Protective effects of xanthoceraside on learning and memory impairment induced by Aβ25–35 in mice

This study examined the effects of xanthoceraside (1) on learning and memory impairment induced in mice by intracerebroventricular injection of aggregated peptide β-amyloid 25–35 (Aβ_25–35). Learning and memory functions in mice were examined using step-through, Y-maze and water maze tests. Administration of 1 reduced the number of errors and prolonged latency in the step-through test in mice impaired by Aβ_25–35. Likewise, latency to find the terminal platform was decreased and the number of right reflects was increased in the water maze test, and the percentage of alternation behaviors in the Y-maze test was increased. Biochemical studies showed that decreased activities of superoxide dismutase, glutathione peroxidase, and acetylcholinesterase, and increased content of malondialdehyde in mice impaired by Aβ_25–35 were significantly ameliorated by administration of 1. The present results suggest that 1 may provide a potential treatment strategy for Alzheimer's disease.     

Dose–response involvement of constitutive androstane receptor in mouse liver hypertrophy induced by triazole fungicides

To clarify the dose–response relationship between constitutive androstane receptor (CAR) activity and induction of cytochrome P450 2B (CYP2B) expression and hypertrophy by triazole fungicides in mouse liver, three dose levels of cyproconazole (Cypro), tebuconazole (Teb), fluconazole (Flu), and phenobarbital (PB), a typical CYP2B inducer, were administrated in diet to male wild-type (WT) and CAR-knockout (CARKO) mice for one week. In WT mice, all compounds dose-dependently induced liver weight increases and hepatocellular hypertrophy accompanied by CYP2B expression. In CARKO mice, these effects were not induced by PB, while Cypro or Flu induced these effects only at the highest dose. Dose-dependent liver hypertrophy was detected in CARKO mice treated with Teb, but at the lowest dose the intensity was weakened compared to WT mice. The present results indicate that Cypro and Flu mainly induced CAR-mediated liver hypertrophy, while Teb slightly involved CAR. The involvement of CAR in triazole-induced liver hypertrophy was dose-responsive. In addition, all three triazoles have non-CAR-mediated liver hypertrophy pathways, indicating that the hypertrophy induced by these triazoles differs from that of PB.     

Effects of Xanthoceraside on learning and memory impairment in mice induced by i.c.v.Aβ_(1-42)

Objective To investigate the improvement of Xanthoceraside on learning and memory impairment in mice induced by intracerebroventricular injection of Aβ1-42(i.c.v.Aβ1-42)and the possible mechanisms of its protection against AD.Methods Y-maze test,water-maze test and step-down test were used to investigate the learning and memory ability of mice;Biochemical analysis was used to detect the activity of CAT,T-AOC,ATPase and the content of MDA.Results The results showed that Xanthoceraside could significantly increase the alternation behavior in Y-maze test,shorten swimming time in water maze test and increase the latency and decrease the number of errors and the total time of shock in step-down test.Xanthoceraside markedly increased the activity of CAT,T-AOC,ATPase,at the same time,decreased the content of MDA.Conclusions Xanthoceraside can improve learning and memory impairment in mice induced by i.c.v.Aβ1-42 significantly.The mechanism may be associated with the protection against damage induced by free radicals;the inhibition of membrane lipid peroxidation and the improvement of metabolism of brain.     

Liuwei Dihuang-active fraction combination,LW-AFC,improved spatial learning and memory impairment induced by TNF-α in mice

OBJECTIVE Tumor necrosis factor-α(TNF-α) plays a vital role in cognitive dysfunction caused by stress.In our previous study, Liuwei Dihuang-active fraction combination(LW-AFC) could attenuate the effects of mental stress and non-psychotic stress in mice. The aim of this study is to investigate the effects of LW-AFC on cognitive dysfunction caused by TNF-α in mice. METHODS 40 male BALB/c mice were divided into 4 groups according to their body weight,including control, TNF-α model, LW-AFC treatment and Etanercept(TNF-α antagonist) treatment groups. LW-AFC(1.6 or 3.2 g·kg~(-1) per day) were orally administrated for 7 consecutive days before TNF-α administration. Etanercept was injected subcutaneously at 30 mg·kg~(-1) the day before TNF-α administration. One hour before the behavioral test, TNF-αwere injected intraperitoneally at 0.2 mg·kg~(-1) to mice. RESULTS Compared with control group, the time of mice stayed in the target quadrant and the number of mice crossing the plate significantly decreased after TNF-α injection, suggested that the spatial learning and memory ability of the mice were impaired. LW-AFC administration could increase the time of mice stayed in the target quadrant and the number of mice crossing the plate significantly at 1.6 g·kg~(-1), indicated that LW-AFC could improve spatial learning and memory in TNF-α treated mice. CONCLUSION LW-AFC can improve spatial learning and memory impairment induced by TNF-α in mice, the further mechanism still need to be clarified.     

Anti -inflammatory effect of Vam3 on asthmalike reaction induced by allergen in sensitized mice

An alcoholic extract of Vitis amurensis （ Vit A ） has been demonstrated to have strong anti - asthma action in two guinea pig models of acute asthma. Vam3 is the major component of Vit A and its anti - inflammatory action has been extensively investigated in our laboratory. Here, the effects of Vam3 on airway inflammation, cytokine production, and lung pathology were evaluated in a murine model of asthma. BALB/c mice were sensitized and challenged with ovalbumin （ OVA）, and developed airway inflammation and asthmalike syndrome. Oral administration of Vam3 significantly inhibited OVA- induced increases in total bronchoalveolar lavage （BALF） leukocyte numbers;     

Dose–response relationship of duloxetine in placebo-controlled clinical trials in patients with major depressive disorder

Rationale The optimal dose for achieving the maximum antidepressive effect of selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenalin reuptake inhibitors (SNRIs) remains a controversial issue. The varying sensitivity of scales that measure the severity of depression is one of the many factors affecting the evaluation of the dose–response relationship with antidepressants.Objectives To determine if the 6-item Hamilton rating scale for depression (HAM-D₆) demonstrates a clearer association between dose and antidepressive effect compared with the 17-item Hamilton rating scale for depression (HAM-D₁₇) for fixed doses of duloxetine hydrochloride (40, 60, 80, and 120 mg daily) from six double-blind, randomized, placebo-controlled clinical trials assessing safety and efficacy in the acute treatment of patients with DSM-IV-defined major depressive disorder (MDD).Methods Mantel–Haenszel adjusted effect sizes were determined by dose for change from baseline to endpoint in HAM-D₆ and HAM-D₁₇ scores from the six studies. To confirm, assessments were repeated on the subset of the population corresponding to the 70% of patients with the longest duration of treatment regardless of study, treatment, dose, geography, or completion status.Results For the majority of assessments, HAM-D₆ effect sizes were numerically larger than those estimated from the HAM-D₁₇. Findings support that duloxetine 60 mg daily is the best effective dose.Conclusions In this assessment of patients with MDD, the HAM-D₆ was shown to be more sensitive compared with the HAM-D₁₇ at detecting treatment effects. These findings are consistent with published results of other effective antidepressants.Drs. Porsdal and Kajdasz are employees of Eli Lilly & Company.     

Anti-amnesic effect of ESP-102 on Aβ1-42-induced memory impairment in mice

The aim of this study was to characterize the effects of ESP-102 on the memory impairments and pathological changes induced by amyloid-β (Aβ)_1-42 peptide in mice. The ameliorating effect of ESP-102 on memory impairment was investigated using the passive avoidance and the Morris water maze tasks, and the pathological changes were identified by immunohistochemistry and western blotting. Aβ_1-42 peptide (3 μg/3 μl) was administered by intracerebroventricular injection. By the single administration of ESP-102 (100 mg/kg, p.o), the memory impairment induced by Aβ_1-42 peptide was significantly attenuated (P < 0.05). Moreover, ESP-102 (100 mg/kg, p.o) significantly inhibited acetylcholinesterase (AChE) activity in the hippocampus compared to the Aβ_1-42 peptide-injected control group. In the subchronic treatment study, ESP-102 (50 or 100 mg/kg/day, p.o) administration for seven days ameliorated the memory impairments induced by Aβ_1-42 peptide. Moreover, ESP-102 inhibited lipid peroxidation induced by Aβ_1-42 peptide in the hippocampus. Aβ_1-42-induced increases in the expression of GFAP (an astrocyte marker) and inducible nitric oxide synthase (iNOS) in the hippocampal region were also attenuated by ESP-102 treatment. These results suggest that the ameliorating effect of ESP-102 on Aβ_1-42 peptide-induced memory impairment is mediated via its AChE inhibitory, antioxidative, and/or anti-inflammatory activities.     

Study on the protective effect of salidroside on memory impairment in mice under high altitude hypoxia北大核心CSCD

目的探究红景天苷在高原低氧条件下改善小鼠学习记忆能力的作用。方法48只C57BL/6J♂小鼠按体重随机分成平原对照组、高原模型组和红景天苷组,每组16只,各组动物按剂量预防给药3 d后急进海拔4010 m的高原,缺氧暴露1 d后进行Morris水迷宫实验测试小鼠学习记忆能力;测定丙二醛(MDA)、过氧化氢(H_(2)O_(2))、谷胱甘肽(GSH)、谷氨酸含量及超氧化物歧化酶(SOD)、乙酰胆碱酯酶(AChE)活力;通过HE染色及尼氏染色观察海马组织病理学变化;通过Western blot法检测谷氨酸受体1(Grin1)和Bax、caspase-3的表达。研究高原低氧条件下红景天苷对小鼠记忆损伤的保护作用,并初步探讨其保护机制。结果与高原模型组比较,给予红景天苷后能明显缩短小鼠潜伏期、增加穿越平台次数,不同程度的降低小鼠脑组织MDA、H_(2)O_(2)、谷氨酸含量及AChE活力,增加GSH含量及SOD活力,改善海马体中的神经元损伤,降低海马组织中Grin1和凋亡蛋白Bax、caspase-3的表达。结论红景天苷可以减轻氧化应激损伤、调节神经递质水平、缓解海马组织损伤并减少神经元凋亡,最终改善由高原低氧造成的小鼠记忆损伤。     

The possible protective mechanism of Hyperbaric oxygen (HBO) in memory impairments induced by Aβ25–35 in rats

Alzheimer’s disease is characterized by the accumulation and deposition of Aβ peptides in human brains. Aβ peptides are toxic to neurons by lots of mechanisms of which Aβ induced oxidative stress is one of the hypothesis. The present study aimed to determine the effect of Hyperbaric oxygen (HBO) on Aβ_25–35 induced cognitive deficits and oxidative stress and apoptosis effects in rats. Rats were given an injection of aggregated Aβ_25–35. After treatment with HBO for 20days, the learning and memory ability, hippocampus neuronal apoptosis, the activity of SOD, GSH content and the MDA level and mRNA and proteins expression of Bcl-2 and Bax were detected. Our results demonstrated that HBO could significantly improved the apoptosis hippocampus neuronal induced by Aβ_25–35, involving the improvement of the learning and memory impairment, which accompanied of increasing the gene and protein expression of bcl-2 and enhancing the activity of SOD and GSH content. These findings suggest that treatment of HBO might prevent the Aβ_25–35 induced learning and memory impairment by increasing the gene and protein expression of bcl-2 and enhancing the activity of SOD and GSH content to alleviate the apoptosis hippocampus neuronal. This suggests that HBO may be a potential therapeutic agent for AD.     

Comparison of the protective effect of (R)-α-methylhistamine and its prodrugs on gastric mucosal damage induced by ethanol in the rat

• 1.1. The gastroprotective activity of two azomethine prodrugs of (R)-α-methylhistamine was examined in lesions induced by absolute ethanol (1 ml/rat intragastrically for 1 h).
• 2.2. Pretreatment with (R)-α-methylhistamine as well as with the prodrugs (30 and 100 mg/kg intragastrically [IG]) significantly reduced macroscopically visible lesions caused by ethanol, with protection being almost complete at 100 mg/kg.
• 3.3. Histologically, in rats pretreated with the three compounds at a dose of 100 mg/kg, the evidence of damage was rare, with the appearance of gastric mucosa being similar in the different treatment groups.
• 4.4. Present results are suggestive of a local component in the protective activity of (R)-α-methylhistamine.

     

RNase attenuates acute lung injury induced by ischemia–reperfusion in mice

Treatment with ribonuclease (RNase) reportedly protects the heart after myocardial ischemia–reperfusion (I/R), but its potential effect on lung I/R injury (LIRI) is unknown. Thus, we aim to explore whether RNase treatment would relieve LIRI. Thirty-six C57BL/6J adult male wild-type mice were evenly divided into I/R + RNase (I/R + R) group, I/R group, and sham group. Lung I/R was induced by left pulmonary hilum occlusion for 1 h and reperfusion for 2 h. All mice were treated with RNase or same dosage of normal saline in advance. After I/R, blood and lung tissues were collected for analysis. The results showed that lung injury scores, wet/dry ratio, expressions of inflammatory cytokines, pulmonary apoptosis, and levels of serum extracellular RNA (exRNA), including microRNAs, were markedly elevated after I/R. However, RNase treatment significantly attenuated cytokine production in both lung tissue and serum and also suppressed pulmonary apoptosis as reflected by TUNEL staining and activated caspase-3. In addition, total serum exRNA levels in the I/R + R group had a downward trend versus the I/R group. In conclusion, the increase of circulating exRNA levels contributed to LIRI in adult mice, which could be relieved by injection of RNase during perioperative window. The potential mechanism is the decrease of serum exRNA level and the suppression of pulmonary inflammation and apoptosis.     

Reduction of liver tumerogenic effect of N-nitrosodiethylamine by treatment with ɣ-oryzanol in Balb/C mice

In recent years, naturally occurring phytochemicals with antioxidant capacity have generated surmount interest in their therapeutic usage against a wide range of pathological and toxicological conditions. The present study was designed to evaluate potential of ɣ-oryzanol (OZ), a bio-active natural antioxidant against hepatocellular carcinoma effect of the carcinogen N-nitrosodiethylamine in Balb/c mice. OZ inhibited the proliferation of Hep–3 B cell line in concentration dependent manner. Administration of OZ to N-nitrosodiethylamine induced Balb/c mice for 16 and 32 weeks showed reduction in levels of liver injury markers, restored the levels of liver tumor markers, suppressed the hepatic nodular incidence and multiplicity, and favorably modulated the liver antioxidant status in a time dependent manner. Histologically, no obvious signs of neoplasia in the liver tissues were observed in OZ supplemented rats with N-nitrosodiethylamine induced liver tumerogenesis. OZ was found to be effective for reduction of N-nitrosodiethylamine induced hepatocellular carcinoma.     

Prospective memory impairment in “ecstasy” (MDMA) users

Rationale Considerable research indicates that “ecstasy” users perceive their memory for future intentions (prospective memory) to be impaired. However, only one empirical study to date has directly tested how this capacity is affected by ecstasy use, and this study provided relatively limited information regarding the extent, scope, or implications of problems experienced. Objectives The present study assessed prospective performance on a laboratory measure of prospective memory that closely represents the types of prospective memory tasks that actually occur in everyday life and provides an opportunity to investigate the different sorts of prospective memory failures that occur (“Virtual Week”). Method Ecstasy user group (27 current users and 34 nonusers) was between participants, and prospective memory task (regular, irregular, time-check) was within participants. A measure sensitive to specific aspects of psychopathology was also administered. Results Ecstasy users were significantly impaired on Virtual Week, and these deficits were of a comparable magnitude irrespective of the specific prospective memory task demands. The pattern of results was unchanged after controlling for marijuana use, level of psychopathology, and sleep quality. Further, prospective memory was shown to be significantly impaired for both relatively infrequent and relatively frequent ecstasy users, although for the latter group the magnitude of this deficit was greater. Conclusions Prospective memory performance is sensitive to regular and even moderate ecstasy use. Importantly, ecstasy users experience generalized difficulties with prospective memory, suggesting that these deficits are likely to have important implications for day-to-day functioning.     

Reversal of propoxur-induced impairment of memory and oxidative stress by 4′-chlorodiazepam in rats

Carbamate pesticides like propoxur have been shown to adversely affect memory and induce oxidative stress on both acute and chronic exposure. The present study was designed to explore the modulation of the effects of propoxur over cognitive function by progesterone (PROG) and 4′-chlorodiazepam (4CD). Cognitive function was assessed using step-down latency (SDL) on a passive avoidance apparatus, transfer latency (TL) on a plus maze and spatial navigation test on Morris water maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and reduced glutathione (GSH) levels and catalase (CAT) activity. A significant reduction in SDL and prolongation of TL and spatial navigation test was found for the propoxur (10 mg/kg/d; p.o.) treated group at weeks 6 and 7 as compared with control. One-week treatment with 4CD (0.5 mg/kg/d; i.p.) antagonized the effect of propoxur on SDL, spatial navigation test as well as TL; whereas, PROG failed to modulate this effect at a dose of 15 mg/kg/d, i.p. Propoxur produced a statistically significant increase in the brain MDA levels and decrease in the brain GSH levels and CAT activity. Treatment with 4CD at the above dose attenuated the effect of propoxur on oxidative stress whereas PROG (15 mg/kg/d; i.p.) failed to influence the same. The results of the present study thus show that 4-CD has the potential to attenuate cognitive dysfunction and oxidative stress induced by toxicants like propoxur in the brain.     

Facilitating effect of histamine on spatial memory deficits induced by dizocilpine as evaluated by 8-arm radial maze in SD rats

AIM: To investigate whether or not histamine is involved in spatial memory deficits induced by dizocilpine (MK-801) as evaluated by 8-arm radial maze of rats. METHODS: 8-Arm (4-arm baited) radial maze was used to measure spatial memory in rats. RESULTS: Bilaterally intrahippocampal (ih) injection of MK-801 (0.3 μg/site) impaired working memory and reference memory in rats. Both histamine (50, 100 ng/site, ih) and intraperitoneal (ip) injection of histidine (100, 200 mg/kg) markedly improved the spatial memory deficits induced by MK-801. On the other hand, the ameliorating effect of histidine (100 mg/kg, ip) was completely antagonized by α-fluoromethylhistidine (α-FMH, 5 μg/site, ih), a potent and selective histidine decarboxylase (HDC) inhibitor, and H_1-antagonist pyrilamine (1 μg/site, ih), but not by H_2-antagonist cimetidine, even at a high dose (2.5 μg/site, ih). CONCLUSION: The hippocampal histamine plays an important role in the ameliorating effect on MK-801-induced spatial memory deficits,     

Effect of α-asarone on ethanol-induced learning and memory impairment in mice and its underlying mechanism

OBJECTIVE To investigate the effect ofα-asarone on ethanol-impaired cognitive ability and explore the underlying mechanism in mice. METHODS A mouse model of impaired learning and memory was created by ethanol(2.0 g · kg~(-1), ig). α-Asarone(7.5, 15 and 30 mg·kg~(-1), ip) was delivered 10 min prior to ethanol administration. After 40 min, the locomotor activity of mice with learning and memory impairment was evaluated by the open field test and the behavioral effect of α-asarone was evaluated using the novel object recognition test.Glutamate(Glu) and γ-aminobutyric acid(GABA) levels in the hippocampus were determined by ELISA, and the proteins expression levels of hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid(AMPA) receptor(Glu R2), N-methyl-D-aspartic acid(NMDA)receptor(NMDAR2 B), synaptophysin I(SYNΙ), glutamate transporter type 1(GLT-1) and calcium/calmodulindependent protein kinaseⅡ(Ca MKⅡ) were detected by Western blotting. RESULTS There was no significant difference in the horizontal or vertical locomotor activity between the ethanol and normal groups or the 7.5, 15 and 30 mg·kg~(-1)α-asarone groups[F(5, 48)=0.6536, P>0.05; F(5, 49)=1.995, P>0.05]. The recognition index in the ethanol group was significantly decreased as compared with that in the normal group[F(5, 46) =6.739, P<0.05]and was markedly increased in the α-asarone groups as compared with that in the ethanol group(P<0.05), with the exception of the 7.5 mg · kg~(-1)α-asarone group(P>0.05). The hippocampal Glu: GABA ratio in mice was significantly elevated in the ethanol group as compared with that in the normal group(33.42±0.8972 vs 30.79±0.2102, P<0.05) and significantly lower in the α-asarone groups(31.99±0.4986 vs. 33.42±0.8972; 30.97±0.1757 vs. 33.42±0.8972; 30.83 0.1723 vs. 33.42±0.8972, P<0.05). The expression levels of GluR2, NMDAR2B, pSYNⅠand p Ca MKII were significantly higher in the ethanol group as compared with those in the normal group(P<0.05) and obviously lower in the α-asarone groups(P<0.05), with the exception of GluR2, NMDAR2B and pCaMKⅡ in the 7.5 mg·kg~(-1)α-asarone group(P>0.05).And the expression level of GLT-1 was significantly lower in the ethanol group as compared with that in the normal group(P<0.05) and obviously higher in the α-asarone groups(P<0.05). CONCLUSION Pretreatment with α-asarone significantly improved the learning and memory impairment. A possible underlying mechanism is regulation of the calcium signaling cascade to correct functioning of related proteins, and thus, maintain the level of Glu.     

Tokishakuyakusan ameliorates spatial memory deficits induced by ovariectomy combined with β-amyloid in rats

Previously, we reported that ovariectomy (OVX) combined with β-amyloid peptide (Aβ) impaired spatial memory by decreasing extracellular acetylcholine (ACh) levels in the dorsal hippocampus. Here, we investigated the effect of tokishakuyakusan (TSS), a Kampo medicine, on the impairment of spatial memory induced by OVX combined with Aβ in rats. Repeated administration of TSS (300 mg/kg, p.o.) significantly decreased the number of errors in the eight-arm radial maze test. Though TSS had no effect on extracellular ACh levels at baseline, TSS significantly increased extracellular ACh levels in the dorsal hippocampus. These results suggest that TSS improves the impairment of spatial memory induced by OVX combined with Aβ by (at least in part) increasing extracellular ACh levels in the dorsal hippocampus.     

Dose–response relationship for the pharmacokinetic interaction of grapefruit juice with dextromethorphan investigated by human urinary metabolite profiles

Grapefruit juice (GFJ) has been shown to affect the pharmacokinetics of a large number of drugs, essentially by inhibition of efflux transporters and CYP3A4 monooxygenase in the small intestine. The GFJ dose usually used in human studies was one glass single-strength (1×). Information on a respective dose–response relationship is not available. We investigated the effect of GFJ of different concentration (0.25×, 0.5×, 1×, 2×) dosed in biweekly intervals in 19 volunteers. Components considered responsible for drug interactions, naringin, naringenin, bergamottin, and 6′,7′-dihydroxybergamottin were determined by LC–tandem mass spectrometry. Immediately after ingestion of GFJ, participants took an aqueous solution of dextromethorphan (DEX) as probe drug. Urine was collected in two sampling periods, 0–2 and 2–4 h, and excreted amounts of DEX and five metabolites associated with CYP3A4 and/or CYP2D6 enzyme activity were determined. Effects of GFJ were analyzed by the Wilcoxon matched-pairs signed-rank test against an average of four water control experiments. Two effects were highly significant: (i) a delay of total metabolite excretion in the first 2 h and (ii) an inhibition of the CYP3A4-dependent metabolic pathways. Effect magnitude and significance levels were dose-dependent and indicated 200 ml 1× GFJ as “lowest observed effect level” LOEL.