【作者】 佘加其；

【导师】 阮迪云；

【作者基本信息】 中国科学技术大学 ， 生物物理， 2009， 博士

【摘要】 铅是一种重要的环境毒和神经毒。大量研究表明,铅暴露损伤中枢神经系统的结构和功能。如何减轻以及预防铅暴露所造成的损伤是一个具有重大现实意义的课题。神经节苷脂是一种广泛存在于细胞膜上的鞘糖脂类物质,它在神经再生,神经系统损伤的修复以及突触传递中均起着重要的作用。本文应用在位电生理技术和生化方法研究了神经节苷脂对铅暴露引起的神经系统损伤的修复和保护作用,主要结果如下:1.用电生理记录技术研究神经节苷脂对于慢性铅暴露所引起的LTP/DP损伤的修复作用。将Wistar大鼠分为三组(60-90天):对照组,慢性铅暴露组,慢性铅暴露+药物处理组),在PP-DG通路上记录I/O效应曲线,PPF和LTP/DP。结果表明:(1).慢性铅暴露损伤了大鼠海马DG区的EPSP和PS的LTP/DP.;(2)外源性补充神经节苷脂一定程度上可以修复慢性铅暴露引起的突触可塑性LTP/DP的损伤。结果提示神经节苷脂可以部分修复慢性铅暴露造成的学习记忆功能的损伤,它可能是一种潜在的治疗铅中毒的药物。2.应用在位电生理记录,生化检测,激光共聚焦的技术来研究了神经节苷脂对急性铅铅暴露的保护作用。将动物分为五组(空白对照,盐水对照,药物组,急性铅暴露组,以及急性铅+药物组),用电生理技术记录I/O效应曲线,基线水平和LTP;用生化方法检测了急性铅暴露对氧化功能的损伤,以及神经节苷脂对这种损伤的保护作用;用激光共聚焦技术检测了急性铅和神经节苷脂对细胞内钙平衡的影响。结果发现:(1)急性铅暴露显著地损伤了大鼠海马DG区的I/O,基础兴奋性以及LTP水平。若提前使用神经节苷脂,可以明显的减弱这种损伤作用;(2)急性铅暴露引起SOD活性以及MDA水平的显著提高,若提前使用神经节苷脂处理,可以明显的减弱这种作用。(3)急性铅暴露引起细胞内钙水平的提高,神经节苷脂可以明显地降低铅暴露引起的细胞内钙水平变化。结果表明,如果提前使用神经节苷脂GM1可以显著性的降低急性铅暴露造成的大鼠海马突触可塑性以及细胞功能上的损伤,神经节苷脂GM1可能是一种潜在的预防铅中毒的药物。更多还原

【Abstract】 Lead is one of the most common neurotoxic metals present in our environment, which causes impairment to the central nervous system（CNS）.Of great importance is how to diminish the impairment on CNS induced by lead.Gangliosides are particularly abundant in nervous system and play a variety of important roles in regulating proliferation,neurogenesis and synaptic transmission.The purpose of this study is to evaluate the repairing and protective effect of ganglioside on the lead-induced impairment of synaptic plasticity.The results show that:1.The effects of ganglioside on the lead-induced impairments of LTP and DP were evaluated in rat dentate gyrus in vivo.The experiments were carried out in three groups of rats（control,chronic lead-exposed,ganglioside treated lead-exposed, respectively）.The input-output（I/O） function,pair-pulses reaction,excitatory postsynaptic potential（EPSP） and population spike（PS） amplitude were measured in the dentate gyrus（DG） of adult rats in response to stimulation applied to the lateral perforant path.The results showed that:（1）.chronic lead exposure impaired LTP/DP measured on both EPSP slope and PS amplitude in DG area of the hippocampus.（2）. the amplitudes of LTP/DP of lead-exposed group were significantly increased by supplying ganglioside.These results suggested intraperitoneally injection with ganglioside could repair the lead-induced impairments of synaptic plasticity in rats partyly and ganglioside might be one effective agent in repairing the lead induced impairment on synaptic plasticty.2.The effects of monosialoganglioside（GM1） were studied on synaptic plasticity, antioxidant system function and intracellular calcium levels in the hippocampus of acute Pb²⁺ exposed rats by electrophysiological recordings in vivo,biochemical analysis and confocal image analysis in vitro.The experiments were carried out in five groups of rats（Blank control,Saline control,Acute lead exposed,GM1 control and GM1 treaed acute lead exposed）.The results showed that:（1） Acute lead exposure impaired synaptic transmission（I/O and baseline） and plasticity（LTP） in the hippocampus and GM1 preconditioning rescued to some extent this impairment in urethane anesthetized rats.（2） Superoxide dismutase（SOD） activities and malondialdehyde（MDA） levels were significantly increased in the acute-Pb²⁺-exposed hippocampus which could be reduced by GM1 preconditioning. （3） Acute Pb²⁺ exposure caused the internal free Ca²⁺ fluctuation in the cultured hippocampal neurons and GM1 preconditioning could abate this fluctuation.Taken together,GM1 preconditioning could reduce the acute lead induced impairment on synapstic plasiticity and cell function,GM1 might be one useful tool in protecting against Pb²⁺ toxicity and its treatment.更多还原