奥沙利铂神经毒性机制及预测

 作为大肠癌的主要化疗药物之一，奥沙利铂的应用正逐步扩展到其他肿瘤的治疗中，然而奥沙利铂相关外周神经病变却限制了其临床应用。奥沙利铂神经毒性的机制尚未明确，最新研究认为急性神经毒性是通过改变Na+短暂电导介导的；体外实验证实了丝裂原活化蛋白激酶(MAPK)在奥沙利铂慢性神经病变中的作用。多种指标可用于预测奥沙利铂相关的外周神经病变，为实现个体化药物治疗、提高化疗的连续性带来了希望。     

咖啡酸对神经毒素MPP+诱发大鼠小脑颗粒细胞凋亡的保护作用

目的:探讨咖啡酸(CA) 是否对1-甲基-4-苯基吡啶离子(1-methyl-4-phenylpyridinium ion, MPP ) 诱导的大鼠小脑颗粒细胞凋亡具有保护作用.方法: 用咖啡酸孵育大鼠小脑颗粒细胞, 经MPP 处理后, 用MTT法测定细胞存活率, 荧光法检测caspase-3的活性.结果:咖啡酸对MPP 致小脑颗粒细胞存活率降低和caspase-3活性增强具有很好的抑制作用,并呈现稳定的量效和时效关系.结论:咖啡酸对MPP 诱导小脑颗粒细胞凋亡具有明显的保护作用.     

八肽胆囊收缩素对谷氨酸神经毒性的拮抗作用

目的：探讨八肽胆囊收缩素（ＣＣＫ－８）对谷氨酸神经兴奋毒性的作用。方法：采用神经元原代分离培养技术，应用电镜观察经不同药物处理后的大鼠大脑皮层神经元的形态学变化，同时测定细胞上清液中ＬＤＨ活性值，并进行ｔ检验等统计学分析。结果：ＣＣＫ－８能明显改善由谷氨酸诱导的神经元结构的破坏和减少神经元损伤后ＬＤＨ的释放，该作用可被ＣＣＫ＿Ｂ受体拮抗剂阻断。结论：ＣＣＫ－８可通过Ｂ受体介导产生对谷氨酸神经毒性的拮抗作用。     

谷氨酸载体在鼠脑缺血神经元死亡中的作用

目的研究谷氨酸载体在脑缺血神经元死亡中的作用。方法用原位杂交和免疫组织化学方法观察大鼠脑缺血后脑内谷氨酸载体ＧＬＡＳＴｍＲＮＡ和胶质纤维酸性蛋白（ＧＦＡＰ）表达的变化，用药理分析手段观察谷氨酸载体摄取抑制剂Ｌ反式吡咯烷２，４二羧酸（ＬｔｒａｎｓＰＤＣ）对脑缺血致神经元损伤的影响。结果脑缺血后２４小时，大脑皮层缺血周边区ＧＬＡＳＴｍＲＮＡ和ＧＦＡＰ表达无显著变化；而缺血后７２小时，缺血周边区ＧＬＡＳＴｍＲＮＡ和ＧＦＡＰ表达都显著增加，脑缺血后２４小时和７２小时，缺血侧海马ＣＡ１区ＧＬＡＳＴｍＲＮＡ表达则无显著变化；与侧脑室注射生理盐水组相比，侧脑室注射１μｇ或２μｇＬｔｒａｎｓＰＤＣ有使脑梗塞体积增大的趋势，但差异无显著意义；侧脑室注射５μｇＬｔｒａｎｓＰＤＣ使脑梗塞体积显著增大。结论脑缺血后谷氨酸载体功能可能呈代偿性增强，提示谷氨酸载体在限制脑缺血时谷氨酸神经毒中起重要作用。     

The role of neurotransporters in excitotoxicity, neuronal cell death, and other neurodegenerative processes

Neurotransporters are high-affinity transport proteins located in the plasma membrane of both presynaptic nerve and glial cells that mediate the removal of neurotransmitters from the synaptic cleft or represent intracellular transport systems that concentrate neurotransmitters in synaptic vesicles. They comprise three subgroups, Na⁺/Cl^–- or Na⁺/K⁺-dependent cell surface transporters and H⁺-dependent transporters associated with synaptic vesicles. The new insights into neurotransporter diversity provide the means for novel approaches of studying neurotransmitter uptake processes at the molecular level, such as substrate translocation, antagonist binding, and regulation of gene expression, intracellular trafficking, and posttranslational modification. Moreover, modeling neurotransporter-related disorders and therapeutic strategies in genetically engineered animals are now feasible research strategies. Through an improved understanding of the modulation of neurotransporter function in the brain it may be possible to identify the molecular factors underlying the etiopathogenesis and pathophysiology of neurodegenerative disorders. Due to their specificity for distinct neuronal systems neurotransporters and their genes are potential targets for novel therapeutic strategies.Abbreviations ChAT Choline acetyltransferase - CRE cAMP response element - DAT Dopamine transporter - GABA -Aminobutyric acid - GluT Glutamate transporter - 5-HT 5-Hydroxytryptamine - 5-HTT 5-HT transporter - ILPR Insulin gene linked polymorphic region - MDMA 3,4-Methylenedioxymethamphetamine - MPP ⁺ 1-Methyl-4-phenylpyridine ion - MPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - PD Parkinson's disease - TBZOH Dihydrotetrabenazine - VAChT Vesicular ACh transporter - VMT Vesicular monoamine transporter     

Ibotenic acid-induced neuronal degeneration: A morphological and neurochemical study

Summary Possible neurotoxic actions of intracerebral injections of ibotenic acid, a conformationally restricted analogue of glutamic acid, have been evaluated in rat brain and compared with those of kainic acid.Light microscopical analysis revealed that ibotenic acid produced a marked disappearance of nerve cells in all areas studied, namely striatum, the hippocampal formation, substantia nigra and piriform cortex. Lesions in areas distant to the injection site were not seen. Axons of passage and nerve terminals of extrinsic origin did not seem to be damaged, since, e.g., no apparent degeneration of the dopaminergic terminals in the neostriatum was observed except for a small area surrounding the cannula. In the neostriatum, enkephalin immunoreactive neuronal cell bodies as well as nerve terminals disappeared after injection of ibotenic acid into this nucleus. After injection into the substantia nigra tyrosine hydroxylase immunoreactive cell bodies in the zona compacta disappeared, whereas no certain effect could be seen on the enkephalin immunoreactive nerve fibers.In vitro experiments, conducted with striatal synaptosomal and membrane preparations, showed that ibotenic acid differed from kainic acid by being devoid of a significant inhibitory effect on high affinity glutamate uptake and by having a low affinity for ³H-kainic acid binding sites. Furthermore, ibotenic acid did not interfere with the binding of a number of radioligands for other transmitter receptors.As compared to kainic acid, ibotenic acid has the advantage of being less toxic to the animals and of producing more discrete lesions, possibly due to faster metabolism and/or other fundamental biochemical differences. Because of these special features, ibotenic acid seems to represent a valuable new tool in the morphological and functional analysis of central neuronal systems.     

Comparison of the "toxic" and antigenic regions in toxin alpha isolated from Naja nigricollis venom

The present paper describes the “toxic” site and one topologically distinct antigenic determinant of N. nigricollis toxin α.     

氯化锰致PC12细胞损伤的研究

探讨氯化锰（MnCl2）对PC12细胞的损伤作用。方法：构建MnCl2诱导的PC12细胞模型，用MTT法检测细胞存活率，用荧光分光光度法检测乳酸脱氢酶（LDH）和活性氧（ROS）生成量，用化学比色法测定细胞内丙二醛（MDA）含量和超氧化物歧化酶（SOD）活性。结果：MnCl2诱导的PC12细胞存活率明显下降，并与诱导时间和浓度呈正相关；MnCl2使PC12细胞LDH外溢量和ROS生成量显著增加，同时细胞内MDA含量增加，SOD活性下降。结论：MnCl2可导致PC12细胞的氧化损伤。     

肉毒毒素中毒的诊断和治疗

肉毒毒素(botulinum neurotoxin,BoNT)是由肉毒梭状芽胞杆菌产生的神经毒素,通过水解可溶性N-乙基马来酰亚胺-敏感因子附着蛋白受体(soluble N-ethylmaleimide-sensitive factor attachment protein receptor,SNARE)复合体,阻断神经递质释放,达到化学性去神经支配作用,已在临床诊疗及美容整形等多学科领域得到了广泛的应用。BoNT中毒是由BoNT过量导致的一种神经瘫痪性疾病。医源性BoNT中毒大多与使用非正规渠道来源的Bo NT或不规范使用Bo NT有关。BoNT中毒的临床症状主要为急性、对称性、下行性迟缓性瘫痪,严重者可致呼吸衰竭而死亡。BoNT中毒最有效的治疗方法是尽早使用Bo NT抗毒素,因此早期诊断至关重要。由于病原菌检测或BoNT检测耗时较长,因此临床诊断BoNT中毒主要依靠病史和临床表现,而神经电生理检查则有助于鉴别诊断。本文对Bo NT中毒相关文献进行总结和讨论,以期为BoNT中毒的诊断和治疗提供指导。