BCEF0083对慢性应激抑郁模型大鼠海马神经元及脑源性神经营养因子mRNA表达的影响研究

目的:研究BCEF0083对慢性应激抑郁模型大鼠海马神经元及脑源性神经营养因子(BDNF)mRNA表达的影响。方法:将大鼠随机分为对照组、模型组、吗氯贝胺20mg/kg组以及BCEF0083100、50、25mg/kg组,用HE染色法观察海马神经元数目的变化,用逆转录-聚合酶链反应法检测海马BDNFmRNA的表达。结果:BCEF0083可增加慢性应激抑郁模型大鼠海马神经元数目及上调BDNFmRNA的表达。结论:BCEF0083的抗抑郁作用可能与增加慢性应激抑郁模型大鼠海马神经元数目及上调BDNFmRNA的表达有关。     

利奈唑胺对大鼠血细胞的影响及与氧化应激间的关系

目的研究利奈唑胺对大鼠血细胞的影响及与氧化应激间的关系。方法将80只大鼠分为4组:空白对照组、利奈唑胺50、100、250 mg/kg组,连续给药15 d,监测血细胞及血清超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、还原型谷胱甘肽(GSH)、谷胱甘肽过氧化物酶(GSH-Px)、还原型辅酶Ⅱ(NADPH)、丙二醛(MDA)的变化。结果 250 mg/kg利奈唑胺可引起大鼠血细胞减少,血清SOD、CAT活性下降,MDA含量增加;100、250mg/kg利奈唑胺可引起大鼠血清NADPH含量升高,与空白对照组比较差异有统计学意义;各组利奈唑胺对大鼠血清GSH、GSH-Px活性无显著性影响。结论高剂量利奈唑胺较长时程给药后可引起大鼠血细胞减少,其机制可能与引起机体氧化应激后诱导脂质过氧化产生有关。     

柴胡疏肝散对肝郁性乳腺增生模型大鼠的保护作用

目的:研究柴胡疏肝散对肝郁性乳腺增生模型大鼠的保护作用。方法:以夹尾激怒大鼠,每天1次,连续30 d;联合im给予苯甲酸雌二醇(0.5 mg/kg),每天1次,连续25 d后,im给予黄体酮(4 mg/kg),每天1次,连续5 d以复制大鼠肝郁性乳腺增生模型。80只Wistar大鼠随机均分为正常对照(等容生理盐水)组、模型(等容生理盐水)组、预防给药[复制模型同时ig给药,每天1次,6.3 g(生药)/kg,连续60 d]组、三苯氧胺(1.8 mg/kg)组、乳癖消(0.6 g/kg)组与柴胡疏肝散高、中、低剂量[12.6、6.3、3.15 g(生药)/kg]组,除预防给药组外其余各组大鼠均于复制模型结束后ig给药,每天1次,连续30 d。测定大鼠乳房直径、乳头高度;称定大鼠第2对乳房的乳腺质量;采用酶联免疫吸附(ELISA)法测定大鼠血清促性腺激素释放激素(Gn RH)、促卵泡激素(FSH)、黄体生成素(LH)、催乳素(PRL)、雌二醇(E2)、孕酮(P)、5-羟色胺(5-HT)和乳腺组织中血管内皮生长因子(VEGF)、碱性成纤维细胞生长因子(b FGF)的水平。结果:与正常对照组比较,模型组大鼠乳房直径、乳头高度和乳腺质量增加;血清Gn RH、FSH、PRL、E2、5-HT水平增加,血清P含量减少;乳腺组织VEGF、b FGF含量增加,差异均有统计学意义(P<0.01或P<0.05)。与模型组比较,预防给药组与柴胡疏肝散高、中剂量组大鼠乳房直径、乳头高度和乳腺质量减少,血清Gn RH、FSH、E2、5-HT水平降低,乳腺组织b FGF含量减少;预防给药组与柴胡疏肝散高剂量组大鼠血清P含量增加,乳腺组织VEGF含量减少;预防给药组与柴胡疏肝散高、中、低剂量组大鼠血清PRL含量减少;柴胡疏肝散高剂量组大鼠血清LH活性增强,差异均有统计学意义(P<0.01或P<0.05)。结论:柴胡疏肝散对乳腺增生模型大鼠有一定的保护作用,其机制与改善血清相关激素水平有关。     

乳泉冲剂对实验性泌乳不足大鼠泌乳量的影响

目的评价乳泉中剂对实验性泌乳不足大鼠泌乳量的影响.方法取Wistar大鼠,随机分为6组,选用己烯雌酚建立实验性泌乳不足模型.各组母鼠自产后当天起,每日给药一次,连续10d,记录母鼠的泌乳量,用放射免疫法测定母鼠血清催乳素(PRL)水平,并取乳腺活检.结果乳泉冲剂可使母鼠泌乳量明显增多,仔鼠体重增长加速,且母鼠的血清催乳素分泌水平有所提高.结论乳泉冲剂可有效地拮抗己烯雌酚抑制泌乳作用.     

吗氯贝胺的一般药理研究

药理试验结果表明，剂量低于200mg／kg吗氯贝胺对中枢神经系统无明显作用，高于200mg／kg时具有抑制作用。吗氯贝胺对血压、心率、心电图、呼吸频率与幅度均无明显影响，亦无抗胆碱能作用。     

抗抑郁剂慢性给药对强迫游泳大鼠下丘脑c-Fos蛋白表达水平的下调作用

应用c-Fos蛋白免疫组织化学定位观察的方法, 在强迫游泳大鼠抑郁模型上, 观察地昔帕明(5, 20 mg·kg^-1), 吗氯贝胺 (10, 40 mg·kg^-1)和氟西汀 (5, 20 mg·kg^-1) 慢性给药 (ip 每日1次, 连续7 d)对大鼠游泳不动时间和下丘脑核团c-Fos蛋白表达水平的影响. 结果表明: 强迫游泳可使大鼠下丘脑多个核团的c-Fos蛋白表达水平明显升高, 而地昔帕明, 吗氯贝胺, 氟西汀明显缩短强迫游泳大鼠的不动时间, 并选择性地使强迫游泳诱导增加的下丘脑室旁核Fos样免疫阳性神经元数目明显减少. 提示下丘脑室旁核可能是介导抗抑郁剂抑制大鼠绝望行为的中枢部位之一. Fos蛋白可能是不同类型抗抑郁剂共同的受体后信号转导物质.     

乳结平胶囊对乳腺增生大鼠乳腺组织ER、PR表达的影响

目的:探讨乳结平胶囊对乳腺增生大鼠病理组织雌激素受体(ER)和孕酮受体(PR)表达的影响。方法:先采用苯甲酸雌二醇注射液连续im25d,后改用黄体酮注射液连续im5d,从而建立大鼠乳腺增生模型,以三苯氧胺为阳性对照药物,用乳结平胶囊高、低剂量治疗30d。结果:三苯氧胺组及乳结平胶囊高、低剂量组均能减轻大鼠乳头红肿或增生症状,降低大鼠血清雌二醇(E2)、催乳素(PRL)水平及升高孕酮(P)水平,降低子宫指数,明显减少导管上皮细胞层数和腺泡数,同时减少乳腺组织ER、PR的含量,抑制乳腺组织增生。结论:乳结平胶囊可通过调节雌激素水平,改善增生乳腺的病理形态变化,从而有效治疗大鼠乳腺增生。     

吗氯贝胺治疗抑郁症

目的 :比较吗氯贝胺和丙米嗪治疗抑郁症的疗效及不良反应。方法 :10 7例抑郁症分成 3组。吗氯贝胺双盲组 (吗氯贝胺组 ) 2 5例 (男性 16例 ,女性 9例 ;年龄 36a±s 10a) ,予吗氯贝胺 2 0 0mg ,po ,bid。丙米嗪双盲组 (丙米嗪组 ) 2 6例 (男性 14例 ,女性 12例 ;年龄 36a± 12a) ,予丙米嗪 10 0mg ,po ,bid。吗氯贝胺开放组 (开放组 ) 56例 (男性 2 7例 ,女性 2 9例 ;年龄 39a± 13a)予吗氯贝胺 2 0 0mg ,po ,bid ;均 4wk为一个疗程。结果 :吗氯贝胺组有效率 96% ,丙米嗪组 96% ,Ridit分析P >0 .0 5,开放组 95%。药物不良反应发生率丙米嗪组高于吗氯贝胺组。结论 :吗氯贝胺与丙米嗪治疗抑郁症疗效相同 ,不良反应少     

急性肝衰竭时催乳素变化的实验研究

目的探讨急性肝衰竭大鼠催乳素变化及雌二醇对该变化的影响。方法Wistar雄性大鼠被随机分成三组,正常组(对照组),硫代乙酰胺(thioacetamide,TAA)组,苯甲酸雌二醇加硫代乙酰胺(TAA E2)组。TAA组、TAA E2组大鼠用硫代乙酰胺(600 mg.kg-1)间隔24 h两次皮下注射,复制大鼠急性肝衰竭的动物模型,TAA E2组同时皮下注射苯甲酸雌二醇注射液。对照组以同样方法皮下注射生理盐水。1 d后眼球取血,离心后放射免疫法观察血清PRL及雌二醇(E2)浓度。结果TAA、TAA E2两组血清PRL浓度与对照组相比有明显变化(P<0.05),但TAA组与TAA E2组之间血清PRL浓度无变化(P>0.05),TAA组与E2 TAA组血清雌二醇存在差异(P<0.05)。结论TAA诱导急性肝衰竭时,血清PRL可升高,但不受外源雌二醇影响。     

不同疗程灯盏细辛对大鼠脑缺血恢复期内源性脑源性神经营养因子及酪氨酸激酶受体B表达的影响

目的:观察灯盏细辛对大鼠脑缺血恢复期内源性脑源性神经营养因子(BDNF)及酪氨酸激酶受体B(TrkB)合成的影响.方法:采用改良Zealonga法建立大鼠大脑中动脉局灶缺血/再灌注梗死(MCAO)模型.将60只大鼠随机分为MCAO模型组、假手术组、短期给药组(灯盏细辛2.7ml/kg,共7d)、长期给药组(灯盏细辛2.7ml/kg,共28d),各15只.4周末处死作BDNF、TrkB免疫组化.结果:2给药组BDNF和TrkB的IOD值均高于MCAO模型组,差异有统计学意义(P<0.05);且长期给药组BDNF和TrkB IOD值高于短期给药组,差异有统计学意义(P<0.05).结论:灯盏细辛可诱导脑梗死后BDNF及其高亲和性受体TrkB表达上调,这可能是灯盏细辛对脑梗死恢复期保护作用的机制之一.     

The male mammary gland: A target for the xenoestrogen bisphenol A

Males of some strains of mice retain their mammary epithelium even in the absence of nipples. Here, we have characterized the mammary gland in male CD-1 mice both in whole mounts and histological sections. We also examined the effects of bisphenol A (BPA), an estrogen mimic that alters development of the female mouse mammary gland. BPA was administered at a range of environmentally relevant doses (0.25–250 μg/kg/day) to pregnant and lactating mice and then the mammary glands of male offspring were examined at several periods in adulthood. We observed age- and dose-specific effects on mammary gland morphology, indicating that perinatal BPA exposures alter the male mammary gland in adulthood. These results may provide insight into gynecomastia, the most common male breast disease in humans, where proliferation of the mammary epithelium leads to breast enlargement.     

围刺配合电针对乳腺增生大鼠血清激素水平和乳腺组织形态、ER 表达的影响

目的观察围刺配合电针对乳腺增生大鼠血清性激素雌与孕激素的比值（E2／P）、泌乳素（PRL）、睾酮（T）、乳腺组织形态和乳腺组织ER表达的影响,以探讨干预治疗乳腺增生的作用机制。方法随机将40只Wistar大鼠分为模型组、针刺组、三苯氧胺组及正常组,每组10只。采用己烯雌酚联合黄体酮肌内注射进行造模。针刺组：将大鼠固定,分别围刺第2对左右乳房后,接通电针仪持续刺激30min,并针刺膻中穴,留针30min;三苯氧胺组予三苯氧胺1．8mg／kg灌胃治疗,1次／d,共30d。于末次治疗后测定血清E2、P、PRL、T含量,计算E2／P比值;取大鼠第2对乳房常规HE染色,光镜下观察组织形态表现;运用免疫组化法对乳房乳腺组织中ER表达情况进行观察。结果治疗后E2／P：针刺组与三苯氧胺组比值均低于模型组（P〈0．05）。PRL：针刺组和三苯氧胺组均低于模型组（P〈0．05）;针刺组与三苯氧胺组比较差异有统计学意义（P〈0．05）。T：针刺组和三苯氧胺组均低于模型组（P〈0．05）。乳腺组织ER表达：针刺组和三苯氧胺组大鼠乳腺组织ER阳性细胞表达情况显著降低,AOD值低于正常组（P〈0．05）。结论围刺配合电针具有降低模型大鼠乳头高度、缩小乳头直径,改善血清E2／P、PRL、T紊乱状态和乳腺组织病理形态,降低乳腺增生模型大鼠乳腺组织ER表达的作用。     

Carcinogenic potential of o-nitrotoluene and p-nitrotoluene

The potential of o-nitrotoluene and p-nitrotoluene to cause cancer in mammalian species was studied in male and female F344/N rats and B6C3F1 mice. These chemicals are on the EPA list of high production chemicals and there is potential for human exposure (High Production Volume Chemical List (2000) http://oaspub.cpa.gov/opptintr/chemrtk/volchall.htm.). o-Nitrotoluene, administered in the feed for up to 2 years, caused clear evidence for cancer at multiple sites in rats and mice. Male rats, receiving o-nitrotoluene in the feed ( approximately 0, 25, 50, or 90 mg/kg per day), developed treatment-related mesotheliomas, subcutaneous skin neoplasms, mammary gland fibroadenomas, and liver neoplasms. By 2 years, mesotheliomas, skin, liver, mammary gland and liver tumors also occurred in 'stop-study' male rats that received o-nitrotoluene at 125 or 315 mg/kg per day for only the first 3 months of study. These 'stop-studies' showed that the critical events leading to tumor formation occurred after 3 months of dosing, and these events were irreversible and eventually led to cancer at multiple sites. o-Nitrotoluene given in the feed to female rats (approximately 0, 30, 60, or 100 mg/kg per day) and to male and female mice (approximately 0, 150, 320, or 700 mg/kg per day) also caused a carcinogenic response. In female rats, treatment-related subcutaneous skin neoplasms and mammary gland fibroadenomas occurred. Hemangiosarcomas and carcinomas of the large intestine (cecum) were seen in treated male and female mice. In contrast to o-nitrotoluene, p-nitrotoluene given in the feed over approximately the same exposure levels caused only equivocal evidence of carcinogenic activity in male rats (subcutaneous skin neoplasms); some evidence of carcinogenic activity in female rats (clitoral gland neoplasms); equivocal evidence of carcinogenic activity in male mice (lung neoplasms); and no evidence of carcinogenic activity in female mice. Differences in the o-nitrotoluene and p-nitrotoluene carcinogenic activity may be due to differences in the metabolism of the parent compound to carcinogenic metabolites.     

荔枝核提取物抑制大鼠乳腺增生及调节激素水平研究

目的：探讨荔枝核提取物对大鼠乳腺增生病以及激素作用及其作用机制。方法：取健康、未孕雌性SD大鼠60只,按体重随机分为正常对照组,模型对照组,荔枝核提取物高、中、低剂量组（44、22、11g／kg）,乳结平组（3．3g／kg）,每组10只。实验结束时,观察各组大鼠乳头高度,光镜检查乳腺组织病理变化,用放射免疫法（RIA）分析测量血清雌二醇（E2）、孕酮（P）、泌乳素（PRL）的水平。结果：模型对照组大鼠乳头红肿或增生明显,导管上皮细胞层数、腺泡数明显增加,血清激素B和PRL水平明显升高,而P水平明显降低,与正常对照组比较,差异有统计学意义（P〈0．01）。乳结平组和荔枝核提取物高、中剂量组均能逆转病鼠乳头直径、高度、导管上皮细胞层数和腺泡数（P〈0．01）,并降低B和PRL水平（P〈0．01）,而提高P含量（P〈0．05或0．01）;荔枝核提取物低剂量组也能不同程度地逆转大鼠乳头红肿或乳腺组织增生（P〈0．01）,提高P含量（P〈0．05）,但B和PRL水平则未见统计学明显差异（P〉0．05）。结论：荔枝核提取物可调节乳腺增生大鼠的激素水平,改善增生乳腺的病理形态变化。推测荔枝核的部分作用机制,可能是调整下丘脑-垂体-卵巢性腺轴功能紊乱,从而有效地对抗雌激素性大鼠乳腺增生病。     

Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments

Prolactin-induced mammary carcinogenesis in rodents, particularly rats, is often stated to be of low toxicological relevance to humans. This opinion appears to have developed from a number of lines of cited evidence. Firstly, there had been long experience of use of dopamine antagonists (that increase prolactin) in human medicine and no evidence of an increase in breast cancer incidence or risk had been reported. Secondly, dopamine agonists (that lower prolactin) had been shown to have no effect in human breast cancer treatment. Thirdly, the actions of prolactin were considered different between rodents and humans. However, recent evidence now suggests that prolactin has a major role in human breast cancer, and the similarity of mechanism with the rodent suggests that prolactin-mediated mammary carcinogenesis in rodents could be of much higher toxicological relevance to humans than previously thought. Large epidemiology studies have upgraded a limited database and shown that dopamine antagonists (both antipsychotics and anti-emetics) increase breast cancer risk, that hyperprolactinaemia is consistently associated with human breast cancer growth, development and poor prognosis, and that prolactin is indeed a mitogen in human breast cancer cells that suppresses apoptosis and upregulates BRCA1. It is now clear that initial studies giving dopamine agonists to breast cancer patients had no effect because breast cancer cells also produced prolactin independently of the pituitary, which remained uncontrolled and unrecognized in early clinical studies. The evidence for the role of prolactin in human breast cancer is now strong and consistent, and is discussed and related to the risk assessment of drugs and chemicals. The conclusion is that it is invalid to suggest that prolactin-induced mammary carcinogenesis in rodents is of low relevance to humans because prolactin can induce an adverse response in the mammary tissue of both rodents and humans alike. Drugs and chemicals causing rodent prolactin-induced mammary carcinogenesis may therefore pose a risk to humans via the same mechanism if exposures also increase prolactin secretion in humans.     

Haloperidol treatments increased macrophage activity in male and female rats: influence of corticosterone and prolactin serum levels.

Haloperidol is a receptor D2 antagonist frequently used in the treatment of schizophrenic patients. Haloperidol increased prolactin release from anterior pituitary gland, and prolactin modulates immune system activity. Groups of six male and female rats received an acute 2 mg/kg haloperidol treatment (E1), or a long-term (E2) haloperidol treatments (2 mg/kg/day for 21 days); control rats were treated similarly, but with control solution (groups C1 and C2, respectively). In this work long-term haloperidol treatment (E2) increased macrophage spreading, phagocytosis and NO release in male and female rats. However, acute haloperidol treatment (E1) did not change macrophage activity. Corticosterone and prolactin serum levels were increased after acute (E1) and long-term (E2) haloperidol treatments in male and female rats, being this increment higher in female. Macrophage of male and female rats presented the same pattern of alterations after acute and long-term haloperidol treatments. Haloperidol-induced macrophage activation was discussed in the light of a possible indirect effect through prolactin increments in rats, or, alternatively, as a consequence of a direct action of macrophage dopamine receptor.     

Toxicity and carcinogenicity of androstenedione in F344/N rats and B6C3F1 mice

Androstenedione was marketed as a dietary supplement to increase muscle mass during training. Due to concern over long-term use, the NTP evaluated the subchronic and chronic toxicity and carcinogenicity of androstenedione in male and female F344/N rats and B6C3F1 mice. In subchronic studies, dose limiting effects were not observed. A chronic (2-year) exposure by gavage at 10, 20, or 50 mg/kg in rats and male mice, and 2, 10, or 50 mg/kg in female mice (50 mg/kg, maximum feasible dose) was conducted. Increased incidences of lung alveolar/bronchiolar adenoma and carcinoma occurred in the 20 mg/kg male rats and increases in mononuclear cell leukemia occurred in the 20 and 50 mg/kg female rats, which may have been related to androstenedione administration. In male and female mice, androstenedione was carcinogenic based upon a significant increase in hepatocellular tumors. A marginal increase in pancreatic islet cell adenomas in male (50 mg/kg) and female (2, 10, 50 mg/kg) mice was considered to be related to androstenedione administration. Interestingly, incidences of male rat Leydig cell adenomas and female rat mammary gland fibroadenomas decreased. In conclusion, androstenedione was determined to be carcinogenic in male and female mice, and may have been carcinogenic in rats.     

A novel effect of dioxin: exposure during pregnancy severely impairs mammary gland differentiation.

Many ligands for the aryl hydrocarbon receptor (AhR) are considered endocrine disruptors and carcinogens, and assessment of adverse health effects in humans exposed to such chemicals has often focused on malignancies, including breast cancer. Mammary tissue contains the AhR, and inappropriate activation of the AhR during fetal development causes defects in mammary development that persist into adulthood. However, it is not known whether the extensive differentiation of mammary tissue that occurs during pregnancy is also sensitive to disruption by AhR activation. To examine this, we exposed pregnant C57Bl/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on days 0, 7, and 14 of pregnancy. Examination of mammary glands on days 9, 12, and 17 of pregnancy and on the day of parturition showed severe defects in development, including stunted growth, decreased branching, and poor formation of lobular alveolar structures. This impaired differentiation was biologically significant, as expression of whey acidic protein in the gland was suppressed, and all pups born to TCDD-treated dams died within 24 h of birth. Analysis of circulating progesterone, prolactin, and estradiol suggest that hormone production was slightly impaired by inappropriate activation of the AhR. However, hormone levels were affected only very late in pregnancy. Given that the observed defects in gland development preceded these hormonal effects, altered hormone levels are an unlikely mechanistic explanation for impaired mammary development. This novel finding that AhR activation during pregnancy disrupts mammary gland differentiation raises questions about the susceptibility of mammary tissue to direct injury by endocrine disrupting agents and the potential for AhR-mediated signaling to adversely affect lactation and breast tissue development in human populations.     

麦芽总生物碱对产后缺乳大鼠乳汁分泌的影响及机制研究

目的:探究不同剂量麦芽总生物碱(total barley maiya alkaloids,TBMA)对产后缺乳大鼠乳汁分泌的影响及机制.方法:产后24 h内SD大鼠随机分为对照组、模型组、胃复安组、7.5 g组(成人日服7.5 g生麦芽所含TBMA,下同)、15 g组、30 g组、60 g组,灌胃溴隐亭建立产后缺乳大鼠...     

Decreases in spontaneous tumors in rats and mice after treatment with amphetamine

Toxicology and carcinogenesis studies of dl-amphetamine sulfate, a drug used in the treatment of weight control, narcolepsy, and behavioral syndromes in children, were performed in F344/N rats and B6C3F1 mice. In these studies, amphetamine was administered for 2 years at doses of 0, 20, or 100 ppm in the feed to groups of 50 animals/dose/sex/species. The average amount of amphetamine consumed per day was estimated to be 1 or 5 mg/kg for low or high dose rats, 4 or 30 mg/kg for low or high dose male mice, and 3 or 19 mg/kg for low or high dose female mice. Survival was similar in dosed and control groups. The most notable effect of long-term treatment with this drug was the reduction of body weight in comparison to controls, and reduction in spontaneous tumors including pheochromocytomas of the adrenal gland in male rats, fibroadenomas of the mammary gland in female rats, adenomas of the anterior pituitary gland in male and female rats and female mice, endometrial stromal polyps of the uterus of female rats, adenomas or carcinomas of the liver in male and female mice, adenomas of the Harderian gland in male and female mice, and adenomas or carcinomas of the lung in male and female mice. Decreases in spontaneous tumors have previously been seen in 2-year rodent studies in groups of animals that have a reduced body weight in comparison to controls, but the spectrum of reduction in spontaneous neoplasms after treatment with amphetamine is broader than has previously been observed.