Antiamnesic effects of magnesium pyrrolidone carboxylate (MAG 2) in three models of amnesia in the mouse

The effects of magnesium pyrrolidone carboxylate (MAG 2) on the amnesias induced by scopolamine, diazepam, and electroconvulsive shock (ECS) were studied in a passive avoidance procedure in the mouse and compared with the effects of a standard dose of piracetam. Amnesia was induced by injecting scopolamine or diazepam (1 mg/kg intraperitoneally [i.p.]) 30 min before or ECS administered immediately after the first session (S1) of the passive avoidance task. MAG 2 was studied in a dose range of 128 to 1,024 mg/kg and compared with piracetam (2,048 mg/kg), both drugs being administered orally (p.o.) 60 min before S1. Retention was measured 24 hr later (S2) in the absence of any treatment. Further experiments investigated the effects of repeated administration of MAG 2 (twice daily for 3 days) on diazepam-induced amnesia. Additional experiments investigated the interactions of the compound with the major behavioral effects of the amnesic treatments, namely scopolamine-induced hyperactivity, diazepam-induced release of punished behavior (four plates test), and ECS-induced convulsions. MAG 2 dose-dependently attenuated the memory deficits induced by the three amnesic treatments after acute treatment and more effectively antagonized diazepam-induced amnesia after repeated than after acute treatment. It did not affect either scopolamine-induced hyperactivity, diazepam-induced release of punished behavior or ECS-induced convulsions. These results point to the specificity of MAG 2′s antiamnesic activity and suggest that it might be a useful agent for the treatment of memory deficits of different origins in man.     

Comparative effects of S9977-2 versus tacrine on passive avoidance learning and psychomotor activity

We have studied the time- and dose-dependent effects of S9977-2 versus tacrine (THA) on psychomotor activity (PMA) and passive avoidance learning (PAL) in intact 3-month-old rats. No significant changes were observed in the levels of PMA in animals tested 0, 30 and 60 min after i.p. injections of S9977-2 (0·125 mg/kg) or THA (1 mg/kg). In a PAL maze paradigm, S9977-2 and THA, administered 30, 60 and 120 min before testing, induced time-dependent improvements in learning indices, with maximum effects during the first hour after administration. In the dose–response study, S9977-2 (0·005, 0·025 and 0·125 mg/kg) tended to increase and THA (0·33, 1 and 3 mg/kg) to decrease PMA scores while the two compounds improved learning in a progressive dose-related manner. The present results indicate that S9977-2 and THA exert opposite actions on exploratory behaviour, S9977-2 increasing this parameter and THA decreasing it, and that both molecules improve learning in a similar time- and dose-dependent manner. On a molar basis S9977-2 is 10–20 times more potent than THA in enhancing learning acquisition. © 1997 John Wiley & Sons, Ltd.     

Prevention of experimental amnesia by peripherally administered cholecystokinin octapeptide in the rat

The effect of subcutaneously injected cholecystokinin octapeptide (CCK-8) on amnesia induced by electroconvulsive shock (ECS), CO₂ inhalation, or cycloheximide injection was investigated in rats. In normal rats, single administration of CCK-8 had no significant effect on the passive avoidance response. Treatment with ECS, CO₂, or cycloheximide markedly decreased the latency of the passive avoidance response, but CCK-8 in doses from 0.1 to 10 μg/kg could prevent the induced amnesia when injected 30 min before the training trials, immediately after foot shock or amnesic treatments, and 30 min before the first retention test. The results indicate that peripheral administration of CCK-8 is effective in preventing amnesia in the rat.     

Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia

Objectives: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment.

Methods: In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10?mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals’ locomotor activity was also studied.

Results: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p?p?p?p?Discussion: In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).     

Cognitive enhancing and antioxidant activity of ethyl acetate soluble fraction of the methanol extract of Hibiscus rosa sinensis in scopolamine-induced amnesia

Objective:

The objective of the present study was to evaluate the cognitive enhancing and antioxidant activity of Hibiscus rosa sinensis.

Materials and Methods:

The learning and memory was impaired by administration of scopolamine (1 mg/kg, i.p.) in mice which is associated with altered brain oxidative status. The object recognition test (ORT) and passive avoidance test (PAT) were used to assess cognitive enhancing activity. Animals were treated with an ethyl acetate soluble fraction of the methanol extract of H. sinensis (25, 50 and 100 mg/kg, p.o).

Results:

The ethyl acetate soluble fraction of the methanol extract of H. sinensis (EASF) attenuated amnesia induced by scopolamine and aging. The discrimination index (DI) was significantly decreased in the aged and scopolamine group in ORT. Pretreatment with EASF significantly increased the DI. In PAT, scopolamine-treated mice exhibited significantly shorter step-down latencies (SDL). EASF treatment showed a significant increase in SDL in young, aged as well as in scopolamine-treated animals. The biochemical analysis of brain revealed that scopolamine treatment increased lipid peroxidation and decreased levels of superoxide dismutase (SOD) and glutathione reductase (GSH). Administration of extract significantly reduced LPO and reversed the decrease in brain SOD and GSH levels. The administration of H. sinensis improved memory in amnesic mice and prevented the oxidative stress associated with scopolamine. The mechanism of such protection of H. sinensis may be due to augmentation of cellular antioxidants.

Conclusion:

The results of the present study suggested that H. sinensis had a protective role against age and scopolamine-induced amnesia, indicating its utility in management of cognitive disorders.     

Preventive effect of cholecystokinin octapeptide on scopolamine-induced memory impairment in the rat

In a passive avoidance response, intraperitoneal administration of scopolamine (0.5 mg/kg) at 15 min before the training trials produced a marked impairment of memory in the rat. However, pretreatment with cholecystokinin octapeptide (CCK-8) either given subcutaneously or intracerebroventriculary (i.c.v.) prevented the scopolamine-induced amnesia. Continuous i.c.v. infusion of CCK-8 (1 ng/day) for 7 days significantly prevented the amnesia. The results support our previous findings that CCK-8 has a protective effect against experimental amnesia in the rat.     

Effects of S 9977 on learning and memory in the mouse and rat

S 9977 (1,3,7-trimethyl 8-[3-(4-diethylaminocarbonyl-l-piperazinyl)1-propyl]-3,7-dihydro(1H)2,6-purinedione hydrochloride) is a methylxanthine derivative lacking activity at adenosine receptors and having no phosphodiesterase inhibitory action, but which has been reported to enhance cholinergic function. In mice 0.06 mg/kg ip increased, whereas 0.25 and 1 mg/kg ip decreased, spontaneous alternation in a T-maze. Doses of 0.03 and 0.06 mg/kg ip improved acquisition and retention of a spatial discrimination task when administered on the test days. The dose of 0.06 mg/kg ip was without effect on subsequent retention when given immediately post-acquisition, suggesting it was without effect on storage processes. When it was administered for 14 days prior to testing 0.06 mg/kg ip retained its effects on acquisition and retention of the discrimination task, but no longer had significant effects on spontaneous alternation. In rats, there was no effect on between-day habituation of exploration or on acquisition of a working and reference memory task with a 24 h intertrial interval. However, 0.06 mg/kg ip significantly improved retention of this task and 0.12 mg/kg ip significantly improved acquisition when a 48-h intertrial interval was used, mainly due to a reduction in working memory errors. In a test of reference memory in a helical maze 0.03 mg/kg ip improved acquisition. These results suggest that low, but not high, doses of S 9977 can improve acquisition in tasks relying on both working and reference memory and also can improve performance on retention tasks. The results are discussed with reference to the effects of S 9977 in enhancing cholinergic function. © Wiley-Liss, Inc.     

Brief postnatal PBDE exposure alters learning and the cholinergic modulation of attention in rats.

Polybrominated diphenyl ethers (PBDEs), chemicals commonly used as flame retardants, are ubiquitous in the environment and bioaccumulate in humans and wildlife. However, little is known about their potential toxicological properties. In the present study, male Long-Evans rats orally administered the commercial PBDE mixture DE-71 or corn oil for 1 week, beginning at postnatal day (PND) 6, were tested on a visual discrimination task and two sustained attention tasks. After completion of these tasks, the rats were administered a drug challenge with the muscarinic antagonist scopolamine (0, 0.01, 0.03, 0.05 mg/kg), which was injected subcutaneously 30 min prior to testing on the second sustained attention task. The DE-71-exposed rats demonstrated deficits in learning but not in sustained attention when compared to controls. Scopolamine impaired the animals' ability to detect the brief visual cues in controls, as evidenced by decreases in accuracy and increases in omission errors. However, the DE-71-exposed rats were subsensitive to the effects of scopolamine on omission errors, particularly on trials in which a long delay preceded the cue, suggesting alterations in the cholinergic modulation of sustained attention. For the DE-71-exposed rats, the lack of sustained attention deficits in the absence of the drug, coupled with the subsensitivity to scopolamine's effects on sustained attention, suggest that although this PBDE mixture produced lasting alterations in cholinergic functioning, either (1) these alterations were not of sufficient magnitude to be behaviorally relevant, or (2) behavioral deficits resulting from these alterations were overcome by the development of compensatory neural mechanisms or response strategies in adulthood.     

Further studies on the site of action of diazepam: anticonvulsant effect in the rabbit.

The site of the anticonvulsant action of diazepam was studied by means of direct intracerebral chemostimulation in conscious rabbits with chronically implanted cannulae and recording electrodes. In order to evaluate anticonvulsant effectiveness, two procedures were used: (a) elevation in pentylenetetrazol (PTZ) threshold for appearance of spike activity in the EEG record; (b) elevation in the threshold of limbic after-discharges. Diazepam was injected in one of three regions: anterior amygdaloid nucleus (AA), basal amygdaloid nucleus (AB), and dorsal hippocampus (DH).Application of diazepam in the AA strongly elevated the PTZ threshold in a reversible and doserelated manner; injections in the AB or DH were ineffective. Phenobarbital was also ineffective in all regions investigated.The threshold of amygdalo-hippocampal after-discharges was elevated after application of diazepam in the AA, but not after injection in the DH. Hippocampal-amygdaloid after-discharges were not influenced by the drug from either the AA or DH.It is concluded that the amygdaloid nucleus, and particularly its anterior part, plays a crucial role in the anticonvulsant effect of diazepam in the rabbit.     

中枢烟碱受体亚型对小鼠被动回避行为的影响

目的：探讨中枢烟碱受体亚型在学习、记忆中的作用。方法：采用小鼠的被动回避反应法，观察四种不同选择性的烟碱受体（Ｎ受体）拮抗剂对学习和记忆行为的影响。结果：脑室注射ｋａｐｐａ－银环蛇毒（κ－ＢＴＸ）和六烃季铵（Ｃ６）明显抑制小鼠的学习和记忆行为的获得，且κ－银环蛇毒的作用有量—效关系；而α－银环蛇毒（α－ＢＴＸ）和双氢β－刺酮碱（ＤＨＢＥ）对小鼠的被动回避反应无明显影响。结论：中枢烟碱受体亚型在学习、记忆中起不同的作用，对κ－ＢＴＸ敏感的烟碱受体亚型可能在学习记忆中发挥重要作用。     

Thiamethoxam induced mouse liver tumors and their relevance to humans. Part 1: mode of action studies in the mouse.

Thiamethoxam, a neonicotinoid insecticide, which is not mutagenic either in vitro or in vivo, caused an increased incidence of liver tumors in mice when fed in the diet for 18 months at concentrations in the range 500 to 2500 ppm. A number of dietary studies of up to 50 weeks duration have been conducted in order to identify the mode of action for the development of the liver tumors seen at the end of the cancer bioassay. Both thiamethoxam and its major metabolites have been tested in these studies. Over the duration of a 50-week thiamethoxam dietary feeding study in mice, the earliest change, within one week, is a marked reduction (by up to 40%) in plasma cholesterol. This was followed 10 weeks later by evidence of liver toxicity including single cell necrosis and an increase in apoptosis. After 20 weeks there was a significant increase in hepatic cell replication rates. All of these changes persisted from the time they were first observed until the end of the study at 50 weeks. They occurred in a dose-dependent manner and were only observed at doses (500, 1250, 2500 ppm) where liver tumors were increased in the cancer bioassay. There was a clear no-effect level of 200 ppm. The changes seen in this study are consistent with the development of liver cancer in mice and form the basis of the mode of action. When the major metabolites of thiamethoxam, CGA322704, CGA265307, and CGA330050 were tested in dietary feeding studies of up to 20 weeks duration, only metabolite CGA330050 induced the same changes as those seen in the liver in the thiamethoxam feeding study. It was concluded that thiamethoxam is hepatotoxic and hepatocarcinogenic as a result of its metabolism to CGA330050. Metabolite CGA265307 was also shown to be an inhibitor of inducible nitric oxide synthase and to increase the hepatotoxicity of carbon tetrachloride. It is proposed that CGA265307, through its effects on nitric oxide synthase, exacerbates the toxicity of CGA330050 in thiamethoxam treated mice.     

布拉酵母菌的生物学作用及防治疾病应用研究进展

根据近些年的文献，文章对布拉酵母菌（Saccharomyces boulardii）的生物学特性、防治疾病的作用机制及应用研究进展进行综述。     

地高辛与奎尼丁及二氢奎尼丁协同对乳头肌动作电位时程的影响

应用经典玻璃微电极方法研究地高辛与奎尼丁及二氢奎尼丁协同对豚鼠乳头肌动作电位复极30％（APD30）、复极50％（APD50）、复极90％（APD90）的影响。实验证明：10μmol／L，奎尼丁及二氢奎尼丁均使APD30、APD50、APD90明显延长（P＜0．05），加入6．4×10－4μmol／L地高辛后，均使延长的动作电位时程明显缩短，有正常化趋势（P＜0.05）。     

Recent advances in understanding the antibacterial properties of flavonoids

Antibiotic resistance is a major global problem and there is a pressing need to develop new therapeutic agents. Flavonoids are a family of plant-derived compounds with potentially exploitable activities, including direct antibacterial activity, synergism with antibiotics, and suppression of bacterial virulence. In this review, recent advances towards understanding these properties are described. Information is presented on the ten most potently antibacterial flavonoids as well as the five most synergistic flavonoid-antibiotic combinations tested in the last 6 years (identified from PubMed and ScienceDirect). Top of these respective lists are panduratin A, with minimum inhibitory concentrations (MICs) of 0.06-2.0 μg/mL against Staphylococcus aureus, and epicatechin gallate, which reduces oxacillin MICs as much as 512-fold. Research seeking to improve such activity and understand structure-activity relationships is discussed. Proposed mechanisms of action are also discussed. In addition to direct and synergistic activities, flavonoids inhibit a number of bacterial virulence factors, including quorum-sensing signal receptors, enzymes and toxins. Evidence of these molecular effects at the cellular level include in vitro inhibition of biofilm formation, inhibition of bacterial attachment to host ligands, and neutralisation of toxicity towards cultured human cells. In vivo evidence of disruption of bacterial pathogenesis includes demonstrated efficacy against Helicobacter pylori infection and S. aureus α-toxin intoxication.     

基于网络药理学探明八宝丹治疗原发性肝癌的潜在机制研究

目的 基于网络药理学探讨八宝丹对原发性肝癌（HCC）影响的潜在机制。方法 首先利用二乙基亚硝胺诱导的原发性HCC大模型,观察八宝丹对HCC的影响;然后利用超高效液相色谱-串联质谱法（UPLC-MS）检测八宝丹中的有效成分,再在Swiss Target Prediction数据库等预测八宝丹有效成分的潜在作用靶点。运用GeneCards、OMIM和Therapeutic Target Database筛选HCC对应靶点,取交集后获得八宝丹与HCC的共同靶点。使用Cytoscape软件和STRING数据库绘制蛋白与蛋白间互作网络,筛选出八宝丹调控HCC的关键分子。利用DAVID数据库对有效作用靶点进行GO及KEGG富集分析。最后在TCGA数据库验证关键分子与HCC患者的临床相关性。结果 八宝丹可延缓HCC大鼠肿瘤进展。UPLC-MS检测出八宝丹中化学成分851个,主要活性成分9个,作用靶点285个;筛选出HCC靶点637个,八宝丹调控HCC的靶点16个。GO富集分析显示802个生物过程、11个细胞组成、43个分子功能,KEGG通路共90条。TCGA相关性分析发现3个关键分子与HCC患者生存期相关。结论 通过HCC大鼠模型发现,八宝丹可显著延长HCC大鼠的生存周期并减少肿瘤负荷,通过UPLC-MS及网络药理学方法初步预测八宝丹调控HCC的作用机制,表明八宝丹具有多成分、多通路、多靶点作用原发性HCC的特点,为进一步相关实验研究提供参考。     

Effects of d-amphetamine and scopolamine on activity before and after shock in three mouse strains.

In three experiments the following results were obtained: (a) Activity was greater both prior to and following exposure to shock among C57BL/6J mice than in DBA/2J mice, which in turn was greater than that of A/J mice. (b) Scopolamine hydrobromide increased general activity in DBA/2 and A mice, but had either no effect or decreased activity in the C57BL/6 strain. Following exposure to shock, however, the disinhibitory effects of scopolamine were apparent in all three strains. (c) d-amphetamine increased activity in all three strains. Moreover, following the single shock d-amphetamine had excitatory effects among both A and DBA/2 mice such that activity exceeded the level observed with d-amphetamine alone. Following several shock presentations a small but significant excitation was observed in C57BL/6 mice as well. Data were interpreted in terms of disinhibitory and excitatory effects of scopolamine and d-amphetamine, respectively, as well as possible interactions between the catecholaminergic and cholinergic systems. In addition, implications for sources of strain differences in avoidance behavior are discussed.     

The development of forestomach tumours in the mouse following exposure to 2-butoxyethanol by inhalation: studies on the mode of action and relevance to humans

2-Butoxyethanol, a forestomach carcinogen in mice exposed by inhalation, has been shown to enter the forestomach as a result of grooming and ingestion of material condensed on the skin and fur during exposure. The material entering the stomach concentrates in the forestomach region and persists for at least 48 h post-exposure. Mice given single oral doses of either 2-butoxyethanol or 2-butoxyacetic acid, daily for 10 days, developed a marked hyperkeratosis in the forestomach. 2-Butoxyacetic acid was more potent than 2-butoxyethanol, the NOEL for the former being 50 mg/kg and for the latter, 150 mg/kg. Although a dose dependent increase in cell replication was also seen with both chemicals, the results were confounded by a high labelling rate in the controls. There was no evidence of significant binding of radiolabelled 2-butoxyethanol to proteins in stomach tissues. 2-Butoxyethanol was metabolised in vitro in both mouse and rat forestomach and glandular stomach fractions by alcohol dehydrogenases forming 2-butoxyacetaldehyde which was rapidly converted by aldehyde dehydrogenases to 2-butoxyacetic acid. There was a marked species difference in alcohol dehydrogenase activity between rats and mice with the maximum rates up to one order of magnitude greater in mouse than rat. The alcohol and aldehyde dehydrogenases were heavily concentrated in the stratified squamous epithelium of the forestomach of both rats and mice whereas in the glandular stomach the distribution was more diffuse. In human stomach both enzymes were evenly distributed throughout the epithelial cells of the mucosa. It is concluded that 2-butoxyethanol is ingested following inhalation exposure and concentrates in the forestomach where it is metabolised to 2-butoxyacetic acid which causes cellular damage, increased cell replication and hyperkeratosis. These changes are believed to lead to the tumours seen in mice exposed to 2-butoxyethanol for a lifetime. Differences in structure and enzyme distribution between the rodent and human stomach suggest that the responses seen in the mouse are unlikely to occur in humans.     

Epoxide hydrolase activity in the mitochondrial and submitochondrial fractions of mouse liver

Distribution of epoxide hydrolase activity in subcellular fractions of livers from male Swiss-Webster mice and Sprague-Dawley rats was monitored with trans-β-ethylstyrene oxide, trans-stilbene oxide and benzo[a]pyrene 4,5-oxide following differential centrifugation. With the former two substrates the highest activity was encountered in the cytosolic fraction; however, significant activity was found in the mitochondrial fraction. These fractions hydrated benzo[a]pyrene 4,5-oxide very slowly, and the major benzo[a]pyrene 4,5-oxide hydrolyzing activity was recovered in the microsomal fraction. Using Triton WR-1339-treated mice, it was shown that trans-β-ethylstyrene oxide hydrolyzing activity was predominantly localized in the mitochondria rather than in lysosomes and peroxisomes. Subsequent separation of the mitochondrial fraction into submitochondrial components by swelling, shrinking, and sonication, followed by sucrose density gradient centrifugation, showed that most of the epoxide hydrolyzing activity was present in the matrix and intermembrane space fraction. Significant activity was also present in the outer and inner membrane fractions. However, epoxide hydrolyzing activity in these fractions was reduced if either increased sonication times were used or the fractions were washed, indicating possible contamination of these fractions by the matrix and intermembrane space enzyme(s). The epoxide hydrolase activity in the mitochondrial and cytosolic fractions in mice appeared similar with regard to inhibition, molecular weight, and substrate selectivity.