CNQX对电刺激隐神经诱发大鼠扣带回前部神经元c-Fos基因表达的影响

目的阐明伤害性电刺激隐神经(saphenous nerve,SN)能否引起扣带回前部(anterior cingulategyrus,ACG)神经元c-Fos基因表达及其发生机制。方法用免疫组化方法研究伤害性电刺激SN后不同时间,ACG神经元c-Fos基因表达的变化,以及尾静脉注射α-氨基3-羟基5-甲基4-异恶唑丙酸/海人藻氨酸(α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid/kainate,AMPA/kainate)受体拮抗剂受体是谷氨酸受体之一,6-氰基-7-硝基喹喔啉-2,3-二酮(6-cyano-7-nitroquinoxaline-2,3-dike-tone,CNQX)对该变化的影响。结果伤害性电刺激SN后30 min ACG神经元Fos蛋白表达明显增加,60 min增加最明显,120 min后开始消退;并且尾静脉注射CNQX拮抗了伤害性电刺激SN引起的ACG神经元Fos蛋白表达的显著增加。结论伤害性电刺激SN能够引起ACG神经元Fos蛋白表达的显著增加,这种表达呈时间依赖性,提示ACG存有SN代表区,能够感受SN传入的伤害性信息;CNQX拮抗了伤害性电刺激SN引起的ACG神经元Fos蛋白表达的显著增加,提示AMPA/kainate受体参与此过程。     

左旋金黄紫堇碱抗精神分裂症作用研究

目的研究左旋金黄紫堇碱(l-SLR)的抗精神分裂症作用。方法采用NMDA受体拮抗剂MK-801在动物模型上诱发精神分裂症的阳性症状、阴性症状及认知损伤;评价了化合物l-SLR对MK-801诱发的精神分裂症的作用;并评价了l-SLR对小鼠锥体外系功能的影响。结果 MK-801(0.3 mg·kg-1,ip)引起大鼠前脉冲抑制损伤,l-SLR(10、15mg·kg-1,ip)能抑制MK-801引起的大鼠前脉冲抑制损伤;l-SLR(30 mg·kg-1,ip)能抑制多巴胺受体激动剂阿扑吗啡(2 mg·kg-1,sc)引起小鼠的攀爬行为,说明l-LSR对MK-801及阿扑吗啡诱发的精神分裂症阳性症状有抑制作用。lSLR(30 mg·kg-1,ip)能抑制MK-801(0.2 mg·kg-1,ip)引起的小鼠群居接触抑制及MK-801诱发的小鼠认知损伤,说明l-SLR能改善MK-801诱发的精神分裂症阴性症状和认知障碍。经典抗精神分裂药氟哌啶醇在治疗剂量下(0.8 mg·kg-1,ip)诱发小鼠木僵行为,l-SLR在抗精神分裂的剂量下(30 mg·kg-1,ip)不会诱发木僵行为。结论化合物lSLR对精神分裂症的阳性症状、阴性症状以及认知障碍均有效,而且其在有效剂量时对锥体外系的影响明显小于氟哌啶醇和l-SPD。     

MK-801对四次甲基二砜四胺诱发难治性癫痫的抑制作用

四次甲基二砜四胺(TET)，是国内近年发生的投毒案件中应用最多、危害最大的剧毒杀鼠剂，也是国家公安部、卫生部重点关注的化学恐怖剂，反复发作难治性癫痫（RE）是TET中毒致残及致死主要原因。本文在建立TET所致RE实验动物模型基础上，借助药理学、电生理学、病理学等相关研究手段，系统评价比较了N-甲基-D-天冬氨酸(NMDA)受体拮抗剂MK-801对TET所致RE的治疗效果；在此基础上，从mRNA及蛋白水平，观察了MK-801对NMDA主要受体亚型NR2A及NR2B表达的影响。结果发现MK-801 3和5 mg·kg^-1均可有效抑制RE及由此引发脑损伤，显著提升24 h存活率，其作用明显优于作用于γ-氨基丁酸(GABA)系统药物[CD2]地西泮(DZP)。进一步研究发现，MK-801可显著下调皮质NMDA受体2A, 2B mRNA及蛋白表达但DZP无类似作用。本研究结果初步证实, MK-801对毒鼠强诱发RE具有确切的治疗效果，其良好抗惊厥及神经保护作用可能与其对NMDA受体亚单位的下调作用密切相关。     

海马内注射MK-801对甲醛炎性痛大鼠海马NO含量的影响

目的观察海马内给予N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂MK-801对足底注射甲醛诱导的海马一氧化氮生成增加的影响。方法采用硝酸还原酶法测定海马组织NO含量。结果足底注射甲醛后大鼠即出现舔、咬注射侧脚掌等疼痛相关表现,注射甲醛后12h时,海马组织NO含量显著增加;预先海马内注射MK-801,可使甲醛炎性痛大鼠海马组织NO含量明显降低。结论海马内注射MK-801可逆转甲醛炎性痛诱导的海马NO产生的增加,海马内NO生成增加可能与NMDA受体的活动有关。     

NMDA受体机制在动脉压力反射中的介导作用(英文)

目的:研究N-甲基-D-天门冬氨酸(NMDA)受体机制在动脉压力反射中的作用。方法:头端延髓腹外侧区(RVLM)前交感神经元(presympathetic neuron)与动脉压力反射相关,它们可被电刺激主动脉神经或升高动脉血压所抑制,其自发放电具有心性节律。根据这一特性,本研究用电生理学方法在17只雄性SD大鼠鉴定了27个假想的(putative)RVLM前交感神经元。以这些神经元对电刺激主动脉神经的反应为指标,观察在同侧孤束核(NTS)或尾端延髓腹外侧区(CVLM)微注射选择性NMDA受体拮抗剂CPP(0.1μL,50mmol/L)的作用。结果:在NTS微注射CPP可完全阻断或减弱电刺激主动脉神经引起的神经元抑制,但血压升高引起的神经元抑制不能完全被消除,神经元放电的心性节律仍然存在;在CVLM,CPP不仅完全阻断电刺激主动脉神经引起的神经元抑制,而且阻断血压升高引起的神经元抑制,神经元放电的心性节律消失。结论:NMDA受体机制在动脉压力反射中起着重要的介导作用;单侧孤束核的压力敏感神经元向单侧RVLM投射。     

低频电刺激脚桥核对苍白球内侧部神经元自发放电的影响

【摘要】目的 通过观察低频电刺激帕金森病（Parkinsons’s disease ,PD）模型大鼠脚桥核（pedunculopontine nucleus ,PPN）对苍白球内侧部（GPi）神经元放电的影响,探讨低频电刺激PPN治疗PD的作用机制。 方法 将30只SD大鼠随机分为对照组和PD模型组各15只。大鼠脑右侧黒质致密部注入6-羟基多巴胺建立PD模型,采用细胞外单位记录方法,利用7管玻璃微电极记录观察低频电刺激、微电泳谷氨酸（Glu）及其受体阻断剂MK-801、γ-氨基丁酸（GABA）及其受体阻断剂荷包牡丹碱（BIC）对大鼠GPi神经元放电频率的影响。 结果 低频电刺激PPN,对照组及PD组大鼠GPi神经元反应均以抑制为主,且平均放电频率均较刺激前降低（P＜0.01）;微电泳Glu和BIC对神经元有兴奋作用,而微电泳MK-801和GABA对神经元有抑制作用。在微电泳BIC的兴奋作用的基础上低频电刺激PPN使神经元放电频率明显降低,而在微电泳MK-801抑制作用的基础上低频刺激PPN使神经元放电频率进一步降低。结论 低频电刺激PPN可抑制GPi神经元活动,可能是通过调节投射到GPi神经元的Glu和GABA神经通路实现的。      

GR82334对强电流刺激大鼠隐神经增强扣带回前部Fos蛋白表达的影响

目的研究尾静脉或蛛网膜下腔注射神经激肽(neurokinin,NK)-1受体拮抗剂GR82334对强电流刺激大鼠隐神经(saphenous nerve,SN)增强扣带回前部(anterior cingulate gyrus,ACG)Fos蛋白表达的影响。方法应用免疫组化技术进行实验研究。结果强电流刺激大鼠SN引起ACG Fos蛋白表达显著增强;尾静脉或蛛网膜下腔注射GR82334拮抗了强电流刺激大鼠SN引起的ACG Fos蛋白表达的显著增强。然而,蛛网膜下腔注射GR82334并没有完全拮抗强电流刺激大鼠SN引起的ACG Fos蛋白表达的显著增强。结论大鼠SN传导的伤害性信息能够到达ACG,激活c-fos基因表达;外周NK-1受体与中枢NK-1受体参与大鼠SN传入信息引起的ACG Fos蛋白表达增强的过程,但是,还存在其他递质和受体参与的大鼠SN信息传入的其它中枢通路引起ACG Fos蛋白表达的显著增强。     

谷氨酸对大鼠纹状体神经元活动的影响

目的:研究谷氨酸(L-glutamic acid,GLU)及受体阻断剂MK-801对雄性大鼠纹状体(striatum,STR)神经元自发放电活动的影响。方法:应用微电泳方法记录纹状体神经元自发放电活动。结果:微电泳GLU使84.13%STR神经元自发放电频率加快。在43个STR神经元中直接微电泳MK-801可使62.79%STR神经元自发放电频率降低。在微电泳GLU产生兴奋效应的33个STR神经元中,微电泳GLU期间给予MK-801拮抗GLU的兴奋效应,可使90.91%已对GLU产生兴奋效应的STR神经元放电频率减慢。结论:GLU对STR神经元起兴奋作用,但其兴奋作用可被MK-801所拮抗,当直接微电泳MK-801时,可使STR神经元产生抑制效应。研究提示抗谷氨酸作用的药物有抗帕金森病(Parkinson disease,PD)的作用。     

CNQX对伤害性刺激隐神经诱发大鼠脊髓Fos蛋白表达的影响

目的 探讨伤害性刺激隐神经（SN）能否诱发脊髓神经元Fos蛋白表达及发生机制.方法 应用免疫组化方法观察伤害性刺激SN和尾静脉注射谷氨酸非NMDA受体拮抗剂（CNQX）后诱发脊髓神经元Fos蛋白表达的变化.结果 伤害性刺激SN后,诱导脊髓神经元Fos蛋白表达显著增强,CNQX拮抗了Fos蛋白表达的显著增强.结论 以伤害性刺激SN模拟躯体痛后,CNQX拮抗了伤害性刺激SN引起的脊髓神经元Fos蛋白表达的显著增加,表明非NMDA受体在躯体痛的调控中起到了重要的作用.     

艾芬地尔治疗骨癌痛的实验研究

目的 观察N-甲基-D-天门冬氨酸 (NMDA)受体2B亚型选择性拮抗剂艾芬地尔对大鼠胫骨癌痛的治疗作用.方法 采用Walker256乳腺癌细胞建立雌性Wistar大鼠胫骨癌痛模型.于第15天将模型大鼠随机分为10组,每组6只:生理盐水组、吗啡(5、10、20 mg)组、艾芬地尔(2.5、5、10 mg)组和MK-801(0.1、0.25、0.5 mg)组.腹腔注射后,观察各种药物及不同剂量对大鼠自发疼痛和机械超敏反应的影响.结果 艾芬地尔对胫骨癌痛大鼠的自发疼痛和机械超敏反应呈剂量依赖性的抑制作用,作用与吗啡相似;而MK-801仅在较大剂量产生明显的镇痛作用.结论 全身给予NMDA受体2B亚型选择性拮抗剂艾芬地尔有明显的镇痛作用.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg x kg(-1)) or i.p. (50 mg x kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) 1 x h(-1) x kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) 1 x h(-1) x kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was approximately 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8 +/- 2.0%) compared with the female rat (11.7 +/- 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis

AIM: To study the potential pathological role of endogenous angiopoietins in daunorubicin-induced progressive glomerulosclerosis in rats. METHODS: Seventy male Wistar rats were allocated randomly into a daunorubicin group (DRB; n=40) or a control group (n=30). The rats in the DRB group were injected with DRB (15 mg/kg), in their tails. Subsequently, at intervals of 1, 2, 4, 6, 8, and 12 weeks, 5 male Wistar rats in each group were chosen randomly for 24 h urinary protein quantitative measurements (24 h UPQM), and determination of plasma tumor necrosis factor alpha (TNF-alpha), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) levels. Kidney sections were examined by electron microscopy, Periodic Acid Schiff (PAS) staining, immunohistochemical staining and in situ hybridization histochemistry. RESULTS: As glomerulosclerosis progressed in the DRB group, expression of Ang1 mRNA and protein in glomeruli decreased and expression of TNF-alpha protein, Ang2 mRNA and protein in glomeruli increased. Expression of Ang1 mRNA and protein in glomeruli were negatively correlated with 24 h UPQM, Fn protein expression, and mean area of extracellular matrix (MAECM). In comparison, expression of Ang2 mRNA and protein in glomeruli were positively correlated with 24 h UPQM, Fn protein expression and MAECM; furthermore, there was a positive correlation between plasma Ang2 and 24 h UPQM. Plasma TNF-alpha and expression of TNF-alpha in glomeruli were positively correlated with expression of Ang2 mRNA and protein in glomeruli. There was a negative correlation between Ang1 protein expression and Ang2 protein expression in glomeruli. CONCLUSION: During DRB-induced glomerulosclerosis, podocyte injury led to a shift in the balance of Ang1 and Ang2 in glomeruli. Increased TNF-alpha in plasma and glomeruli may upregulate Ang2 expression in glomeruli. Elevated Ang2 in both plasma and glomeruli may mediate protein permeability through the glomerular filtration barrier. Moreover, local expression of Ang2 may facilitate the progress of glomerulosclerosis by upregulating a component expression of extracellular matrix.     

Trichinellosis in immigrants in Switzerland

We describe a case of trichinellosis diagnosed at the Division of Infectious Diseases, Hospital of Lugano, in January 2009. This case was associated with a cluster of cases and was traced to the consumption of contaminated meat after a wild boar hunt in Bosnia.