奥沙利铂治疗大鼠坐骨神经线粒体呼吸功能及抗氧化酶活性改变的研究

目的:观察奥沙利铂治疗大鼠坐骨神经线粒体呼吸功能的改变及抗氧化酶活性的变化。方法:选取SD雄性大鼠36只,用5%葡萄糖将奥沙利铂溶液稀释到2mg/mL,连续5d(d 0～d 4)腹腔注射2mg/kg;对照组大鼠接受对照液5%葡萄糖注射。并于d 0、d 8、d 15、d 22、d 29、d 35及d 41测定机械异常痛敏(4g VFH)和机械痛敏(15g VFH)。取d 27～d 35并确认存在异常痛敏和机械痛敏的大鼠及对照组大鼠各9只,处死大鼠并取坐骨神经,将神经制作成切碎的纤维细丝(M&T)标本,将标本放入呼吸测定仪里,分别加入底物并测定呼吸比率变化;再取模型和对照组大鼠各9只,取坐骨神经并提取线粒体,分别测定抗氧化酶硫氧还原蛋白还原酶(TrR)和谷胱甘肽过氧化物酶(GPx)的活性。结果:与对照组大鼠比较,注射奥沙利铂大鼠在疼痛高峰期(d 27～d 35)呼吸比率明显下降(下降16%),奥沙利铂治疗大鼠线粒体加入细胞色素C后呼吸明显增加;而且TrR(下降23%)和GPx(下降15.4%)的活性明显下降。结论:奥沙利铂治疗大鼠坐骨神经线粒体功能受损,引起线粒体呼吸功能失调,预示损伤存在于复合物I或复合物II;抗氧化酶活性下降可能是线粒体呼吸功能降低的另一个原因。     

鞘内和侧脑室内注射米贝地尔对慢性坐骨神经松结扎大鼠痛阈的影响

目的观察鞘内和侧脑室内注射T型钙通道阻断剂对慢性坐骨神经结扎大鼠痛阈的影响,探讨脊髓和脊髓上水平T型钙通道在神经病理性疼痛中的作用。方法建立慢性坐骨神经结扎(CC I)神经病理痛模型,运用鞘内和侧脑室给药技术,用von Frey纤维细丝和热辐射仪测定脊髓和脊髓上水平不同剂量的米贝地尔在对CC I大鼠机械缩是阈值(MWT)和热缩是潜伏期(TWL)的影响。结果CC I大鼠从术后3 d开始到本实验观察的21 d表现出明显的热痛敏和机械痛敏,鞘内注射各个剂量的米贝地尔能明显减轻热痛敏和机械痛敏;侧脑室注射米贝地尔100、200μg组却增强大鼠的机械和热痛敏。结论阻断脊髓水平T型钙通道具有镇痛作用,阻断脊髓上水平T型钙通道有致痛作用。     

侧脑室微量注射NMDA受体拮抗剂对神经病理疼痛的作用

目的:观察大鼠侧脑室微量注射N-甲基-D-天冬门氨酸(N-methyl-D-aspartate,NMDA)受体拮抗剂对神经病理性疼痛的影响,探讨脊髓上水平镇痛的机制,为临床上开发新的镇痛药物提供实验依据.方法:建立大鼠坐骨神经结扎(partial scicticnerve ligature,PSL)神经病理性疼痛模型,采用压爪-缩腿法和辐射热缩腿法测定大鼠的机械痛阈和热痛阈,观测侧脑室微量注射MK-801(NMDA受体非竞争性拮抗剂)与APV(NMDA受体竞争性拮抗剂)对神经病理性疼痛模型大鼠痛阈的影响.结果:PSL模型大鼠术后数小时痛阈即明显降低(P＜0.05),出现机械痛敏和热痛敏.侧脑室微量注射MK-801(5 nmol)、APV(2 nmol)后,大鼠机械痛阈和热痛阈明显升高,痛敏现象明显减轻(P＜0.05).结论:NMDA受体在中枢脊髓上水平与痛觉的形成和维持过程中可能起重要的作用.     

细胞因子参与EPO预防神经病理性疼痛的机制探讨

目的 探讨预防性给予重组人红细胞生成素(rhEPO)对神经病理性疼痛大鼠模型机械、热痛觉高敏的影响及可能的机制.方法 雄性SD大鼠30只随机均分成三组.A、B组切断L5脊神经建立大鼠神经病理性疼痛模型;C组为假手术对照.术前1d,A组腹腔注射rhEPO 5000 U/kg,连续7d;B组腹腔注射生理盐水作为模型对照.采用von Frey仪测定各组0、3和7d机械缩足反射阈值;术后第7天用ELISA法测定大鼠L5脊髓组织TNF-α、IL-1β、IL-6和IL-10表达.结果 与C组相比,A、B组大鼠L5脊神经损伤术后,术侧均出现明显的机械痛阈下降(P＜0.01);但A组大鼠的机械痛高敏行为较B组明显缓解(P＜0.01).与C组比较,大鼠脊髓TNF-α、IL-1β、IL-6和IL-10表达明显增高(P＜0.01);与B组比较,A组脊髓组织IL-6水平明显降低,而IL-10水平明显升高(P＜0.01).结论 rhEPO能预防模型大鼠神经病理性疼痛的发生,其效应与减少促炎细胞因子和增加抗炎细胞因子释放有关.     

鞘内注射T型钙通道反义寡聚核苷酸对慢性背根节压迫大鼠痛阈的影响

目的观察鞘内注射T型钙通道(Cav3.0)反义寡聚核苷酸对慢性背根节压迫(chronic compression of dorsal root ganglion,CCD)大鼠痛阈的影响,初步探讨脊髓T型钙通道在神经病理性疼痛形成中的作用。方法鞘内置管♂SD大鼠32只,随机分为4组(n=8):CCD+NS组、CCD+Cav3.0反义寡聚核苷酸组(CCD+Cav3.0-AS)、CCD+Cav3.0错义寡聚核苷酸组(CCD+Cav3.0-MM)、假手术(sham)+NS组。各组大鼠在CCD或sham术后d1始连续4d每天2次鞘内分别注射12.5μg,容积均为10μl的Cav3.0-AS、Cav3.0-MM或NS10μl,分别观察手术后1～14d大鼠机械缩足阈值(mechanical withdrawal threshold,MWT)和热缩足潜伏期(thermal withdrawal latency,TWL)。结果鞘内注射Cav3.0反义寡聚核苷酸能延缓CCD大鼠痛敏的形成,在CCD术后d8～9才形成与CCD+NS组类似的痛敏,而鞘内注射Cav3.0错义寡聚核苷酸则与CCD+NS组差异无统计学意义。结论脊髓T型钙通道参与神经病理性疼痛的形成,抑制脊髓T型钙通道基因的表达具有疼痛治疗作用。     

鞘内注射米诺四环素对慢性坐骨神经结扎大鼠机械痛敏和热痛敏的影响

目的观察鞘内注射小胶质细胞抑制剂米诺四环素对慢性坐骨神经结扎大鼠机械痛敏和热痛敏的影响。方法所有大鼠术前8d鞘内置管,用机械缩足反射阈值和热缩足潜伏期来分别评价大鼠机械痛敏和热痛敏。前给药组:生理盐水10μl或米诺四环素50μg,于坐骨神经结扎前1d开始持续到术后1d(每天2次)鞘内注射,机械缩足反射阈值和热缩足潜伏期分别于术前2d,术后1,3,5,7,14d测定;后给药组:坐骨神经结扎后7d,鞘内注射1次生理盐水10μl或米诺四环素50μg,其对机械缩足反射阈值和热缩足潜伏期的影响分别于给药后0.5、1、2、4、8h测定。结果CCI大鼠从术后1d形成稳定的热痛敏和机械痛敏,前鞘内注射米诺四环素明显增加CCI大鼠MWT和TWL(P<0.05,P<0.01),相反,后鞘内注射米诺四环素对CCI大鼠MWT和TWL无明显影响。结论前鞘内注射米诺四环素明显抑制CCI大鼠机械痛敏和热痛敏,提示小胶质细胞的活化参与慢性坐骨神经结扎引发神经病理痛的形成。     

A型肉毒毒素对神经病理性疼痛大鼠镇痛作用及作用途径的研究

目的：观察A型肉毒毒素（BTX—A）对L5前根切断（L5 VRT）神经病理性疼痛模型大鼠的镇痛作用并探讨其最佳给药途径。方法：雄性SD大鼠108只,随机分为3组（n=36）,皮下注射给药组、坐骨神经表面给药组、坐骨神经注射给药组,制备L5 VRT模型,各组又分为术后4d给药组、术后8d给药组、术后16d给药组且同时各设0．9％氯化钠注射液对照组（n=6）,于术前、术后及术后不同给药时间测定50％撤足阈值（PWT）。结果：①皮下给药组能明显的改善机械痛敏,坐骨神经表面及坐骨神经注射给药组机械痛敏改善不明显。②皮下给药组术后各不同时间给药小组,均能明显的改善机械痛敏,与对照组相比有统计学意义（P〈0．05）;给药后第15天效果最明显;这种镇痛作用持续至少20余天。③坐骨神经表面及坐骨神经注射给药组动物的机械痛敏改善不明显,与对照组相比无统计学意义（P〉0．05）。结论：皮下注射BTX—A,能改善L5VRT模型大鼠的机械痛敏,有镇痛作用,且为最佳给药途径。     

神经病理性疼痛大鼠背根神经节TRPM8表达变化的研究

目的: 观察慢性神经病理性疼痛大鼠背根神经节TRPM8表达的变化.方法: 健康成年雄性SD大鼠72只,体质量250~280 g,随机分为慢性坐骨神经束缚性损伤(CCI)组和假手术组(n = 36), CCI或假手术前1 d,术后1、4、7、10、14 d每组各随机取6只大鼠,测定冷痛阈值、热痛阈值和机械痛阈值后立即处死大鼠,取L5背根神经节行免疫组织化学染色,观察瞬时受体电位melastatin 8(TRPM8)在慢性神经病理性疼痛下的表达变化.结果: CCI组于术后4 d术侧冷痛阈值、机械痛阈值和热痛阈值开始下降,至术后14 d仍处于较低水平,冷痛阈值和热痛阈值于术后10 d降至最低,机械痛阈值术后14 d降至最低(P ＜ 0.05或P ＜ 0.01);CCI组术侧L5背根神经节TRPM8的表达于术后4 d开始增加,术后10 d达到高峰,至术后14 d仍维持在高水平(P ＜ 0.05或P ＜ 0.01).结论: 背根神经节TRPM8受体表达的上调参与神经病理性疼痛的发生和维持.     

延胡索乙素对小鼠坐骨神经CCI模型背根神经节Cav1.2表达的影响

目的探讨延胡索乙素对小鼠坐骨神经慢性压迫性损伤(CCI)所致神经病理性疼痛的镇痛作用以及对背根神经节Cav1.2表达的影响。方法♂C57BL/6小鼠40只,随机分为5组,分别为假手术组(S组)、CCI组(C组)、延胡索乙素组(L组)。建立稳定的小鼠坐骨神经慢性压迫性损伤致神经病理性疼痛模型。按照神经病理性疼痛的诱发和持续时间,又将L组分为诱导期组、诱导维持期组、长程低剂量组。诱导期组于疼痛诱导期(0~5 d)、诱导维持期组于疼痛诱导期及维持期(0~5 d、14~19 d)腹腔给予延胡索乙素45mg·kg~(-1),每日1次;长程低剂量组从术后即刻开始腹腔给予延胡索乙素15 mg·kg~(-1),每日1次,给予19 d。监测小鼠行为学变化,检测小鼠机械痛阈和热痛阈,Western blot及免疫组织化学方法测定背根神经节中Cav1.2表达。结果脊髓背根神经节Cav1.2在C组表达水平最低,S组表达水平最高,在诱导期组、诱导维持期组及长程低剂量组表达明显上调,差异具有统计学意义(P<0.05,P<0.01)。与C组比较,诱导期组、诱导维持期组高剂量以及长程低剂量组长程低剂量给予延胡索乙素可以明显缓解神经病理性疼痛诱导的机械痛敏和热痛敏(P<0.05,P<0.01)。高剂量延胡索乙素可以缓解诱导期、维持期的机械痛敏及维持期的热痛敏(P<0.05),低剂量延胡索乙素对诱导期机械痛敏和热痛敏均无明显作用(P>0.05)。结论小鼠CCI模型疼痛的诱导期、诱导维持期应用高剂量以及长程应用低剂量延胡索乙素可明显缓解坐骨神经慢性压迫性损伤所致神经病理性疼痛,其可能机制之一是延胡索乙素通过上调脊髓背根经节Cav1.2亚基的表达来发挥镇痛作用。     

奥沙利铂慢性神经毒性对背根神经节尼氏体及P物质的影响

目的:观察奥沙利铂慢性神经毒性对大鼠背根神经节细胞尼氏体及P物质的影响。方法:30只Wistar大鼠随机分成奥沙利铂组、对照组各15只。奥沙利铂组腹腔注射奥沙利铂4mg/kg,对照组腹腔注射等容积5%葡萄糖注射液,每周2次,共9次。每次给药后2h检测50%缩足阈,最后一次给药后24h取第5腰椎背根神经节切片、染色。观察背根神经节神经元细胞形态以及尼氏体和P物质的形态和积分光密度。结果:奥沙利铂组大鼠50%缩足阈从第3次给药后明显低于对照组(P<0.01);背根神经节内神经元细胞体、细胞核及核仁面积减小(P<0.05,P<0.01),偏心核与多核仁比例增高(P<0.01);尼氏体、P物质积分光密度较对照组降低(P<0.05,P<0.01)。结论:奥沙利铂引起背根神经节尼氏体及P物质的改变,与周围神经病变有关。     

Effect of intraperitoneal acetyl-L-carnitine (ALCAR) on anxiety-like behaviours in rats

Acetyl-L-carnitine (ALCAR) is an acetyl derivative of carnitine, an endogenous molecule synthesized in vivo and supplemented by diet (mainly via meat and dairy products). Several parallel, double-blind, placebo-controlled studies have demonstrated that ALCAR treatment produces beneficial effects in geriatric depression. Since most antidepressants also have anti-anxiety effects we examined whether ALCAR shows anti-anxiety effects in a rat model of anxiety. Compared to a saline-injected control group, chronic administration of ALCAR at doses of 10 and 100 mg/kg (tested 24 h after the last dose administration) showed no effects, whereas doses of 50 and 75 mg/kg significantly reduced anxiety-like behaviours in the elevated plus-maze. Acute ALCAR (100 mg/kg), on the other hand (tested 6 h after administration), demonstrated anxiogenic effects. Our data suggest that chronic ALCAR administration may produce an inverted U-shaped curve of dose-dependent changes in anxiety-like behaviour. The precise mechanism by which ALCAR decreases anxiety-like behaviour after peripheral administration remains to be determined.     

Uterotrophic assay, Hershberger assay, and subacute oral toxicity study of 4,4′-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols

We performed a uterotrophic assay, the Hershberger assay, and a 28-day repeated-dose toxicity study [enhanced Organization for Economic Co-operation and Development (OECD) test guideline No. 407] of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol) and 3-(dibutylamino)phenol, based on the OECD draft protocols. In the uterotrophic assay of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol), female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 4,4'-butylidenebis(2-tert-butyl-5-methylphenol), the test chemical was orally administered to castrated male SD rats at doses of 0, 50, 200, and 1,000 mg/kg/day for ten consecutive days beginning on postnatal day 56, and no changes were observed. When this chemical was orally administered at doses 0, 5, 25, and 125 mg/kg/day for at least 28 days in the subacute oral toxicity study, an increase in thyroid weight was observed in the female rats in the 125 mg/kg group, an increase in serum thyroid-stimulating hormone (TSH) values in the male and female rats in the 125 mg/kg group, and a decrease in serum T3 and T4 values in the male rats in the 125 mg/kg group, and thyroid follicular epithelial cell hypertrophy was observed in some of the female rats in the 125 mg/kg group. These findings were concluded to be the result of endocrine-mediated effects of the chemical on thyroid function. In addition, increased liver weight, abnormal histological findings in the liver, and abnormal biochemical parameters related to liver function were observed in male and/or female rats in 5 mg/kg group and higher dose groups. The no-observed-effect level for 4,4'-butylidenebis(2-tert-butyl-5-methylphenol) was concluded to be <5 mg/kg/day. In the uterotrophic assay of 3-(dibutylamino)phenol, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and no changes were observed. In the Hershberger assay of 3-(dibutylamino)phenol, the test chemical was orally administered at doses of 0, 50, 200, and 400 mg/kg/day to castrated male SD rats for ten consecutive days beginning on postnatal day 56, and no changes were observed. On the other hand, when this test chemical was orally administered at doses 0, 30, 100, and 300 mg/kg/day for at least 28 days in the subacute oral toxicity study, thyroid weight increased in the male rats in the 300 mg/kg group, thyroid follicular epithelial cell hypertrophy was observed in a small number of male rats in the 300 mg/kg group, serum T3-values decreased in the female rats in the 300 mg/kg group, and a tendency for TSH-values to increase was observed in the male and female rats in the 300 mg/kg group. Therefore, 3-(dibutylamino)phenol was also concluded to have slight anti-thyroid acting effects as the endocrine-mediated effects. On the other hand, increased hemosiderin deposition in the spleen, increased spleen weight, hematological abnormalities, and squamous epithelial hyperplasia of the forestomach were detected in male and/or female rats in the 100 and/or 300 mg/kg groups, and thus the no-observed-effect level for 3-(dibutylamino)phenol was concluded to be 30 mg/kg/day.     

Acetyl-l-carnitine partially prevents benzene-induced hematotoxicity and oxidative stress in C3H/He mice

Benzene is an environmental pollutant and occupational toxicant which induces hematotoxicity. Our previous metabonomics study suggested that acetyl-l-carnitine (ALCAR) decreased in the mouse plasma and bone marrow (BM) cells due to benzene exposure. In the present study, the topic on whether ALCAR influences hematotoxicity caused by benzene exposure was explored. Thirty-two male C3H/He mice were divided into four groups: control group (C: vehicle, oil), benzene group (150 mg/kg body weight (b.w.) benzene), benzene + A1 group (150 mg/kg b.w. benzene + 100 mg/kg b.w. ALCAR), and benzene + A2 group (150 mg/kg b.w. benzene + 200 mg/kg b.w. ALCAR). Benzene was injected subcutaneously, and ALCAR was orally administrated via gavage once daily for 4 weeks consecutively. After the experimental period, the blood routine, BM cell number and frequency of hematopoietic stem/progenitor cell (HS/PC) were assessed. The mitochondrial membrane potential and ATP level were determined to evaluate the mitochondrial function. Reactive oxygen species (ROS), hydrogen peroxide (H₂O₂) and malondialdehyde (MDA) levels were also examined, and the comet assay was performed to measure oxidative stress. Results showed that ALCAR intervention can partially reduce the benzene-induced damage on BM and HS/PCs and can simultaneously alleviate the DNA damage by reducing benzene-induced H₂O_2, ROS, and MDA.     

No toxicological effects on acute and repeated oral gavage doses of single-wall or multi-wall carbon nanotube in rats

Three female Crl:CD(SD) rats/group were dosed with single wall carbon nanotube (SWCNT) or multi wall carbon nanotube (MWCNT) four times by gavage at a total of 50 mg/kg bw or 200 mg/kg bw (four equally divided doses at one-hour intervals). Acute oral doses of SWCNT and MWCNT caused neither death nor toxicological effects, and thus the oral LD50 values for SWCNT and MWCNT were considered to be greater than 50 mg/kg bw and 200 mg/kg bw, in rats respectively. Five or ten Crl:CD(SD) rats/sex were dosed with SWCNT once daily by gavage at a dose of 0 (control), 0.125, 1.25 or 12.5 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 12.5 mg/kg bw/day groups). Six or twelve Crl:CD(SD) rats/sex were dosed with MWCNT once daily by gavage at a dose of 0 (control), 0.5, 5.0 or 50 mg/kg bw/day for 28 days with a 14-day recovery period (0 and 50 mg/kg bw/day groups). Based on no toxicological effects, the no observed adverse effect levels (NOAELs) of repeated dose toxicity of SWCNT and MWCNT were considered to be 12.5 mg/kg bw/day and 50 mg/kg bw/day (the highest dose tested), respectively. It was suggested that SWCNT and MWCNT dosed by gavage reached the gastro-intestinal tract as agglomerates and were mostly excreted via feces.     

Dose determination of haloperidol, risperidone and olanzapine using an in vivo dopamine D2-receptor occupancy method in the rat

The purpose of the present study was to determine antipsychotic doses that achieve 80% striatal dopamine D₂-receptor occupancy for haloperidol, risperidone and olanzapine in rats. Wistar rats were treated with normal saline vehicle (controls), haloperidol (0.25 and 0.5 mg/kg/day), risperidone (3, 5 and 6 mg/kg/day) and olanzapine (5 and 10 mg/kg/day) for 7 days via osmotic minipumps. Striatal and cerebellar tissue were collected and in vivo dopamine D₂-receptor occupancies were determined using ³H-raclopride. The doses required to achieve dopamine D₂-receptor occupancy of 80% in 11- and 24-week old rats were: haloperidol 0.25 mg/kg/day, risperidone 5 mg/kg/day and olanzapine 10 mg/kg/day.     

Novel indoline-based acyl-CoA:cholesterol acyltransferase inhibitor with antiperoxidative activity: improvement of physicochemical properties and biological activities by introduction of carboxylic acid

A series of novel indoline derivatives with an ionizable moiety were synthesized to find a bioavailable acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor with antiperoxidative activity. [7-(2,2-Dimethylpropanamido)-4,6-dimethyl-1-octylindolin-5-yl]acetic acid hemisulfate (2, pactimibe sulfate) with low lipophilicity and high water solubility showed good oral absorption and inhibitory activity against foam cell formation in THP-1 cells exposed to acetyl-LDL after differentiation (IC50: 0.3 microM) and an antiperoxidative effect in LDL of hypercholesterolemic rabbits (IC50: 1.0 microM). 2 inhibited macrophage, hepatic, and intestinal ACAT activity (IC50: 1.9, 0.7, and 0.7 microM, respectively). Maximal plasma concentration after oral administration of 2 at 10 mg/kg was 0.9 microg/mL in rats, 3.0 microg/mL in rabbits, and 11.2 microg/mL in dogs. Repeated administration of 2 lowered plasma LDL/VLDL cholesterol in hypercholesterolemic rabbits at 1 mg/kg/day, rats and dogs at 3 mg/kg/day, and in normocholesterolemic hamsters at 3 mg/kg/day. 2 is a promising candidate for antihyperlipidemic and antiatherosclerotic drugs.     

Evaluation of the teratogenic potential of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat and rabbit

To assess its teratogenic potential, advantame (N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate) was administered to mated rats (22/group) in the diet at 0, 5000, 15,000, and 50,000 ppm (providing approximately 465, 1418, and 4828 mg/kg body weight/day), and to mated rabbits (24/group) via oral gavage at 0, 500, 1000, and 2000 mg/kg body weight/day throughout gestation. Shortly before delivery (rats: day 20; rabbits: day 29), animals were killed and subjected to a detailed necropsy. Fetuses were examined for external, visceral, and skeletal alterations. Atypical coloration of the feces and cage liners seen with test diets in both rats and rabbits was attributed to excretion of test material/metabolites in the feces and urine. Advantame had no adverse effect on rat offspring survival or development. The no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity in rats was 50,000 ppm, the highest dietary concentration tested. Due to adverse effects associated with reduced food intake and fecal output, approximately 20% of mated rabbits receiving 200 0mg/kg body weight/day and 1 animal at 1000 mg/kg body weight/day had to be terminated before scheduled necropsy. A NOAEL of 500 mg/kg body weight/day was established for maternal toxicity in rabbits. No teratogenic effects were observed in any animals, and based on a slightly increased incidence of fetal deaths at 2000 mg/kg body weight/day, a finding that was considered to be indirectly related to advantame treatment, 1000 mg/kg body weight/day was considered the NOAEL for developmental toxicity.     

Comparison of the effects of vitamin E and/or quercetin in attenuating chronic cyclosporine A-induced nephrotoxicity in male rats

1. The aim of the present study was to investigate the effects of vitamin E and/or quercetin (Q) on renal function, oxygen radical concentrations in the kidney and some anti-oxidant enzyme activities in rats treated with cyclosporine A (CsA). 2. Groups of rats (270 +/- 15 g), on standard rat chow and water, received all their treatments by gavage for either 4 or 8 weeks. Control groups received either olive oil (0.5 mL) or 25% ethanol (0.5 mL) + olive oil (0.5 mL) per day as vehicle. All experimental groups received 25 mg CsA/kg per day in 0.5 mL olive oil. The vitamin E group received 100 mg vitamin E/kg per day in olive oil in addition to CsA treatment. The quercetin group received 15 mg of Q/kg per day in 0.5 mL of 25% ethanol in addition to CsA treatment. The vitamin E + quercetin group received the two anti-oxidants at the concentrations given in addition to CsA treatment. 3. Quercetin, at a concentration less than one-quarter of vitamin E, was more efficient in lowering blood urea nitrogen, serum creatinine and kidney malondialdehyde in CsA-treated rats. However, neither of the two anti-oxidants was able to normalize these analytes to control values after either 4 or 8 weeks treatment. 4. Quercetin (50 micromol/kg per day) elevated all renal anti-oxidant enzyme activities to values observed in the negative controls. However, vitamin E (232 micromol/kg per day) only normalized glutathione peroxidase activity at the end of either 4 or 8 weeks treatment. Combination treatment with the two anti-oxidants abolished all the ill-effects of CsA. 5. Combination treatment with the two anti-oxidants of renal transplant patients receiving CsA may be beneficial in ameliorating the chronic nephrotoxic effects of the important immunosuppressive drug CsA.     

Prenatal cocaine exposure in the Long-Evans rat: II. Dose-dependent effects on offspring behavior

Pregnant Long-Evans rats were injected daily with 40, 60, 80 or 100 mg/kg cocaine HCl (SC, 2% solution) from gestational days 7-20 (sperm positive = day 0). Daily doses were split with half given between 9:00-10:00 a.m. and half between 3:00-4:00 p.m. An ad lib-fed group as well as nutritional control groups that were pair-fed to the 80 and 100 mg/kg cocaine dams were also evaluated (N = 11-18 litters/group). The negative geotactic reaction of the offspring, evaluated from day 2-14 (birth = day 0), showed no group differences. Spontaneous alternation behavior in a T-maze showed no evidence of perseveration in any group on either day 21 or day 80. Most cocaine-treated offspring showed an altered preference in turning right versus left on day 21. Activity monitor behavior showed that the cocaine-treated and pair-fed offspring were hypoactive on day 20. Some degree of hypoactivity was still evident on day 49, but absent on day 80. The passive avoidance behavior of day 19 offspring showed no group differences in acquisition of task learning. The 100 mg/kg cocaine offspring did show significantly poorer retention of task learning 48 hr later. On day 80, no group differences were seen in passive avoidance behavior. Acquisition of an active avoidance behavior on day 80 was significantly poorer in the 100 mg/kg cocaine group.     

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.