animals)-induced memory impairment and the potential molecular mechanism. Chronic unpredictable mild stress was used to generate animal models of depressive-like symptoms. Sixty adult male Sprague-Dawley rats were randomly divided into the following five groups: control group (group C); depressive-like model group (group D); ECS group (group DE); ketamine+ECS group (group DKE); and ketamine group (group DK). The sucrose preference test and Morris water maze were used to assess behavioral changes. The expression levels of Iba-1, IL-1β and TNF-α were measured by immunohistochemistry and real-time PCR. Enzyme-linked immunosorbent assays were used to detect the levels of soluble Aβ. We found that ECS up-regulated the expression of Iba-1, promoted the release of IL-1β and TNF-α, increased the levels of Aβ1-40 and Aβ1-42 in the hippocampus, and aggravated memory impairment of the depressive-like rats. However, ketamine reversed these ECS-induced molecular changes and effectively attenuated ECS-induced memory impairment. This cognitive protective effect of ketamine may be attributed to its suppression of ECS-induced neuroinflammation and reduction of the levels of soluble Aβ.

Sepsis induced denervation-like changes at the neuromuscular junction.

BACKGROUND The aim of this study was to determine the functional and biochemical changes at the neuromuscular junction (NMJ) induced by sepsis. MATERIALS AND METHODS Male Sprague-Dawley rats were divided into three groups as follows: control, denervation, and sepsis. The rats were subjected to cecal ligation and puncture (CLP) or tibias nerve transection. NMJ function and the area of end plates were assessed, and the protein level of acetylcholine receptors and axonal neuregulin-1 was evaluated on postoperative days 1, 7, and 14. RESULTS In the control group, the amplitude of compound muscle action potential (CMAP) was 16.51 ± 2.53 mV. In the sepsis group, the amplitude of CMAP decreased, and duration was prolonged on postoperative days 7 and 14 (P < 0.01). Meanwhile, motor conduction velocity decreased significantly (P < 0.01). CMAP was lost in the denervation group. The twitch tension magnitude gradually declined (P < 0.05) in the sepsis group, although it could not be recorded after lesion. Sepsis and denervation upregulated the expression of γ-nicotinic acetylcholine receptor (nAChR) and α7-nAChR in muscle membrane, compared with those in normal NMJ (261.4 ± 26.5 μm(2)). The NMJ area decreased from 254.6 ± 23.8 μm(2) (1 d after CLP) to 275.4 ± 22.6 μm(2) (7 d after CLP) to 322.7 ± 34.4 μm(2) (14 d after CLP). The postsynaptic NMJ had more discrete fragments (3.84 ± 0.6) compared with the control group (2.13 ± 0.4; P < 0.01). After denervation, NMJ underwent fragmentation and the number of discrete fragments increased (5.57 ± 1.2; P < 0.01). NMJ area increased from 254.6 ± 23.8 μm(2) (1 d after CLP) to 275.4 ± 22.6 μm(2) (7 d after CLP) to 322.7 ± 34.4 μm(2) (14 d after CLP). Sepsis induced neuregulin-1 to decrease from 1 d up to 2 wk compared with the control group (P < 0.05). CONCLUSIONS Chronic sepsis has a denervation-like effect on the NMJ, which was indicated by upregulation of heterogeneous nAChRs, the increased area of end plates, and demyelination of the motoneuron axon.

Effects of low-dose ketamine combined with propofol on phosphorylation of AMPA receptor GluR1 subunit and GABAA receptor in hippocampus of stressed rats receiving electroconvulsive shock.

Objectives To investigate the effects of low-dose ketamine combined with propofol on the antidepressant efficacy in stressed rats undergoing electroconvulsive shock (ECS) and its impact on phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit glutamate receptor 1 (GluR1) and &ggr;-aminobutyric acid receptor subunit A (GABAAR). Methods Sprague-Dawley rats were stressed by chronic unpredictable mild stress. Fifty stressed rats were randomly divided into 5 groups (n = 10 per group): depression group (with no application, group D), ECS group (applied with ECS after intraperitoneal injection of isotonic sodium chloride solution, 8 mL/kg, group E), ketamine + ECS group (applied with ECS after intraperitoneal injection of ketamine, 10 mg/kg, group KE), propofol + ECS group (applied with ECS after intraperitoneal injection of propofol, 80 mg/kg, group PE), and ketamine + propofol + ECS group (applied with ECS after intraperitoneal injection of ketamine, 10 mg/kg, and propofol, 80 mg/kg, group KPE). All groups except group D underwent ECS once a day for 7 consecutive days. Sucrose preference test, open-field test, and Morris water maze were performed to assess the depressive behavior. Phosphorylation of GluR1 and GABAAR were evaluated by Western blot. Results Compared with group D, sucrose preference percentage and open-field scores were increased after ECS application in the 4 other groups; rats in group E reported prolonged escape latency and shortened space exploration time, whereas the escape latency were decreased and space exploration time were prolonged in group KPE; the ratio of p-GluR1/p-GABAAR in hippocampus were increased in the 4 other groups. When using group E as control, rats in group KPE exhibited higher sucrose preference percentage and open-field scores; the escape latency was shortened and space exploration time was prolonged in groups KE, PE, and KPE; the ratio of p-GluR1/p-GABAAR in the hippocampus was up-regulated in groups KE and KPE. When compared with groups KE and PE, the rats in group KPE exhibited higher sucrose preference percentage and open-field scores, the escape latency of group KPE was shortened and space exploration time was prolonged, the ratio of p-GluR1/p-GABAAR in the hippocampus of group KEP is between those of groups KE and PE. Conclusions Low-dose ketamine combined with propofol may play a role in enhancing the antidepressant efficacy of ECS in stressed rats, ameliorating the cognitive impairment associated with ECS by balancing the expression of p-GluR1 and p-GABAAR in the hippocampus of stressed rats.

Effect of Low Dose of Ketamine on Learning Memory Function in Patients Undergoing Electroconvulsive Therapy-A Randomized, Double-Blind, Controlled Clinical Study.

Objectives Converging evidence suggests that low doses of ketamine have antidepressant effects. The feasibility and safety of administering low doses of ketamine as adjunctive medication during electroconvulsive therapy (ECT) to enhance ECT efficacy and mitigate cognitive impairment has attracted much attention. This study investigated the effects of low doses of ketamine on learning and memory in patients undergoing ECT under propofol anesthesia. Methods This randomized, placebo-controlled, double-blind study recruited patients with moderate to severe depressive disorders who failed to respond to antidepressants and were scheduled to receive ECT. Participants were randomly assigned to a study group, which received an intravenous administration of 0.3 mg/kg ketamine and then underwent ECT under propofol anesthesia, and a control group, which received isovolumetric placebo (normal saline) and then underwent ECT under propofol anesthesia. The Hamilton Depression Rating Scale was used to assess the severity of depression after ECT. Before and after the ECT course, the Mini-mental State Examination and the Wechsler Memory Scale-Chinese-Revision were used to assess global cognitive and learning and memory functions, respectively. Psychotropic effects were assessed using the Brief Psychiatric Rating Scale. Vital signs and other adverse events were recorded for each ECT procedure. Results Of 132 patients recruited, 66 were assigned to each group; 63 patients in study groups and 64 patients in the control group completed the ECT course during the study. Afterward, the incidence of global cognitive impairment in the control group was higher than it was in the study group. In addition, the decline in the Wechsler Memory Scale-Chinese-Revision scale was greater in the control group than in the study group. The necessary ECT treatment times were shorter in the study group than in the control group (8 [7, 9] vs 9 [8, 10]). No significant escalations of the positive Brief Psychiatric Rating Scale scores or adverse events were observed in the study group when compared with the control group. Conclusions As adjunctive medication, ketamine can attenuate learning and memory impairment, especially for short-term memory, caused by ECT performed under propofol anesthesia. Ketamine can also reduce ECT treatment times during the therapy course without inducing significant adverse effects.

Advanced age enhances the sepsis-induced up-regulation of the γ- and α7-nicotinic acetylcholine receptors in different parts of the skeletal muscles

BACKGROUND The muscle mass decreases with age, leading to frailty and weakness; however, the role of acetylcholine receptors in this process has not been properly studied. In this article, we hypothesize that diaphragmatic as well as peripheral muscle weakness may be caused by the up-regulation of gamma and alpha 7 nicotinic acetylcholine receptors (nAChRs) on muscle cell membranes. METHOD Adult male rats were randomly divided into sham and sepsis groups. Sepsis was induced by cecal ligation and puncture (CLP). Blood specimens and biopsies of tibialis anterior muscle and diaphragm were obtained at 24h post CLP. RESULTS Up-regulation of gamma and alpha 7 nAChRs was detected in both sham and septic groups; however, this response was more robust in septic animals. Compared to tibialis anterior muscle, the diaphragm expressed a higher number of both receptor types. CONCLUSIONS Muscle weakness in old age and sepsis may have common molecular underpinnings. Loss of diaphragmatic strength may explain hypoxia and respiratory failure often encountered in frail elderly.

Propofol ameliorates electroconvulsive shock-induced learning and memory impairment by regulation of synaptic metaplasticity via autophosphorylation of CaMKIIa at Thr 305 in stressed rats

Electroconvulsive therapy (ECT) is an effective treatment for depression, but it can induce learning and memory impairment. Our previous study found propofol (γ-aminobutyric acid (GABA) receptor agonist) could ameliorate electroconvulsive shock (ECS, an analog of ECT to animals)-induced cognitive impairment, however, the underlying molecular mechanisms remain unclear. This study aimed to investigate the effects of propofol on metaplasticity and autophosphorylation of CaMKIIa in stressed rats receiving ECS. Depressive-like behavior and learning and memory function were assessed by sucrose preference test and Morris water test respectively. LTP were tested by electrophysiological experiment, the expression of CaMKIIa, p-T305-CaMKII in hippocampus and CaMKIIα in hippocampal PSD fraction were evaluated by western blot. Results suggested ECS raised the baseline fEPSP and impaired the subsequent LTP, increased the expression of p-T305-CaMKII and decreased the expression of CaMKIIα in hippocampal PSD fraction, leading to cognitive dysfunction in stressed rats. Propofol could down-regulate the baseline fEPSP and reversed the impairment of LTP partly, decreased the expression of p-T305-CaMKII and increased the expression of CaMKIIα in hippocampal PSD fraction and alleviated ECS-induced learning and memory impairment. In conclusion, propofol ameliorates ECS-induced learning and memory impairment, possibly by regulation of synaptic metaplasticity via p-T305-CaMKII.

Propofol Mitigates Learning and Memory Impairment After Electroconvulsive Shock in Depressed Rats by Inhibiting Autophagy in the Hippocampus.

Background The present study explored the effects of propofol on hippocampal autophagy and synaptophysin in depression-model rats undergoing electroconvulsive shock (ECS). Material/Methods The rat depression model was established by exposing Sprague-Dawley rats to stress for 28 consecutive days. Forty rats were assigned randomly into the depression group (group D; no treatment), the ECS group (group E), the propofol group (group P), and the propofol + ECS group (group PE). Open field tests and sucrose preference tests were applied to evaluate the depression behavior; and Morris water maze tests were used to assess the learning and memory function of the rats. Western blotting was used to detect the expression of Beclin-1 and LC3-II/I; and ELISA was applied to assess the expression of synaptophysin. Results Rats in group E and group PE scored higher in the open field and sucrose preference tests compared with those in group D. Furthermore, rats in group E also had a longer escape latency, a shorter space exploration time, and increased expression of Beclin-1, LC3-II/I, and synaptophysin. Compared with group E, rats in group PE possessed a shorter escape latency, a longer space exploration time, reduced expression of Beclin-1, LC3-II/I, and synaptophysin. Conclusions Propofol could inhibit excessive ECS-induced autophagy and synaptophysin overexpression in the hippocampus, thus protecting the learning and memory functions in depressed rats after ECS. The inhibitory effects of propofol on the overexpression of synaptophysin may result from its inhibitory effects on the excessive induction of autophagy.

Electroacupuncture alleviates neuromuscular dysfunction in an experimental rat model of immobilization

Immobilization-related skeletal muscle atrophy is a major concern to patients in Intensive Care Units and it has a profound effect on the quality of life. However, the underlying molecular events for the therapeutic effect of electroacupuncture to treat muscle atrophy have not been fully elucidated. Here we developed an immobilization mouse model and tested the hypothesis that skeletal muscle weakness may be caused by the increased expression of γ and α7 nicotinic acetylcholine receptors (nAChRs) on muscle cell membranes, while electroacupuncture could decrease the expression of γ and α7 nicotinic acetylcholine receptors. Compared with the rats in control, those treated with immobilization for 14 days showed a significant reduction of tibialis anterior muscle weight, muscle atrophy and dysfunction, which was associated with a significant decrease expression of neuregulin-1 and increased expression of γ- and α7-nAChR in tibialis anterior muscle. Electroacupuncture significantly enhanced the expression of neuregulin-1 and alleviated the muscle loss, while diminished the expression of γ- and α7-nAChR. Taken together, the beneficial effect of electroacupuncture may be attributed to suppressing γ- and α7-nAChR production, enhancing neuromuscular function and neuregulin-1 protein synthesis. These results suggest that electroacupuncture is a potential therapy for preventing muscle atrophy during immobilization.