FG7142 combined with restraint stress induces anxiogenic-like effects via downregulation gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine 1A receptors expression in the hippocampus.

OBJECTIVES: The existing anxiety animal models are susceptible to interference, and no single animal anxiety model can predict the future anxiolytic potential and profile of new putative anxiolytics. Therefore, to find a better anxiety animal model, we used FG7142, a nonselective benzodiazepine inverse agonist. This anxiety animal model was established by intraperitoneal injection of FG7142 combined with restraint stress. METHODS: Adult male C57BL/6J mice (18-20 g) were randomly classified into five groups (n = 10 per group), namely the control, restraint stress, restraint stress + 10 mg/kg FG7142, restraint stress + 20 mg/kg FG7142, restraint stress +30 mg/kg FG7142. The impact on behavior was explored by elevated plus maze, and marble burying test, followed by immunohistochemistry and quantitative real-time PCR enabled the elucidation of the possible mechanism. RESULTS: Compared with the control group and restraint stress group, intraperitoneal injection of FG7142 combined with restraint stress model group was found to induce anxiogenic-like behavior in elevated plus maze and marble burying test. Moreover, relative to the control group, significantly increased expression of c-fos in the hippocampus and amygdala in the model group was evident, whereas the expression of gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine receptor 1A mRNA was significantly decreased in the hippocampus. CONCLUSIONS: These results indicated that FG7142 combined with restraint stress is sufficient to induce anxiety, and its mechanism is associated with downregulation of hippocampal gamma-aminobutyric acid type A receptor subunit alpha1 and 5-hydroxytryptamine 1A receptors.

Protective effect of ginsenoside Rb1 against chronic restraint stress (CRS)-induced memory impairments in rats.

Ginsenoside Rb1 (Rb1) is one of the most active components found in ginseng and provides important benefits to the central nervous system, especially for the improvement of learning and memory. Previous studies demonstrated that Rb1 protected against scopolamine-induced amnesia and exhibited memory-enhancing effects in the SAMP8 mouse model. However, the effects of Rb1 against chronic restraint stress (CRS)-induced cognitive impairments, especially the role of Rg1 on the performance of reward directed instrumental conditioning have not been investigated. In this study, rats were subjected to CRS (6 h/day) for 28 days. Thereafter, behavioural tests including reward-directed instrumental conditioning task (RICT) and the Morris water maze (MWM) task were conducted. Administered of Rb1 (6.75 and 13.5 mg/kg, i.p.) remarkably ameliorated the memory impairments caused by CRS as evident from the results of RICT and MWM task, and this effect was accompanied by noticeable alterations in the levels of oxidative markers (superoxide dismutase, catalase, and lipid peroxidation) in the hippocampus. Additionally, Rb1 reduced the ratio of Bax:Bcl-2 and the expression of cleaved caspase-3 and cleaved caspase-9, increased the levels of synaptophysin (SYP) and postsynaptic density 95 (PSD95) and activated the BDNF/TrkB pathway in the hippocampus. In summary, the present study demonstrated that Rb1 rescues cognitive deficits induced by CRS is partially mediated by antagonizing oxidative stress and apoptosis, improving synaptic plasticity and restoring the BDNF/TrkB signalling pathway. This newly discovered effect of Rb1 sheds light on its applications in the development of therapeutic interventions to alleviate the deleterious effects of chronic stress.

The Protective Effect of Lavender Essential Oil and Its Main Component Linalool against the Cognitive Deficits Induced by D-Galactose and Aluminum Trichloride in Mice.

Lavender essential oil (LO) is a traditional medicine used for the treatment of Alzheimer's disease (AD). It was extracted from Lavandula angustifolia Mill. This study was designed to investigate the effects of lavender essential oil (LO) and its active component, linalool (LI), against cognitive impairment induced by D-galactose (D-gal) and AlCl3 in mice and to explore the related mechanisms. Our results revealed that LO (100 mg/kg) or LI (100 mg/kg) significantly protected the cognitive impairments as assessed by the Morris water maze test and step-though test. The mechanisms study demonstrated that LO and LI significantly protected the decreased activity of superoxide dismutase (SOD), glutathione peroxidase (GPX), and protected the increased activity of acetylcholinesterase (AChE) and content of malondialdehyde (MDA). Besides, they protected the suppressed nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression significantly. Moreover, the decreased expression of synapse plasticity-related proteins, calcium-calmodulin-dependent protein kinase II (CaMKII), p-CaMKII, brain-derived neurotrophic factor (BDNF), and TrkB in the hippocampus were increased with drug treatment. In conclusion, LO and its active component LI have protected the oxidative stress, activity of cholinergic function and expression of proteins of Nrf2/HO-1 pathway, and synaptic plasticity. It suggest that LO, especially LI, could be a potential agent for improving cognitive impairment in AD.

Protective effects of linalool against amyloid beta-induced cognitive deficits and damages in mice.

AIM: Amyloid-beta (Aß)-mediated neurotoxicity plays a pivotal role in the pathogenesis of Alzheimer's disease (AD), which induces oxidative stress and apoptosis. Linalool (LI) is a volatile monoterpene showing positive effect in AD treatment. This study was designed to research the protective effect of LI against neurotoxicity and cognitive deficits induced by Aß1-40 in mice. MAIN METHODS: Aß1-40 (4µg) solution was injected in the bilateral hippocampus to induce cognitive deficits of mice. The protective effects of LI were evaluated by behavioral tests and the related mechanism was further explored by observing the apoptosis and oxidative stress changes in the hippocampus of mice. KEY FINDINGS: LI (100mg/kg, i.p.) administration significantly improved the cognitive performance of model mice in Morris water maze test and step-through test. Meanwhile, LI effectively reversed the Aß1-40 induced hippocampal cell injury in histological examination, apoptosis in TUNEL assay, changes of oxidative stress indicators (SOD, GPX, AChE). Besides, the activated cleaved caspase (caspase-3, caspase-9) was suppressed and Nrf2, HO-1 expression was elevated by LI treatment. SIGNIFICANCE: LI could attenuate cognitive deficits induced by Aß, and the neuroprotective effect of LI might be mediated by alleviation of apoptosis, oxidative stress depending on activation of Nrf2/HO-1 signaling. We could assume that LI has the potential to be a neuroprotective substance for AD therapy.

Effects of the chronic restraint stress induced depression on reward-related learning in rats.

Chronic mild or unpredictability stress produces a persistent depressive-like state. The main symptoms of depression include weight loss, despair, anhedonia, diminished motivation and mild cognition impairment, which could influence the ability of reward-related learning. In the present study, we aimed to evaluate the effects of chronic restraint stress on the performance of reward-related learning of rats. We used the exposure of repeated restraint stress (6h/day, for 28days) to induce depression-like behavior in rats. Then designed tasks including Pavlovian conditioning (magazine head entries), acquisition and maintenance of instrumental conditioning (lever pressing) and goal directed learning (higher fixed ratio schedule of reinforcement) to study the effects of chronic restraint stress. The results indicated that chronic restraint stress influenced rats in those aspects including the acquisition of a Pavlovian stimulus-outcome (S-O) association, the formation and maintenance of action-outcome (A-O) causal relation and the ability of learning in higher fixed ratio schedule. In conclusion, depression could influence the performances in reward-related learning obviously and the series of instrumental learning tasks may have potential as a method to evaluate cognitive changes in depression.

Is adjunctive treatment with medication of liver-soothing-oriented method beneficial for depression after cerebrovascular accident?: A PRISMA-compliant meta-analysis.

BACKGROUND: Adjunctive treatment with medication of liver-soothing-oriented method (MLSM) is one of the most commonly used approaches for subjects with depression after cerebrovascular accident (DCVA) in China. The purpose of this meta-analysis was to evaluate the outcome of MLSM treatment in subjects with DCVA using relevant published literature. METHODS: The PubMed, Cochrane Library, Embase, Chinese databases of China National Knowledge Infrastructure, WanFang, Sinomed, and VIP were used to collect all publications until March 2016. Randomized controlled trials comparing treatments with and without MLSM for subjects with DCVA were included. The quality of each publication was assessed based on the recent Handbook (5.1 version) for Cochrane Reviewers. Cochrane Collaboration's software RevMan 5.3 software was applied for data analysis. RESULTS: Thirty studies, including 2599 cases, were identified and collected. Adjunctive treatment with MLSM noticeably enhanced total effective rates (odds ratio 3.76; 95% confidence interval [CI] 2.92-4.85, I = 0%, P = 0.96) in comparison to non-MLSM conventional pharmacotherapy. Compared to non-MLSM treatment, the changes of Hamilton Depression Scale in adjunctive treatment with MLSM, respectively, decreased and showed beneficial effects after 3 weeks (weighted mean difference [WMD] -4.83; 95% CI -6.82 to -2.83; I = 86%, P < 0.001), 4 weeks (WMD -4.20; 95% CI -5.06 to -3.33; I = 78%, P < 0.001), 6 weeks (WMD -3.36; 95% CI -4.05 to -2.68; I = 54%, P = 0.02), 8 weeks (WMD -4.83; 95% CI -5.62 to -4.04; I = 73%, P < 0.001), and 12 weeks (WMD -2.88; 95% CI -4.09 to -1.67; I = 58%, P = 0.09). As for changes in inflammatory cytokine levels, adjunctive treatment with MLSM was associated with a significant decrease in tumor necrosis factor-α, IL-6, and interleukin-1ß levels in comparison to non-MLSM treatment. Moreover, there were positive effects on score changes for National Institute of Health Stroke Scale, activities of daily living, Hamilton Anxiety Scale, Modified Edinburgh Scandinavian Stroke Scale, and Self-Rating Anxiety Scale. No serious adverse events were reported. CONCLUSION: MLSM appears to improve symptoms of depressive disorders, enhance immediate responses, and the quality of life in subjects with DCVA. The positive action of MLSM might be potentially connected with its immunoregulating effects. More prospective trials with strict design and larger sample sizes are warranted to clarify its effectiveness and safety.

Generation and analysis of the Rett syndrome-associated MeCP2- null rat model.

MeCP2 mutations are associated with the Rett syndrome (RTT). Currently, there is an urgent need for new animal models for RTT as the existing MeCP2 knockout mouse models fail to fully mimic the pathogenesis and symptoms of RTT patients. In order to investigate the role of MeCP2 in brain development and RTT pathogenesis, we aimed to set up the MeCP2-null rat model using the CRISPR/Cas9 technology. Firstly we constructed the MeCP2 targeting vector and then microinjected Cas9 mRNA and sgRNA mixtures into fertilized ova of SD rats. The sgRNA was designed to target the exon 2 of MeCP2. Next, knockout rats were confirmed using DNA sequencing and Western blotting. Lastly, phenotypes including growth and behaviors of MeCP2 knockout rats were analyzed. The results indicated that the MeCP2 knockout rats showed body weight loss, anxiety tendency and cognitive deficits. The MeCP2-null rat model established in this study recapitulates the major symptoms of RTT patients and provides an alternative tool for future studies of MeCP2 functions.

Protective effect of lavender oil on scopolamine induced cognitive deficits in mice and H2O2 induced cytotoxicity in PC12 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Lavender essential oil (LO), an aromatic liquid extracted from Lavandula angustifolia Mill., has been traditionally used in the treatments of many nervous system diseases, and recently LO also reported to be effective for the Alzheimer's disease (AD). AIM OF THE STUDY: The improvement effect of lavender oil (LO) on the scopolamine-induced cognitive deficits in mice and H2O2 induced cytotoxicity in PC12 cells have been evaluated. The relevant mechanism was also researched from the perspective of antioxidant effect and cholinergic system modulation. MATERIALS AND METHODS: Cognitive deficits were induced in C57BL/6J mice treated with scopolamine (1mg/kg, i.p.) and were assessed by Morris water maze (MWM) and step-through passive avoidance tests. Then their hippocampus were removed for biochemical assays (acetylcholinesterase (AChE), superoxide dismutase (SOD), glutathione peroxidase (GPX) and malondialdehyde (MDA)). In vitro, the cytotoxicity were induced by 4h exposure to H2O2 in PC12 and evaluated by cell viability (MTT), lactate dehydrogenase (LDH) level, nitric oxide (NO) release, reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP). RESULTS: The results demonstrated that LO (100mg/kg) could improve the cognitive performance of scopolamine induced mice in behavioral tests. Meanwhile, it significantly decreased the AChE activity, MDA level, and increase SOD and GPX activities of the model. Moreover, LO (12µg/mL) protected PC12 cells from H2O2 induced cytotoxicity by reducing LDH, NO release, intracellular ROS accumulation and MMP loss. CONCLUSIONS: It was suggested that LO could show neuroprotective effect in AD model in vivo (scopolamine-treated mice) and in vitro (H2O2 induced PC12 cells) via modulating oxidative stress and AChE activity.

Cognitive-enhancing effects of hydrolysate of polygalasaponin in SAMP8 mice.

OBJECTIVES: The aim of the study is to evaluate the cognitive-enhancing effects of hydrolysate of polygalasaponin (HPS) on senescence accelerate mouse P8 (SAMP8) mice, an effective Alzheimer's disease (AD) model, and to research the relevant mechanisms. METHODS: The cognitive-enhancing effects of HPS on SAMP8 mice were assessed using Morris water maze (MWM) and step-through passive avoidance tests. Then N-methyl-D-aspartate (NMDA) receptor subunit expression for both the cortex and hippocampus of mice was observed using Western blotting. RESULTS: HPS (25 and 50 mg/kg) improved the escape rate and decreased the escape latency and time spent in the target quadrant for the SAMP8 mice in the MWM after oral administration of HPS for 10 d. Moreover, it decreased error times in the passive avoidance tests. Western blotting showed that HPS was able to reverse the levels of NMDAR1 and NMDAR2B expression in the cortex or hippocampus of model mice. CONCLUSIONS: The present study suggested that HPS can improve cognitive deficits in SAMP8 mice, and this mechanism might be associated with NMDA receptor (NMDAR)-related pathways.

Do Chinese Researchers Conduct Ethical Research and Use Ethics Committee Review in Clinical Trials of Anti-Dementia Drugs? An Analysis of Biomedical Publications Originating from China.

BACKGROUND: Medical research using human participants must conform to the basic ethical principles found in the Declaration of Helsinki (DoH) of the World Medical Association. OBJECTIVE: The purpose of this review was to assess whether journals in China have improved in regard to the fulfillment of ethical disclosure procedures for clinical trials of anti-dementia drugs. METHODS: Four medical databases were searched for articles reporting clinical trials of oral anti-dementia drugs published in China in 2003, 2009, and 2014. The frequencies of reporting of informed consent from participants (ICP), approval of a regional ethical committee (REC), reference to DoH, and study registration were estimated respectively. Statistical analyses were conducted with SPSS v21 software. RESULTS: Among those randomized controlled trials published in 2003, 2009, and 2014, disclosure of REC approval was present for 2.67%, 1.15%, and 6.84%; statements of ICP were included in 9.33%, 7.76%, and 17.34%; reference to DoH was found for 4.00%, 1.44%, and 7.45%; and study registration reporting was included in 2.67%, 2.59%, and 9.28%, respectively. Improvements to reporting rates between 2009 and 2014 were seen, with more than twice as many trials reporting REC approval, ICP, reference to DoH, and study registration compared with 2009. CONCLUSION: Compared with 2003 and 2009, reporting rates for REC approval, ICP, reference to DoH, and study registration for clinical trials of anti-dementia drugs were enhanced in 2014 in the major medical journals of China. However, biomedical publications without definite statements of ethical considerations remain common, and this continues to be seen in Chinese journals. It is imperative that measures are taken to reinforce the ethical protection in clinical trials in China.

Can Chinese Herbal Medicine Adjunctive Therapy Improve Outcomes of Senile Vascular Dementia? Systematic Review with Meta-analysis of Clinical Trials.

Many publications have reported the growing application of complementary and alternative medicine, particularly the use of Chinese herbal medicine (CHM) in combination with routine pharmacotherapy (RP) for senile vascular dementia (SVD), but its efficacy remains largely unexplored. The purpose of this study is to evaluate the efficacy of CHM adjunctive therapy (CHMAT), which is CHM combined with RP, in the treatment of SVD. Publications in seven electronic databases were searched extensively, and 27 trials with a total of 1961 patients were included for analysis. Compared with RP alone, CHMAT significantly increased the effective rate [odds ratio (OR) 2.98, 95% confidence interval (CI) 2.30, 3.86]. In addition, CHMAT showed benefits in detailed subgroups of the Mini-Mental State Exam (MMSE) score from time of onset to 4 weeks (WMD 3.01, 95% CI 2.15, 3.87), 8 weeks (weighted mean difference (WMD) 2.30, 95% CI 1.28, 3.32), 12 weeks (WMD 2.93, 95% CI 2.17, 3.69), and 24 weeks (WMD 3.25, 95% CI 2.61, 3.88), and in the activity of daily living scale score from time of onset to 4 weeks (WMD -4.64, 95% CI -6.12, -3.17), 8 weeks (WMD -4.30, 95% CI -6.04, -2.56), 12 weeks (WMD -3.89, 95% CI -4.68, -3.09), and 24 weeks (WMD -4.04, 95% CI -6.51, -1.57). Moreover, CHMAT had positive effects on changes in the Hasegawa dementia scale, National Institutes of Health Stroke Scale, Clinical Dementia Rating, and Montreal Cognitive Assessment scores, as well as blood fat levels (total cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apolipoprotein E), platelet aggregation rate (1-min platelet aggregation rate, 5-min platelet aggregation rate, and maximal platelet aggregation rate), and blood rheology (whole-blood viscosity and hematocrit). No serious or frequently occurring adverse effects were reported. Weaknesses of methodological quality in most trials were assessed using the Cochrane risk of bias tool, while the quality level of Grades of Recommendations Assessment Development and Evaluation (GRADE) evidence classification indicated 'very low'. This systematic review suggests that CHM as an adjunctive therapy can improve cognitive impairment and enhance immediate response and quality of life in SVD patients. However, because of limitations of methodological quality in the included studies, further research of rigorous design is needed.

Modified Si-Miao-San () regulates adipokine expression and ameliorates insulin resistance by targeting IKKß/Insulin receptor substrate-1 in mice.

OBJECTIVE: To evaluate modified Si-Miao-San (mSMS, ) regulation of insulin sensitivity and explore the molecular mechanism by which mSMS inhibits inflammation and improves insulin action in mice. METHODS: Insulin resistant model in mice was prepared by stimulation with macrophage-derived condition medium (Mac-CM) and the effects of mSMS on oral glucose tolerance, insulin sensitivity and liver glycogen content in mice was observed. The mice adipose tissue was isolated and the regulation of inflammation-related adipokine expression and insulin phosphatidylinositol 3-kinase (PI3K) signaling transduction by mSMS was investigated. Effect of mSMS on insulin-mediated glucose uptake was also investigated in adipocytes. RESULTS: Oral administration of mSMS improved glucose tolerance in mice. Treatment of mice with Mac-CM resulted in glucose intolerance in mice and this change was effectively reversed by mSMS. Meanwhile, mSMS enhanced insulin sensitivity and increased glucose load-stimulated liver glycogen when mice were exposed to Mac-CM. Mac-CM stimulation induced dysregulation of adipokine expression in adipose tissue of mice. mSMS downregulated tumor necrosis factor α and interleukin 6 (IL-6) overexpression and upregulated adiponectin and peroxisomal proliferator activated receptor γ with inhibition of inhibitory kappa B kinase-ß (IKKß) and p65 phophsphorylation. Meanwhile, mSMS inhibited IL-6 production and increased adiponectin secretion in adipocytes against Mac-CM insult. Mac-CM challenge impaired insulin phosphatidylinositol 3 kinase (PI3K) signaling in adipose tissue. Oral administration mSMS inhibited inflammation-induced serine phosphorylation of insulin receptor substrate-1 (IRS-1) and restored insulin-mediated tyrosine phosphorylation, and thereby facilitated insulin PI3K signaling manifested by restoration of Akt phosphorylation. The resultant improvement of insulin sensitivity promoted insulin-stimulated glucose uptake when adipocytes were exposed to Mac-CM. CONCLUSIONS: mSMS improves glucose tolerance in mice by enhancing insulin sensitivity in mice. mSMS inhibits IKKß/NF κ B (p65)-dependent inflammatory response with beneficial regulation of adipokine expression in adipose tissue. mSMS inhibits inflammation and improves insulin sensitivity by blocking inflammatory interaction between IKKß/IRS-1.