Minocycline Synergizes with N-Acetylcysteine and Improves Cognition and Memory Following Traumatic Brain Injury in Rats

Background: There are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models. Methodology/Principal Findings: Drugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Coadministration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when th

Evaluation the effect of neuropeptide of Bombesin on modulation of anxiety reaction in mice

Background & Objective: Bombesin (BBS) is a tetra-decapeptide amino acid neuropeptide in central nervous system within a variety of mammalian species. Also it has many biological effects that may be effective in modulation of anxiety. The aim of present study was to determine the effect of BBS on modulation anxiety reaction in elevated plus maze (EPM) in mice.   Materials & Methods: 60 male mice (25-30 g) were used in this study. Bombesin in doses of 1.25, 2.5, 5, 10 and 20 µg/kg IP or saline was injected in different groups 10 min before of evaluation. Five minutes later for increase of activity, animal was put in black box for 5 min. Then each animal in regulated time transferred to standard elevated plus-maze and the time spent in the open arms and the ratio of open arm entries during 5 min, were measured. The data analyzed by using ANOVA and Tukey test.   Results: BBS in dose dependently manner increase which the anxiety reaction in mice. Animals had spent lower time and ratio of open arm entries in compare with control group significantly (P<0.05) and BBS only in dose of 1.25 µg/kg did not showed significantly effect.   Conclusion: This study indicated that Bombesin in dose dependently manner have important role in modulate anxiety reaction in EPM in mice

A comparative evaluation of acute stress and corticosterone on the process of learning and emotional memory in rat

&quot;nBackground: Previous studies suggested that stressful events that release Glucocorticoid from adrenal cortex and also injection of agonists of glucocorticoids receptors probably affect emotional learning and memory process and modulate them. The aim of this study was to determine the effects of acute stress and systemic injection of Corticosterone (as agonist of glucocorticoid receptors) on acquisition (ACQ), consolidation (CONS) and retrieval (RET) of emotional memory in rat. &quot;nMethods: In this experimental study we used 180 male Wistar rats (220-250). At the first rats was training in one trial inhibitory avoidance task. On the retention test given 48 h after training, the latency to re-enter the dark compartment of the apparatus (Step-through latency, STL) and the time spent in light chamber (TLC) were recorded during 10 min test. Intraperitoneal corticosterone in doses of 0.5, 1 and 3mg/kg injected 30min before, immediately after instruction and 30min before retrieval test. Also some groups received 10min stressful stimulation by restrainer at the same time. At the end locomotor&apos;s activity was measured for all animals. &quot;nResults: The data indicated that administration of corticosterone 30min before ACQ (1mg/kg), and immediately after CONS (1, 3mg/kg) enhance and 30min before RET (1, 3mg/kg) impair emotional memory (p&amp;lt;0.05). Acute stress impaired emotional memory in all phases (p&amp;lt;0.05). Also acute stress and injection of Corticosterone have not significantly affect motor activity.&amp;nbsp; &quot;nConclusions: These findings show that Glucocorticoid receptors in activation dependently plays an important role in modulation of emotional spatial memory processes (ACQ, CONS and RET in new information) for emotional events and these effects varies in different phases

The Effect of Reversible Abolition of Basolateral Amygdala on Hippocampal Dependent Spatial Memory Processes in Mice

Introduction: Many evidences have suggested that the Basolateral Amygdala (BLA) are probably involved in emotional learning and modulation of spatial memory processes. The aim of this present study was assessment of the effect of reversible abolition of BLA on spatial memory processes in a place avoidance learning model in a stable environment. Methods and Materials: Long-Evans strain rats (280-320 gr.) were selected and cannulae aimed at the BLA were surgically implanted bilaterally. The mice were trained to avoid a 60° segment of the arena by punishing with a mild foot shock upon entering the area. The punished sector was defined by room cues during the place avoidance training, which occurred in a single 30-min session and the avoidance memory was assessed during a 30-min extinction trial after 24 hours. The time of the first entry and the number of entrances into the punished sector during extinction were used to measure the place avoidance memory. Bilateral injections of Tetrodotoxin (5ng/0.6ml per side) were used to inactivate the BLA 60 min before acquisition, immediately, 60 and 120 min after training, or 60 min before the retrieval test. Control mice were injected saline at the same time. Results : The results indicated that acquisition, consolidation (immediately, 60 min after training) and retrieval of spatial memory in stable arena were impaired (p0.05). Conclusion: We conclude that the Basolateral Amygdala (BLA) modulate spatial memory processes in place avoidance learning model in stable arena and this effect in regard to consolidation is time dependent

The effect of fruit Cassia fistula aqueous extract on sleeping time and the level of anxiety in mice

Background and Objective: Several investigations have indicated the antinociceptive, anti-inflammatory, antipyretic effects and smooth muscle relaxant activity of Cassia species. This study was done to determine the effect of Cassia fistula on sleeping time and the level of anxiety in mice. Materials and Methods: In this experimental study, 80 male albino mice (25-30 g) randomly allocated in 8 groups. For measuring the sleeping time we used the Angle method and animals were divided into three experimentals (250, 500 and 1000 mg/kg) and one control group. For evaluating of anxiety levels, animals randomly were divided into three experimentals and one control group, and elevated plus maze (EPM) model was used. The evaluation of anxiety indices included number and percent of time spent in open arm. Different doses of the aqueous extract of Cassia fistula (250, 500, 1000 mg/kg IP) were injected intraperitoneally to the treated groups. Controls were recived 10 ml/kg/BW normal saline intraperitoneally in both methods. Results: The extract of Cassia fistula (250, 500 and 1000 mg/kg) significantly increased sleeping time [F (3, 39)=23.19, P<0.05]. Also open time [F (3,39)=15.55, P<0.05] and the number of open arm entries [F (3, 39)=24.21, P<0.05] were significantly in doses (250mg and 500 mg) were singnificantly more than control group, respectively (P<0.05). Conclusion: This study showed that the aqueous extract of Cassia fistula fruit incerase the sleeping time and deereasing level of anxity in mice

Characteristics and knowledge synthesis approach for 456 network meta-analyses: a scoping review

Background Network meta-analysis (NMA) has become a popular method to compare more than two treatments. This scoping review aimed to explore the characteristics and methodological quality of knowledge synthesis approaches underlying the NMA process. We also aimed to assess the statistical methods applied using the Analysis subdomain of the ISPOR checklist. Methods Comprehensive literature searches were conducted in MEDLINE, PubMed, EMBASE, and Cochrane Database of Systematic Reviews from inception until April 14, 2015. References of relevant reviews were scanned. Eligible studies compared at least four different interventions from randomised controlled trials with an appropriate NMA approach. Two reviewers independently performed study selection and data abstraction of included articles. All discrepancies between reviewers were resolved by a third reviewer. Data analysis involved quantitative (frequencies) and qualitative (content analysis) methods. Quality was evaluated using the AMSTAR tool for the conduct of knowledge synthesis and the ISPOR tool for statistical analysis. Results After screening 3538 citations and 877 full-text papers, 456 NMAs were included. These were published between 1997 and 2015, with 95% published after 2006. Most were conducted in Europe (51%) or North America (31%), and approximately one-third reported public sources of funding. Overall, 84% searched two or more electronic databases, 62% searched for grey literature, 58% performed duplicate study selection and data abstraction (independently), and 62% assessed risk of bias. Seventy-eight (17%) NMAs relied on previously conducted systematic reviews to obtain studies for inclusion in their NMA. Based on the AMSTAR tool, almost half of the NMAs incorporated quality appraisal results to formulate conclusions, 36% assessed publication bias, and 16% reported the source of funding. Based on the ISPOR tool, half of the NMAs did not report if an assessment for consistency was conducted or whether they accounted for inconsistency when present. Only 13% reported heterogeneity assumptions for the random-effects model. Conclusions The knowledge synthesis methods and analytical process for NMAs are poorly reported and need improvement

Comparative safety and effectiveness of serotonin receptor antagonists in patients undergoing chemotherapy: a systematic review and network meta-analysis

Background Although serotonin (5-HT3) receptor antagonists are effective in reducing nausea and vomiting, they may be associated with increased cardiac risk. Our objective was to examine the comparative safety and effectiveness of 5-HT3 receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron) alone or combined with steroids for patients undergoing chemotherapy. Methods We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception until December 2015 for studies comparing 5-HT3 receptor antagonists with each other or placebo in chemotherapy patients. The search results were screened, data were abstracted, and risk of bias was appraised by pairs of reviewers, independently. Random-effects meta-analyses and network meta-analyses (NMAs) were conducted. Results After screening 9226 citations and 970 full-text articles, we included 299 studies (n = 58,412 patients). None of the included studies reported harms for active treatment versus placebo. For NMAs on the risk of arrhythmia (primary outcome; three randomized controlled trials [RCTs], 627 adults) and mortality (secondary outcome; eight RCTs, 4823 adults), no statistically significant differences were observed between agents. A NMA on the risk of QTc prolongation showed a significantly greater risk for dolasetron + dexamethasone versus ondansetron + dexamethasone (four RCTs, 3358 children and adults, odds ratio 2.94, 95% confidence interval 2.13–4.17). For NMAs on the number of patients without nausea (44 RCTs, 11,664 adults, 12 treatments), number of patients without vomiting (63 RCTs, 15,460 adults, 12 treatments), and number of patients without chemotherapy-induced nausea or vomiting (27 RCTs, 10,924 adults, nine treatments), all agents were significantly superior to placebo. For a NMA on severe vomiting (10 RCTs, 917 adults), all treatments decreased the risk, but only ondansetron and ramosetron were significantly superior to placebo. According to a rank-heat plot with the surface under the cumulative ranking curve results, palonosetron + steroid was ranked the safest and most effective agent overall. Conclusions Most 5-HT3 receptor antagonists were relatively safe when compared with each other, yet none of the studies compared active treatment with placebo for harms. However, dolasetron + dexamethasone may prolong the QTc compared to ondansetron + dexamethasone. All agents were effective for reducing risk of nausea, vomiting, and chemotherapy-induced nausea or vomiting