奥氮平致糖脂代谢紊乱的病理机制

自第二代抗精神病药物在临床上得到广泛应用以来,其引起患者血糖脂代谢异常的问题日益受到关注,本文就奥氮平致患者糖脂代谢紊乱的病理机制研究进展综述如下。     

链脲佐菌素剂量对C57BL/6J小鼠糖尿病神经病理性疼痛诱导效应的影响

目的观察不同剂量链脲佐菌素(STZ)对C57BL/6J小鼠糖尿病神经病理性痛诱导效应的影响,探讨其量效关系及最佳剂量。方法雄性C57BL/6J小鼠85只,随机分为正常对照组(n=10)和A～E 5个实验组(n=15,STZ腹腔注射剂量分别为80、100、120、140、160mg/kg),对照组腹腔注射等体积柠檬酸缓冲液。观察各组血糖、机械痛阈值、热刺痛阈值和28d生存率的变化,分析其与STZ剂量的关系。结果 A～E各组糖尿病成模率均>86.7%。C组神经病理性疼痛成模率(66.7%)均高于其余各组;E组28d生存率(46.7%)与A、B组间均存在显著差异(P<0.05)。结论 C57BL/6J小鼠腹腔注射STZ以120mg/kg为最佳剂量。     

奥氮平诱导的小鼠肥胖模型MCP-1水平分析

目的 探讨脂肪因子和重要的炎症趋化刺激因子——单核细胞趋化蛋白1 (MCP-1)的血清水平在奥氮平诱导的肥胖中的作用.方法 20只雄性小鼠随机分为两组:实验组和对照组,实验组训练小鼠每天自主摄入奥氮平3 mg/kg体重.7周后取小鼠血浆并检测血浆MCP-1水平.解剖小鼠并留取附睾脂肪垫及肾周脂肪,计算小鼠腹腔脂肪指数及肥胖指数.结果 实验组体重、附睾脂肪垫及肾周脂肪湿重均高于对照组.经计算,腹腔脂肪指数及肥胖指数均高于对照组,可判断为建模成功.实验组血浆MCP-1水平显著高于对照组.结论 在奥氮平诱导的肥胖小鼠模型血浆MCP-1水平升高提示炎症可能参与奥氮平诱导的肥胖.     

低能量膳食对奥氮平所致体质量增加的男性精神分裂症患者糖脂代谢的影响

目的:探讨低能量膳食对奥氮平所致体质量增加的男性精神分裂症患者糖脂代谢的影响。方法:选择2018年4月至2019年4月124例奥氮平所致体重增加的精神分裂症患者为研究对象,按照随机数字法分为A组(奥氮平片20 mg/d)、B组(奥氮平片20 mg/d联合二甲双胍片750 mg/d)和C组(奥氮平片20 mg/d联合低能量膳食)。比较3组患者治疗前和治疗3个月后体质量指数和糖脂代谢的变化。结果:治疗3个月后,A组体质量指数、空腹血糖、餐后2 h血糖、总胆固醇、三酰甘油、低密度脂蛋白胆固醇均高于B组和C组,高密度脂蛋白胆固醇低于B组和C组(P均0.05)。B组低密度脂蛋白胆固醇高于C组(P0.05),B组和C组在体质量指数、空腹血糖和餐后2 h血糖、总胆固醇、三酰甘油、高密度脂蛋白胆固醇方面差异无统计学意义(P均0.05)。结论:低能量膳食控制奥氮平所致体重增加的男性精神分裂症患者糖脂代谢水平的疗效与二甲双胍相当,提示膳食干预可作为该群体糖脂代谢异常的非药物性干预方案。     

异氟醚对胶质瘤C57BL/6小鼠的抑瘤作用研究

目的探讨吸入性麻醉药物异氟醚对胶质瘤C57BL/6小鼠的抑瘤作用和机制。方法将36只C57BL/6小鼠随机分为空白组、模型对照组和实验组,每组12只。采用脑胶质瘤立体定向技术进行U251胶质瘤细胞植入造模;采用核磁共振成像检查(MRI)与苏木精-伊红(HE)染色评价造模成瘤与异氟醚干预后作用;采用荧光定量法检测脑组织匀浆中肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-6的表达水平;采用蛋白印迹法检查核转录因子-κB p65蛋白表达水平。结果第20天实验组肿瘤直径明显小于对照组(1.2±0.5mm vs 1.7±0.3mm),差异有统计学意义(P0.05)。HE染色病理表现提示实验组稍好于对照组,可能有一定抑制作用。实验组TNF-αmRNA表达量显著少于对照组(P0.05),而IL-1β与IL-6表达量亦相对少于对照组,差异有统计学意义(P0.05)。实验组NF-κB p65表达与模型组相比有明显降低(0.323±0.011vs 0.512±0.016),但仍然高于空白组,差异有统计学意义(P0.05)。结论吸入性麻醉药物异氟醚能够抑制胶质瘤的快速生长,其作用机制主要是通过抑制NF-κB p65的表达,从而减少脑组织T辅助细胞炎症因子,起到负调控NF-κB的活化作用。     

小剂量海人酸导致C57BL/6 小鼠产生慢性神经退行性病变

目的探索应用海人酸在C57BL/6小鼠建立慢性进行性神经退行性病变的新的动物模型。方法小剂量(3mg/kg体重)海人酸经鼻滴入C57BL/6小鼠,每3d给药1次,连续20次。观察临床表现,并应用旷场行为实验检测小鼠的行为学变化;通过Nissl染色方法评估鼠脑病理变化以及免疫组织化学方法分析小胶质细胞活化和星形胶质细胞增生情况。结果应用小剂量海人酸反复多次经鼻给药,小鼠虽无明显临床症状,但引起其皮质和海马发生兴奋性毒性所致的神经细胞退行性病变,小胶质细胞活化和星形胶质细胞增生以及行为学变化。结论此慢性动物模型的神经病理改变与人类神经退行性疾病的变化相似,因此,本文为研究人类神经系统慢性退行性疾病的发病机制及治疗提供了一个有用的动物模型。     

抑制雌激素的生物合成会引起C57BL/6J卵巢摘除小鼠的轻微焦虑样行为(英文)

目的来曲唑作为新一代芳香化酶抑制剂已广泛用于治疗妇女绝经后的乳腺癌。虽然来曲唑治疗具有良好的耐受性,但其对中枢神经系统的副作用还需要更多的研究。方法将卵巢摘除的C57BL/6J雌性小鼠每天给予来曲唑(2.5mg/kg)或赋形剂灌胃处理,共持续3周。给药结束后,对小鼠自主运动、探索、焦虑、抑郁以及学习和记忆行为进行分析。结果与对照小鼠相比,来曲唑处理小鼠的体重显著增加,海马组织匀浆中的雌激素水平显著降低。旷场实验中,来曲唑处理小鼠在第3天任务中进入旷场中央区域的潜伏期显著增长。高架十字迷宫中,来曲唑处理小鼠在开放臂上运动距离变短。在明暗箱、强迫游泳和Y-迷宫任务中,来曲唑处理小鼠行为未有显著改变。在Morris水迷宫中,来曲唑给药小鼠的空间学习和记忆能力有所提高。结论系统性芳香化酶抑制剂降低了小鼠中枢神经系统中雌激素的含量,并且导致了焦虑样行为的增加,提示使用芳香化酶抑制剂治疗乳腺癌可能对中枢神经系统产生副作用。     

OX40L在C57BL/6与BALB/c小鼠组织的差异性表达及分析

背景：有研究发现C57BL/6小鼠对动脉粥样硬化易感,而BALB/c小鼠却对动脉粥样硬化不易感。OX40L的表达情况与动脉粥样硬化的狭窄程度和心肌梗死的严重度相关,其在两种品系小鼠中是否存在表达差异？ 目的：分析OX40L在BALB/c和C57BL/6小鼠心脏、大脑、肾脏、骨骼肌和脾脏组织的表达差异。 方法：取C57BL/6和BALB/c小鼠心脏、大脑、肾脏、骨骼肌和脾脏组织,以Trizol提取总RNA, RIPA Buffer提取组织总蛋白。采用RT-PCR和Western Blot方法检测两种品系小鼠心脏、脑、肾脏、脾脏和骨骼肌的OX40L mRNA和蛋白的表达。OX40L在两种品系小鼠不同器官间的表达差异。 结果与结论：RT-PCR结果显示,C57BL/6小鼠心脏OX40L mRNA表达显著高于BALB/c小鼠(P < 0.05),脾脏OX40L mRNA表达明显低于BALB/c小鼠(P < 0.05),两种品系小鼠大脑、肾脏及骨骼肌OX40LmRNA表达差异无显著性意义;Western Blot结果显示,两种品系小鼠OX40L的蛋白表达均在心脏最高;C57BL/6小鼠心、脑及肾OX40L蛋白表达均显著高于BALB/c小鼠(P < 0.05),两种品系小鼠骨骼肌和脾脏OX40L蛋白表达差异无显著性意义。两个品系小鼠OX40L mRNA的表达水平与蛋白表达水平不完全一致。C57BL/6小鼠心脏中OX40L mRNA转录水平较BALB/c高,但在脾脏中表达量较后者低;C57BL/6小鼠心脏、大脑和肾脏OX40L蛋白水平均较BALB/c小鼠高;两种品系小鼠之间的表达差异提示OX40L可能与C57BL/6小鼠易感动脉粥样硬化有关。     

JAK2抑制剂AG490对EAE小鼠C57BL/6的Th17/Treg细胞平衡的影响

目的探讨AG490对EAE小鼠Th17/Treg平衡的影响及其治疗作用。方法以MOG33-35多肽免疫C57BL/6小鼠建立EAE模型,观察AG490干预前后EAE组、AG490组和对照组小鼠脊髓组织炎性细胞浸润情况及p-STAT5、Foxp3和IL-17免疫组化染色阳性细胞数目。结果 AG490组较EAE组小鼠炎症细胞浸润及IL-17阳性细胞数目减少(P<0.05),AG490组小鼠p-STAT5和Foxp3阳性细胞数目较EAE组增多(P<0.05),两组小鼠发病高峰期较发病初期炎症细胞浸润及IL-17阳性细胞数目增多,而p-STAT5和Foxp3阳性细胞数目减少(P<0.05)。结论 (1)AG490通过抑制JAK2-STAT3信号通路抑制炎症反应和免疫应答;(2)JAK2抑制剂可以通过JAK2-STAT3信号通路调节Th17/Treg细胞平衡。     

C57BL小鼠survivin基因miRNA表达载体的构建*★

背景：Survivin在多种肿瘤组织中的高表达，具有调节细胞增殖分裂和强大的抗凋亡功能。 目的：利用RNA干扰技术，构建具有特异性阻断C57BL小鼠survivin基因的微小RNA(micro RNA，miRNA)表达载体。 设计、时间及地点：单一样本观察，于2008-06/11在重庆医科大学附属第一医院神经内科实验中心完成。 材料：环形pcDNA™6.2-GW/EmGFPmiR和BLOCK-iT™ Pol II miR RNA干扰 Expression Vector Kit with EmGFP为Invitrogen公司产品；DH5a大肠杆菌为实验室保存；xho I和BamH I酶、壮观霉素均为上海生工生物工程有限公司产品。 方法：应用设计软件在C57BL小鼠survivin基因的mRNA上寻找特异性的短核苷酸序列，并设计合成4对寡核苷酸序列，经退火后形成双链DNA片段，采用基因克隆技术，将其克隆到pcDNA™6.2-GW/EmGFPmiR的载体中，转化DH5a大肠杆菌，挑单菌落种于含有壮观霉素LB液体培养基中，提取质粒。 主要观察指标：应用测序法和琼脂糖电泳检测对重组体进行鉴定。 结果：测序结果显示插入片段与线性载体连接正确，无碱基突变、缺失、插入等异常。双酶切处理pcDNA™6.2-GW/EmGFP-miR重组质粒结果显示片段大小与预期相符。 结论：实验结果表明成功构建了C57BL小鼠survivin基因的微小RNA表达载体。     

Paraquat induces redox imbalance and disrupts glutamate and energy metabolism in the hippocampus of prepubertal rats

Paraquat (1,1′-dimethyl-4,4′-bipyridinium dichloride; PQ) is a widely used herbicide in Brazilian crops, despite its banishment in many other countries. The present study investigated the effects of repeated dose of PQ on glutamate system, energy metabolism and redox parameters in the hippocampus of prepubertal rats. Twenty-two-day-old rats received daily intraperitoneal injections of PQ (10 mg/Kg) during 5 consecutive days and the effects of the pesticide were assessed 24 h after the last injection. The PQ exposure provoked cytotoxicity associated to decreased cell viability and increased glutamate excitotoxicity, as demonstrated by decreased 14C-glutamate uptake and increased ⁴⁵Ca²⁺ uptake. Downregulated glutamine synthetase (GS) activity, further supports disrupted glutamate metabolism compromising the glutamate-glutamine cycle. Downregulated ¹⁴C-2-Deoxy-D-glucose indicates energy failure and upregulated lactate dehydrogenase (LDH) suggests the relevance of lactate as energy fuel. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) upregulation suggest Krebs cycle replenishment and piruvate production. In addition, PQ disturbed the redox status inducing lipid peroxidation, evaluated by increased TBARS and imbalanced antioxidant system. Downregulated glutathione reductase (GR), gamma-glutamyltransferase (GGT), glutathione-S-transferase (GST) and glucose-6-P-dehydrogenase (G6PD) activities together with upregulated superoxide dismutase (SOD) and catalase activities corroborate the oxidative imbalance. The mechanisms underlying PQ-induced neurotoxicity involves the modulation of GSK-3β, NF-κB and NMDA receptors. These neurochemical and oxidative events observed may contribute to neuroinflammation and neurotoxic effects of PQ on hippocampal cells.     

A comparison of the behavior of C57BL/6 and C57BL/10 mice

Selection of an appropriate animal model is a crucial first step in many research programs. The C57BL/6 (B6) mouse is the most widely used inbred mouse strain in biomedical research; this is particularly so in behavioral studies. However, there are several C57BL substrains, all derived from common ancestors. C57BL/10 (B10) mice are superficially almost identical to B6 mice in appearance and behavior and widely used in inflammation and immunology research, yet rarely in behavioral studies. The present study assessed the comparability of behavioral results from these two strains, to determine whether they could be used interchangeably in future behavioral experiments. The results showed that the behavior of B6 mice clearly differed from that of B10 mice: in tests of cognition, species-typical behaviors, and motor coordination the B6 strain performed better. Consequently, B6 mice will probably remain the preferred choice for behavioral studies. Interpretation of results derived from the B10 strain should take into account its particular behavioral characteristics.     

Brain energy stores in C57BL/6 mice after C. parvum injection

Activation of the immune system has been associated with the development of fatigue of unknown cause. We were interested in brain energy stores (e.g., phosphocreatine (PCr) and creatine kinase) after immune activation to investigate whether this system was altered. In this model, fatigue (defined as > 50% reduction in spontaneous running) was induced in C57BL/6 mice after a single injection of Corynebacterium parvum antigen. Maximal fatigue (about 86% reduction on day 10 post injection) was associated with reduced (about 29%) brain PCr/gamma-ATP and increased creatine kinase levels (approximately 31%), suggesting an active process of brain ATP depletion and replenishment. These findings need to be further delineated to establish the relationship between immune activation, reduced brain energy pools and fatigue.     

Observational learning in C57BL/6j mice

The ability of mice to solve a complex task by observational learning was investigated with C57BL/6j mice. Four female demonstrators were trained to reliably perform a sequence that consisted in pushing a piece of food into a tube attached to the side of a puzzle box, and recovering it by opening a drawer in front of the box. They then performed this sequence in front of naive mice assigned to individual cubicles in a box with a wire mesh front arranged in a row facing the demonstrators. A total of 25 naive mice (13 males and 12 females) were used. Fifteen mice observed 14 demonstrations a day for 5 days; 10 control mice were placed in similar cubicles, but behind a plastic screen which prevented them from observing the demonstrators. The mice were post-tested in the demonstrator situation, and 6 of 15 observers immediately reproduced the complete task successfully, but none of the naive or control mice were able to solve the task. The observers and controls were then subjected to a five level individual learning schedule. Observers learned the individual task significantly faster than the controls. No sex difference was found. These results suggest that observational learning processes at work were based on stimulus enhancement and observational conditioning.     

氯氮平对雄性小鼠血糖和胰岛素的影响

目的：探讨氯氮平对雄性C57BL／6小鼠血糖和胰岛素的影响。方法：63只雄性C57BL／6小鼠随机分为3大组,空白组、氯氮平4mg／kg组、氯氮平20mg／kg组,于灌药后的3h、1周、4周测定空腹血糖、糖耐量、胰岛素。结果：灌药后3h、l周空腹血糖、血胰岛素、血糖曲线下面积都无显著升高;灌药4周后空腹血糖值显著升高。腹腔注射高糖后60min的氯氮平20mg/kg组的血糖值及血胰岛素显著升高,结诊：氯氮可以慢性升高小鼠的空腹血糖和胰岛素,影响糖耐量,但急性期无明显影响。     

氨磺必利与奥氮平治疗老年期精神分裂症的临床疗效及对糖脂代谢影响的比较

目的 比较氨磺必利与奥氮平对老年期精神分裂症患者血糖和血脂代谢的影响。方法 60例老年期精神分裂症患者采用随机数字表法分为氨磺必利组（30例）和奥氮平组（30例）,分别给予氨磺必利片和奥氯平片口服,检测入纽时和治疗2,4,8周后两组空腹血糖（FBS）,总胆固醇（TC）,高密度脂蛋白（HDL）,低密度脂蛋白（LDL）,甘油三酯（TG）及体质量指数（BMI）,并评定入组时和治疗2,4,8周后两组的PANSS评分,治疗不良反应量表（TESS）评定不良反应。结果 氨磺必利组有效率82．8％,奥氮平组为86．2％,两组比较差异无统计学意义（U=0．118,P〉0．05）。两组患者治疗8周末PANSS总分及各量表评分差异无统计学意义（P〉0．05）。奥氮平组MBI,FBS,LDL,TC,TG随时间升高趋势明显,经重复测量方差分析,差异有统计学意义（P〈0．05）,而氨磺必利组内各时点各项指标变化不明显,差异无统计学意义（P〉0．05）。两组治疗8周末TESS评分氨磺必利组为（2．49±1．32）分,奥氮平组（2．95±1．56）分,两组比较差异有统计学意义（t=2．190,P=0．033）,氨磺必利组不良反应发生率低。结论 氨磺必利对老年期精神分裂症的疗效与奥氮平相当,但对患者血糖、血脂的影响明显小于奥氮平。     

MBP-PLP fusion protein-induced EAE in C57BL/6 mice

Gene knock-out and knock-in mice are becoming increasingly indispensable for mechanism-oriented studies of EAE. Most gene-modified mice are on the C57BL/6 background, for which presently there are only two EAE models available, the MOG peptide 35-55 and the PLP 178-191 peptide induced disease. However, because MS is not a single pathogenic entity, different EAE models are required to reproduce and study its various features. Here we are introducing MBP-PLP fusion protein (MP4)-induced EAE for C57BL/6 mice. B cell- and CD8+ T cell-dependence, as well as multi-determinant recognition are among the unique features of this demyelinating EAE.     

Topiramate reduces ethanol consumption by C57BL/6 mice

BACKGROUND: Previous reports indicate that topiramate (TPM) might be an effective treatment for alcohol dependence, perhaps due to a decrease alcohol's rewarding effects resulting from inhibition mesocorticolimbic dopamine (DA) release. Additional reports indicate that TPM antagonizes chronic changes induced by alcohol at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors. In the present study, a C57BL/6 (B6) murine model (n = 40) was used to evaluate the effect of TPM on the consumption of 12% alcohol over a 21-h period. METHODS: TPM (0, 10, 30, 90 mg/kg) injected subcutaneously into B6 mice 60 min prior to access to a 12% ethanol solution (v/v) over 8 days produced dose-responsive reduction in consumption during the first 2-h period after injection. RESULTS: Across the 8 days of treatment ethanol intake (g/kg) for SAL, T10, T30, and T90, respectively, was 1.34, 1.03, 0.72, and 0.67. This reduction appears to require systemically available TPM since it was not statistically supported when assessed over the entire 21-h period of ethanol availability. None of the TPM doses affected food consumption or body weight, and T90 dose did not reduce motor activity either by itself or in combination with ethanol. CONCLUSIONS: Unlike previous experiments using the same B6 mouse model to assess naltrexone or tiagabine, there was no evidence that mice developed tolerance to the TPM-induced reductions in ethanol consumption. Thus, in the B6 mouse, TPM reduced ethanol intake at doses with no readily apparent adverse side effects, an effect consistent with recent clinical reports. Additional study will be directed toward characterizing TPM as a treatment for alcohol dependence.     

Lesion-induced DA supersensitivity in aging C57BL/6J mice

Lesion-induced dopaminergic supersensitivity was investigated in 4-, 10-, and 28-month-old C57BL/6J mice. Apomorphine-induced rotational behavior was examined 5, 10, and 20 days after destruction of the dopamine-containing nigro-striatal pathway by intrastriatal infusion of 6-OHDA. No major differences between ages were observed in the extent or rate of development of contralateral rotation. It is concluded that age-differences in dopaminergic supersensitization are dependent upon the nature and/or severity of the sensitizing stimulus.     

Tripchlorolide protects against MPTP-induced neurotoxicity in C57BL/6 mice

Many current studies of Parkinson's disease (PD) suggest that inflammation is involved in the neurodegenerative process. Tripchlorolide (TW397), a traditional Chinese herbal compound with anti-inflammatory and immunosuppressive properties, has been shown to protect dopaminergic neurons against, and restore their function after, the neurotoxicity induced by 1-methyl-4-phenylpyridinium ions in vitro. This study was designed to investigate the effect of TW397 in vivo in the PD model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned C57BL/6 mice. In the animals that received vehicle-only (i.e., no TW397) treatment with MPTP i.p. injection, the survival ratios of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra pars compacta and TH-IR fibres in the striatum were only 59 and 13%, respectively, compared with the normal controls. Intriguingly, in conjunction with MPTP, treatment with TW397, 1 microg/kg for 16 days, once per day, dramatically improved the survival rate of the TH-IR neurons and TH-IR fibres to 80 and 43% of the control. The treatment with TW397 also significantly improved the level of dopamine in the substantia nigra and striatum to 157 and 191%, respectively, of the MPTP- plus vehicle-treated group. In addition, in MPTP-treated animals the rota-rod performances of those treated with 0.5 or 1 microg/kg TW397 were significantly improved, by approximately 2- and 3-fold, respectively, relative to vehicle-treated animals. The neuroprotective effect of TW397 was coincident with an attenuated astroglial response within the striatum. These data demonstrate a neuroprotective action of TW397 in vivo against MPTP toxicity, with important implications for the treatment of PD.