Blockade of neurokinin-3 receptors modulates dopamine-mediated behavioral hyperactivity

Acute activation or blockade of neurokinin-3 (NK-3) receptors has been shown to alter dopamine-mediated function and behaviors, however long-term effects of NK-3 receptor blockade remain largely unknown. The present study investigated whether acute and repeated administration of the NK-3 receptor antagonist SB 222200 altered hyperactivity induced by cocaine, and examined its effects on dopamine D1 receptor density in the striatum. Adult male CD-1 mice received either vehicle or SB 222200 (2.5 or 5 mg/kg, s.c.) 30 min before a cocaine injection (20 mg/kg, i.p.) and behavioral responses were recorded. Mice that were administered SB 222200 had an attenuated stereotypic response to cocaine compared to vehicle treated mice. Mice were also injected once daily with either vehicle or SB 222200 (5 mg/kg, s.c.) for 5 days, and after a 7-day drug-free period they were challenged with either saline, cocaine or the dopamine D1 receptor agonist SKF 82958 (0.125 or 0.25 mg/kg, i.p.). Mice injected with SB 222200 had significantly enhanced hyperactivity when challenged with cocaine or a low dose of SKF 82958 (0.125 mg/kg, i.p.) compared to control mice. Brains of mice administered vehicle or SB 222200 for 5 days were harvested after a 7-day drug-free period for dopamine D1 receptor quantification by radioligand binding. [³H] SCH 23390 homogenate binding studies showed a 19.7% increase in dopamine D1 receptor density in the striatum of SB 222200 treated mice. These data suggest that repeated blockade of NK-3 receptors enhances subsequent dopamine-mediated behaviors possibly resulting from dopamine D1 receptor up-regulation in the striatum.     

Radioprotective effects of chlorogenic acid against mortality induced by gamma-irradiation in mice

The radioprotective effects of the naturally occurring compound chlorogenic acid have been investigated against mortality induced by gamma-irradiation in mice. Chlorogenic acid was administrated at single doses of 100, 200 and 400 mg/kg 1 or 24 h prior to lethal dose of gamma-irradiation (8.5 Gy). At 30 days after treatment, the percentage of survival in each group was as follows: control, 20%; 100 mg/kg, 20% and 15%; 200 mg/kg, 45% and 15%; 400 mg/kg, 25% and 35% for 1 h and 24 h treatment prior gamma-irradiation, respectively. Survival rate was statistically increased in animals treated with this agent at 200 mg/kg at 1 h prior to irradiation as compared with the irradiation only group. Other doses of chlorogenic acid have not showed any enhanced survival when it was administrated at 1 or 24 h before irradiation. Chlorogenic acid exhibited concentration-dependent activity on 1,1-diphenyl-2-picrylhydrazyl free radical to show strong antioxidant activity. It appeared that chlorogenic acid with antioxidant activity reduced mortality induced by gamma-irradiation.     

Disruption of the female reproductive system by the phytoestrogen genistein

Studies in our laboratory have shown that developmental exposure to genistein causes deleterious effects on the reproductive system. Oral exposure to genistin (25mg/kg) increases uterine weight at 5 days of age similar to subcutaneous injection of genistein (20mg/kg) suggesting that subcutaneous injection of genistein is a suitable model for oral exposure to genistin. Mice treated neonatally by subcutaneous injection of genistein (0.5-50mg/kg) exhibit altered ovarian differentiation leading to multi-oocyte follicles (MOFs). Ovarian function and estrous cyclicity were disrupted in genistein treated mice with increasing severity over time. Reduced fertility was observed in mice treated with genistein (0.5, 5, or 25mg/kg) and infertility was observed at 50mg/kg. Females generated from genistein 25mg/kg females bred to control males have increased MOFs suggesting these effects can be transmitted to subsequent generations. Thus, neonatal treatment with genistein at environmentally relevant doses caused adverse consequences on reproduction in adulthood.     

Effect of the anticarcinogenic drug 6-mercaptopurine on mineral metabolism in the mouse

The effect of 6-mercaptopurine (6-MP) on mineral metabolism was investigated in mice. C57BL mice were given 6-MP for 5 consecutive days. Treatments were: no injection; saline; vehicle injection (carboxymethylcellulose (CMC]; 5 mg/kg 6-MP; 25 mg/kg 6-MP; 50 mg/kg 6-MP; 100 mg/kg 6-MP; and 150 mg/kg 6-MP. After the 5-day period, tissues were removed and the levels of calcium (Ca), magnesium (Mg), zinc (Zn), copper (Cn) and manganese (Mn) were measured. In liver, but not in intestine or kidney, zinc and calcium levels increased in a dose-dependent manner. The weight of the stomach relative to body weight was significantly greater in mice receiving 100 mg/kg and 150 mg/kg BW doses of 6-MP than in those given lower doses, despite significantly lower body weight. This result indicated that 6-MP produced gastric toxicity. Injection of saline or vehicle had no effect on any of the parameters measured. The effect of 6-MP on mineral changes and on stomach-emptying may be partly responsible for at least some of its negative side-effects.     

Encephalopathy in rats and nephropathy in rats and mice after subchronic oral exposure to benzaldehyde

Male and female Fischer 344 rats and B6C3F1 mice were treated daily (5 days/wk) with benzaldehyde by gavage either in 12 doses of 0 (vehicle control), 100 (rats only), 200, 400, 800, 1600 or (for mice only) 3200 mg/kg body weight/day (followed by 2 days' observation without treatment), or for 90 days in doses of 0, 50, 100, 200, 400 or 800 mg/kg/day (rats) or 0, 75, 150, 300, 600 or 1200 mg/kg/day (mice). In the acute studies, benzaldehyde induced deaths and decreased body-weight gain in both sexes of rats given 800 or 1600 mg/kg/day and caused deaths in both sexes of mice given 1600 or 3200 mg/kg/day. In the 90-day studies, deaths occurred in both sexes of rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Body-weight gain was depressed in male rats on 800 mg/kg/day, in male mice on 600 mg/kg/day and in female mice on 1200 mg/kg/day. Necrotic and degenerative lesions were seen in the cerebellar and hippocampal regions of the brain in both sexes of rats given 800 mg/kg/day, but not in mice. Renal tubular necrosis occurred in male and female rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Mild epithelial hyperplasia or hyperkeratosis of the forestomach was seen in male and female rats on 800 mg/kg/day. In this limited study, the no-observed-toxic-effect doses of benzaldehyde administered by gavage were 400 mg/kg/day in male and female rats, 300 mg/kg/day in male mice and 600-1200 mg/kg/day in female mice.     

Dose and time relationships of the radioprotector WR-2721 on locomotor activity in mice

The effects of the radioprotector S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) on locomotor activity were evaluated in CD2F1 male mice. Separate groups of animals (N = 10/group) received an IP injection of vehicle, 25, 50, 100, 200, or 400 mg/kg of WR-2721 immediately before testing. Horizontal and vertical activity were measured using a Digiscan automated animal activity monitor. The latency to onset and duration of action of each dose of the radioprotector were recorded. For both behavioral measures, a significant reduction was observed in activity at doses of 200 and 400 mg/kg. A dose of 200 mg/kg had a 12- to 14-min latency to onset and significantly reduced behavioral activity for 3 hr. Mice injected with 400 mg/kg exhibited locomotor deficits within 8-10 min and were affected for up to 9 hr. The ED50 for horizontal and vertical activities at 1 hr postinjection were determined to be 271 and 105 mg/kg, respectively. The results demonstrate that significant reductions in locomotor activity are exhibited at doses of 200 mg/kg or more and that vertical activity was more sensitive to the disruptive effects of WR-2721 than was horizontal activity.     

delta1-tetrahydrocannabinol, cannabidiol and cannabinol effects on the immune response of mice.

delta1-tetrahydrocannabinol (THC) elicited a dose-dependent (1, 5, 10 mg/kg) depression of the immune response, of immature mice, stimulated with sheep red blood cells. The impairment of humoral immunity was specific for THC but not for cannabidiol at 25 mg/kg or cannabinol at 25 mg/kg. The mice were given four daily doses (i.p.) of either drug or vehicle (Tween 80-propylene glycol in 1% saline) or a single injection (i.p.) of sheep red blood cells in addition to four daily doses (i.p.) of drug or vehicle. Suppression of the antigenic response by THC was reflected as a reduction of splenic weight, reduction in the number of splenic antibody-forming cells, lowered hemagglutination titer and reduction in the percentage of splenic white pulp of total spleen volume.     

Citrus extract modulates genotoxicity induced by cyclophosphamide in mice bone marrow cells

The protective effect of citrus extract was investigated by using the micronucleus assay for anticlastogenic activity in mouse bone marrow cells; liver glutathione (GSH) content was determined against toxicity induced by cyclophosphamide. Mice were orally (gavage) pretreated with solutions of citrus peel extract (Citrus aurantium var. amara) prepared at three different doses (100, 200 and 400 mg kg(-1;) body weight) for 7 consecutive days. Then mice were injected intraperitoneally on the seventh day with cyclophosphamide (50 mg kg(-1)) and after 24 h killed for the evaluation of micronucleated polychromatic erythrocytes (MnPCEs) in bone marrow cells. Non-protein thiol levels in liver were estimated in mice injected with citrus extract with or without cyclophosphamide treatment. Administration of citrus extract before cyclophosphamide treatment significantly reduced the frequency of MnPCEs in mice bone marrow compared with the group treated with cyclophosphamide alone (P<0.0001-0.05). Citrus extract at a dose of 400 mg kg(-1) reduced MnPCEs 2.8 fold against genotoxicity induced by cyclophosphamide. Administration of cyclophosphamide depleted the GSH level in liver. Citrus extract showed excellent scavenging effects on 1,1-diphenyl-2-picryl hydrazyl radical (DPPH) at a concentration of 1.6 mg mL(-1). Application of citrus extract 1 h before cyclophosphamide treatment allowed GSH content to reach the normal level. It appeared that citrus extract, particularly flavonoids constituents with antioxidative activity, may return the GSH level to normal in stress conditions and reduces genotoxicity induced by cyclophosphamide in bone marrow cells.     

Radioprotective properties of the polysaccharide dextran sulfate

It has been shown that a single intraperitoneal injection of dextran sulfate (molecular weight 500 000, 60 mg/kg) to (CBA X C57BL)F1 mice 1-3 days before irradiation in lethal doses, with the irradiation dosage amounting to 8.10(-3), 3.10(-3) and 8.10(-4) Gy/c, increases the animals' survival rate. The effect of dextran sulfate on the degree of postradiation changes in the blood leukocyte count and in the bone marrow karyocyte count depends on the interval between dextran sulfate injection and irradiation.     

Cardiovascular responses to central clonidine, alpha-methyldopa, and 6-hydroxydopamine in conscious normotensive and spontaneously hypertensive rats following naloxone

The possible involvement of endogenous opioid peptides in the cardiovascular responses observed following central alpha-adrenoceptor stimulation with clonidine, alpha-methyldopa (alpha-MD), and 6-hydroxydopamine (6-OHDA) was examined in conscious normotensive Wistar and spontaneously hypertensive (SHR) rats. Clonidine [2.5 micrograms intracisternally (i.c.)] produced rapid hypotension (-36 +/- 2 mm Hg) and bradycardia (-53 +/- 5 beats/min) in SHR that were similar to observations in animals given either naloxone (50 micrograms i.c. or 10 mg/kg i.p.) or appropriate saline control injections. Peripheral doses of naloxone (1-2 mg/kg) or saline did not further change arterial pressure or heart rate in either Wistar rats or SHR given alpha-MD (1.0 mg i.c.) 3 h earlier. In addition, central doses of naloxone (3 X 50 micrograms i.c.) given at hourly intervals did not affect the responses to alpha-MD. Central administration of 6-OHDA acutely releases noradrenaline which produces an initial fall in arterial blood pressure and heart rate. Intracisternal 6-OHDA (400 micrograms) produced similar time course and maximum circulatory effects in rats given naloxone (50 micrograms i.c. before and at each subsequent hour) as in saline-treated animals. Naloxone (1 mg/kg s.c.) significantly attenuated morphine-induced analgesia. These findings do not support a critical role of endogenous opioids in mediating the acute antihypertensive actions of clonidine and alpha-MD or in the cardiovascular responses produced by noradrenaline release following central 6-OHDA.     

Combination of peramivir and rimantadine demonstrate synergistic antiviral effects in sub-lethal influenza A (H3N2) virus mouse model

Efficacy of combination of the intramuscularly administered neuraminidase (NA) inhibitor, peramivir, and the orally administered M2 ion channel blocker, rimantadine was evaluated in mouse influenza A/Victoria/3/75 (H3N2) model. Mice were challenged with a sub-lethal virus dose (0-40% mortality in placebo group) and changes in body weights were analyzed by three-dimensional effect analysis to assess mode of drug interactions. Compounds were administered in a 5-day treatment course starting 1h before viral inoculation. The peramivir and rimantadine doses ranged from 0.3-3 mg/kg/d and 5-30 mg/kg/d, respectively. The maximum mean weight loss of 5.19 g was observed in the vehicle-infected group on day 10. In the 1 and 3 mg/kg/d peramivir monotherapy groups, the weight losses were 4.3 and 3.55 g, respectively. In the rimantadine monotherapy group, the weight losses were 3.43, 2.1, and 1.64 g for the 5, 10, and 30 mg/kg/d groups, respectively. Combination of 1mg/kg/d peramivir with 5 and 10 mg/kg/d rimantadine produced weight losses of 1.69 and 0.69 (p<0.05 vs. vehicle and individual agent), respectively, whereas the combination of 3.0 mg/kg/d peramivir with 10 and 30 mg/kg/d rimantadine did not show any weight loss (p<0.05 vs. vehicle and individual agent). The three-dimensional analysis of the weight loss for the majority of the drug combinations of peramivir and rimantadine tested demonstrated synergistic antiviral effects.     

Toxicological evaluation of 4-vinylcyclohexene. I. Prechronic (14-day) and subchronic (13-week) gavage studies in Fischer 344 rats and B6C3F1 mice

4-Vinylcyclohexene (VCH), a dimer of 1,3-butadiene present in the gases discharged during tire curing, was examined for its toxic effects in Fischer 344 (F344) rats and B6C3F1 mice by 14-d prechronic and 13-wk subchronic testing. In the 14-d studies, VCH was administered orally by gavage in corn oil at doses of 0 (vehicle control), 300, 600, 1250, 2500, or 5000 mg/kg body weight to groups of five F344 rats and B6C3F1 mice of each sex, while the doses for the 13-wk studies (10 animals/group; 5 d/wk) were 0 (vehicle control), 50, 100, 200, 400, or 800 mg/kg body weight for rats and 0 (vehicle control), 75, 150, 300, 600, or 1200 mg/kg body weight for mice. All rats and most mice in the 14-d studies died when administered doses greater than or equal to 1250 mg/kg, although no compound-related gross or histopathologic effects were observed. In the 13-wk studies, extensive mortality was observed only in mice dosed at 1200 mg/kg. Final body weights were reduced in the 13-wk studies in male rats receiving doses greater than or equal to 400 mg VCH/kg, in female rats receiving 800 mg/kg, and in female mice receiving 600 mg/kg. Compound-related histopathologic effects in the 13-wk studies included hyaline droplet degeneration of the proximal convoluted tubules of the kidney in dosed male rats, the severity of which was dose-related, and a reduction in the number of primary follicles and mature graafian follicles in the ovaries of female mice receiving 1200 mg VCH/kg. No compound-related gross or histopathologic effects were evident in dosed female rats or male mice in the 13-wk studies.     

Toxicity and carcinogenicity of hydroquinone in F344/N rats and B6C3F1 mice.

Toxicology and carcinogenesis studies were conducted by administering hydroquinone (more than 99% pure) by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 wk or 2 yr. 14-day studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg, 5 days/wk. In the 13-wk studies, doses for rats and mice ranged from 25 to 400 mg/kg. At those doses showing some indication of toxicity in the 14-day and 13-wk studies, the central nervous system, forestomach and liver were identified as target organs in both species and renal toxicity was observed in rats. Based on these results, 2-yr studies were conducted by administering 0, 25 or 50 mg hydroquinone/kg in deionized water by gavage to groups of 65 rats of each sex, 5 days/wk. Groups of 65 mice of each sex were given 0, 50 or 100 mg/kg on the same schedule. 10 rats and 10 mice from each group were killed and evaluated after 15 months. Mean body weights of high-dose male rats and high-dose mice were approx. 5-14% lower than those of controls during the second half of the study. No differences in survival were observed between dosed and control groups of rats or mice. Nearly all male rats and most female rats in all vehicle control and exposed groups had nephropathy, which was judged to be more severe in high-dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts were increased in male rats. Tubular cell hyperplasia of the kidney was seen in two high-dose male rats, and renal tubular adenomas were seen in 4/55 low-dose and 8/55 high-dose male rats; none was seen in vehicle controls or in female rats. Mononuclear cell leukaemia in female rats occurred with increased incidences in the dosed groups (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). Compound-related lesions observed in the liver of high-dose male mice included anisokaryosis, syncytial alteration and basophilic foci. The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice.(ABSTRACT TRUNCATED AT 400 WORDS)     

重组人粒细胞集落刺激因子融合蛋白对急性放射病小鼠的治疗作用

目的研究重组人血清白蛋白-粒细胞集落刺激因子融合蛋白（GW003）对急性辐射损伤小鼠的治疗作用。方法 80只BALB/c小鼠用60Coγ射线一次全身照射5.0 Gy后随机分为照射对照,GW003 1、3和9 mg/kg 4组,照射后1 h和7 d分别皮下注射生理盐水,GW003 1、3和9 mg/kg。照前1 d和照后30 d内隔日一次检测外周血细胞,照射后30 d处死小鼠取胸骨行组织病理学观察。结果 60Coγ射线5.0 Gy照射后小鼠外周血白细胞、中性粒细胞、淋巴细胞和单核细胞数急剧下降,其中1和3 mg/kg GW003组白细胞和中性粒细胞减少持续时间较照射对照组显著缩短,开始恢复时间提前,白细胞最低值明显升高。GW003 9 mg/kg组上述指标与照射对照组相比有所改善,但无显著差异。3 mg/kg GW003组小鼠单核细胞数于照射后9～13 d明显高于照射对照组。各组间外周血淋巴细胞、血小板及红细胞数无明显差异。胸骨病理组织切片显示照射后30 d各组活存小鼠骨髓造血均十分活跃。结论 GW003对60Coγ射线5.0 Gy照射所致急性放射病小鼠有明显的治疗作用。     

Cocaine sensitization in the mouse using a cumulative dosing regime

Many rodent models of cocaine sensitization use intermittent high doses of cocaine pretreatment followed by testing with a single moderate cocaine dose. The aim of the present study was to investigate the rate and extent of sensitization to the locomotor-stimulant effects of cocaine using multiple cocaine doses (5-40 mg/kg). Eight groups of male Swiss-Webster mice were pretreated with either single doses of cocaine (40 mg/kg) or saline in the home cage, or multiple doses in the test environment, for 4 days. On the fifth day they were tested for locomotor activity, following a single dose of saline and cumulative doses of cocaine (5-40 mg/kg at 10-minute intervals). All eight groups of mice developed context-dependent sensitization to the locomotor stimulant effects of cocaine. Subsequent testing, at 10-day intervals, revealed that sensitization was maximal after five test sessions of cumulative cocaine dosing, regardless of the pretreatment regime. The main determinant of the rate at which sensitization occurred was the frequency of cumulative cocaine dosing. However, both the potency and efficacy of cocaine were altered by different pretreatments associated with exposure to the locomotor activity chambers. This robust context-dependent sensitization was long lasting, and not abolished by a 5-day extinction procedure involving cumulative saline dosing in the locomotor activity chambers. In conclusion, cumulative dosing and its inherent handling, in combination with cocaine, induced marked sensitization not produced by cocaine alone.     

Aegle marmelos (L.) Correa inhibits the proliferation of transplanted Ehrlich ascites carcinoma in mice

The anticancer effect of hydroalcoholic extract of Aegle marmelos (AME) was studied in the Ehrlich ascites carcinoma bearing Swiss albino mice. The spatial effect of various AME administration schedules showed that six-day administration increased the survival of tumor bearing mice. The best antineoplastic action of AME was obtained when AME administered through intraperitoneal route than the oral route at equimolar dose. Administration of AME once daily for six consecutive days to the tumor bearing mice caused a dose dependent remission of the tumor at 400 mg/kg body weight, where the greatest antitumor effect was observed and the higher doses showed toxic manifestations. A 24-d lengthening in life span was observed in EAC animals treated with 400 mg/kg AME. This dose of 400 mg/kg was considered as the best dose, where the animals survived up to 43 d post-tumor-cell inoculation as against no survivors in the saline treated control group. The antitumor activity when tested for different schedules for triple administrations, the best effect was observed for 1-2-3, followed by 1-3-5 and 1-5-9 days, respectively. Stage specific evaluation of AME inhibited the increase in body weight gain in animals due to tumor development during early stages only. The AME treatment resulted in a dose dependent elevation in the median survival time (MST) and average survival time (AST) up to 400 mg/kg AME and decline thereafter. The effective dose of 400 mg of AME is 1/6th of the LD50 dose, which increased the MST and AST up to 29 and 27 d, respectively. The acute toxicity study of AME showed that the drug was non-toxic up to a dose of 1750 mg/kg b. wt. The LD10 and LD50 was found to be 2000 and 2250 mg/kg.     

Phototoxic retinal degeneration and toxicokinetics of sitafloxacin, a quinolone antibacterial agent, in mice

We examined drug concentrations and the incidence of retinal degeneration in the eyes of albino BALB/c mice after a single intravenous administration of sitafloxacin plus a 4 h period of UVA irradiation. Retinal degeneration was induced at 40 mg/kg or more plus UVA irradiation, and there was little decrease in ocular sitafloxacin concentration under UVA irradiation. We then examined the incidence of retinal degeneration with various periods of UVA irradiation in BALB/c mice given a single intravenous administration of 40 mg/kg sitafloxacin. Retinal degeneration occurred in all the groups receiving UVA irradiation immediately after sitafloxacin administration, whereas no retinal degeneration occurred in the groups receiving UVA irradiation starting 30 min or later after administration. In addition, we examined both the retinal degeneration and auricular inflammation in BALB/c mice given a 7-day repeated administration of sitafloxacin at 1, 3.3 and 10 mg/kg per day, which never induce retinal or auricular change by a single administration. Retinal degeneration was not induced at any dose level, although auricular skin inflammation was augmented by repeated administration. These results suggest that the occurrence of retinal degeneration depends on maximum ocular sitafloxacin concentration during UVA irradiation, whereas the severity of auricular inflammation is directly proportional to the total decrease in area under the drug concentration curve for auricular sitafloxacin under UVA irradiation. This difference between retinal degeneration and auricular inflammation may derive from their respective mechanisms of pathogenesis.     

Preventive effects of interleukin-6 in lipopolysaccharide/d-galactosamine induced acute liver injury via regulating inflammatory response in hepatic macrophages

Lipopolysaccharide/d-Galactosamine (LPS/d-Gal)-induced acute liver injury is characterized by significant inflammatory responses including TNF-α and interleukin-6 (IL-6) and is a widely applied experimental model for inflammation research. TNF-α is critical in the progression of LPS/d-Gal-induced liver injury. However, the role of IL-6 in this model is still unknown. In the present study, we aim to elucidate the involvement of IL-6 in the pathogenesis of acute liver injury induced by LPS/d-Gal in mice and its underlying mechanism. To induce acute liver injury, LPS (50 μg/kg body weight) and d-Gal (400 mg/kg body weight) were injected intraperitoneally in the C57BL/6 mice. The vehicle (saline) or a single dose of recombinant IL-6 (200 μg/kg body weight) was administered 2 h prior to LPS/d-Gal injection. Mice were sacrificed 2 h and 6 h after LPS/d-Gal injection. The results indicated that IL-6 treatment could protect mice from LPS/d-Gal-induced tissue damage, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, as well as hepatocyte apoptosis and inflammation. Furthermore, in vitro study showed that IL-6 treatment could significantly suppress LPS-triggered expression of proinflammatory cytokines and chemokines, TNF-α, RANTES and MCP-1 in macrophages while promoting the expression of M2 markers, such as Arg-1 and Mrc-1 in macrophages. Taken together, these findings revealed a novel and unexpected role of IL-6 in ameliorating LPS/d-Gal-induced acute liver injury via regulating inflammatory responses in hepatic macrophages.     

Nisoxetine and amphetamine share discriminative stimulus properties in mice

The interaction of amphetamine with noradrenergic neurons could mediate a portion of the drug's discriminative stimulus properties. To test this hypothesis, mice were trained to discriminate 1.0 or 3.2 mg/kg amphetamine, 32 mg/kg of the selective norepinephrine uptake inhibitor, nisoxetine, or 32 mg/kg nisoxetine + 1.0 mg/kg amphetamine from saline. Differential drug- or saline-appropriate responding was determined using a two photocell-beam procedure with beam interruption as the operant. Reinforcement (5-sec access to evaporated milk) was presented on a fixed-ratio 20 (FR-20) schedule. Mice trained to discriminate 1.0 mg/kg amphetamine from saline generalized to nisoxetine (32 mg/kg) alone and to doses of 0.56 mg/kg amphetamine and above but not to lower doses unless pretreated with nisoxetine (20 or 32 mg/kg). Mice trained to discriminate nisoxetine (32 mg/kg) from saline generalized to 0.56, 1.0 and 3.2 mg/kg amphetamine and generalized to all amphetamine doses when pretreated with nisoxetine (32 mg/kg). Mice trained to discriminate the drug combination from saline generalized to nisoxetine (32 mg/kg) alone, and to 3.2 mg/kg amphetamine tested alone, to 0.56 mg/kg of amphetamine or above when the lower dose of nisoxetine (20 mg/kg) was used, and to all test doses of amphetamine with nisoxetine (32 mg/kg) pretreatment. Mice trained to discriminate 3.2 mg/kg amphetamine from saline generalized to no test dose of amphetamine following either saline or nisoxetine (32 mg/kg) pretreatment. Testing with several doses of pentobarbital (1.0, 3.0, 10.0 and 18.0 mg/kg) resulted in saline-appropriate responding regardless of training group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Ethylenethiourea-induced hindpaw deformities in mice and effects of metabolic modifiers on their occurrence

Time-mated Swiss-Webster mice were pretreated in separate experiments with phenobarbital (60 mg/kg X d sc on d 7-10 of pregnancy), SKF-525A (40 mg/kg ip on d 12 of pregnancy) or 3-methylcholanthrene (20 mg/kg X d on d 10-12 of pregnancy). On the d 12 of pregnancy (1 h after SKF-525A or 3-methylcholanthrene treatment), one group each of pretreated mice was given a single oral dose of 1600, 2000, or 2400 mg/kg of ethylenethiourea (ETU) as a 5% concentrate in a 1.5% aqueous gelatin solution, which as a vehicle was given to other pretreated groups. The respective volume doses were 3.2, 4.0, or 4.8 ml/100 g body weight with the controls given 4.8 ml/100 g body weight of vehicle alone. Maternal toxicity was observed in all groups given ETU, whether pretreated with metabolic modifiers or not. In the three experiments, treatment with ETU alone reduced fetal weight by 15% at 2400 mg/kg and 8% with the remaining 2 doses, and increased the incidence of resorptions (19-62% with the 2400 mg/kg dose, 8-59% at 2000 mg/kg, and 7-32% at the 1600 mg/kg dose). The significant defects with incidence ranges in three experiments were: hindpaw ectrodactyly, 2-6% at 1600 mg/kg, 4-20% at 2000, and 20-29% at 2400 mg/kg; and hindpaw syndactyle, 3% at 16 mg/kg, 6-14% at 2000, and 2-12% at 2400 mg/kg doses. Minor incidences of cleft palate and hindpaw polydactyly were also observed. Phenobarbital pretreatment did not change the ETU-induced maternal or fetal effects. SKF-525A enhanced the resorptions and reduced the litter-size but had no effect on fetal malformations. The 3-methylcholanthrene pretreatment reduced the ETU-induced incidences of hindpaw ectrodactyly, hindpaw syndactyly, and cleft palate at the 2000 and 2400 mg/kg doses. Previous studies with rats and hamsters revealed that SKF-525A enhanced the ETU-induced fetal malformations but phenobarbital and 3-methyl-cholanthrene had no effect in these two species.