摘要
铅是一种重要的环境毒和神经毒。它主要影响神经系统的学习和记忆功能。铅对神经系统功能的损伤与修复机制的研究仍然是人们非常关注的问题。天麻素是我国传统中药材天麻的有效单体和重要的有效成分,它可以调节大脑皮质兴奋与抑制过程的平衡,有镇静、安眠和镇痛等中枢抑制作用并可以改善学习和记忆功能,对神经系统损伤有一定的保护作用。丙戊酸钠是当前一种重要的广谱抗癫痫药,尽管丙戊酸钠在临床上已经被广泛的使用,但其作用机制到现在也没能完全阐明。特别是丙戊酸钠对突触可塑性影响的报道很少,结果也不一致。本论文运用电生理技术和生物化学方法,研究了天麻素和丙戊酸钠对大鼠海马CA1区神经元突触传递特性及可塑性的影响以及天麻素对铅引起的神经损伤的修复作用。主要结果如下:
1.急性灌流天麻素,浓度为0.015-0.9 mM时,天麻素浓度依赖性的增强了海马神经元基础突触传递效能;天麻素增强了海马神经元突触的双脉冲易化(PPF),减少了突触前兴奋性递质的释放,证实了天麻素对基础突触传递效能的增强不是通过突触前的机制作用的;APV不能阻断天麻素对突触传递效能的增强,说明这种增强作用也不是通过NMDA受体介导的。进一步的研究表明天麻素对海马CA1区LTP的诱导没有产生明显的影响。
2.进一步证实了发育期慢性铅暴露损伤了大鼠海马CA1区长时程增强(LTP)、PPF和input/output(I/O)功能;此外,铅暴露还提高了大鼠海马丙二醛(MDA)的含量,降低了超氧化物歧化酶(SOD)的活性和谷胱甘肽(GSH)的含量,以及乙酰胆碱酯酶(AChE)的活性。天麻素对铅引起的这些神经系统功能的损伤具有明显的修复作用。这些实验结果表明铅引起大鼠海马CA1区突触可塑性的损伤可能与铅损伤胆碱能系统和破坏氧化平衡有关。天麻素对铅中毒的治疗有潜在的应用价值。
3.采用全细胞膜片钳技术研究了丙戊酸钠对大鼠海马CA1区神经元突触可塑性及神经兴奋性的影响。结果表明:丙戊酸钠能增加突触前抑制性神经元的活性,但对兴奋性突触传递没有影响;丙戊酸钠降低了海马神经元的兴奋性。这些作用可能参与了丙戊酸钠抗癫痫的作用机制。
Lead is a well known toxin in environment,which can produce severe damage to nervous system.Lines of evidence have shown lead impaired the ability of learning and memory.Gastrodin,the main bioactive component of Tian ma,has been used in China for many years as a clinical drug.Recently,several studies have shown the cognitive-enhancing and neuroprotective effects of gastrodin.Sodium valproate (VPA) is widely used as an antiepileptic drug with a broad spectrum of anticonvulsant activity and particular efficacy in the generalized epilepsies.In spite of its wide use for many years,the mechanisms of action of VPA are still not fully understood.So far,there were few studies about effects of VPA on synaptic transmission and the data presented were not consistent.In the present study,we investigated the effects of gastrodin and VPA on synatic transmission and plasiticity by electrophysiological and biochemical methods.In addition,the neuroprotective of gastrodin on lead-induced dysfunction in rat hippocampal CA1 reigon were also investigated.The main results are as follows:
1.Acute gastrodin perfusion augmented the basal synaptic transmission in a concentration-dependent manner ranging from 0.015 to 0.9 mM.This effect was unlikely due to an increase in glutamate release from presynaptic terminals since there was a significant increase in the paired pulse ratio(PPF).And this effect was not blocked by AP5,an antagonist of NMDA receptor,suggesting this effect was not mediated by NMDA receptors.Furthermore,the result about LTP showed gastrodin didn't affect the induction of LTP.
2.Lead exposure significantly impaired synaptic plasticity in the hippocampal CA1 region,and the abilities of antioxidant defense system and cholinergic system; Gastrodin effectively rescued these lead-induced impairments.The results herein suggest that oxidative and cholinergic mechanisms may underlie the hippocampal effects of lead in developmental rats,in view of the protective effects of gastrodin. Thus,gastrodin may have potential therapeutic value for lead-induced impairments during human development stages.
3.The effects of gastrodin on synaptic transmission and neuroal excitability in rat hippocampus were investigated by whole-cell patch clamp recordings.Perfusion with VPA,at therapeutically attainable concentrations significantly increased the frequency but not the amplitude of miniature inhibitory postsynaptic currents (mIPSCs);while did not alter both amplitude and frequency of miniature excitatory postsynaptic currents(mEPSCs).In acutely dissociated CA1 pyramidal neurons,VPA did not affect the GABA-induced currents.Additionly,we also found the frequency of action potential(AP) firing was significantly reduced and spike frequency adaptation(SFA) was significantly increased by VPA application. These results suggest that VPA presynaptically increases inhibitory synaptic activity without modifying excitatory synaptic transmission and reduces the neuronal excitability,any or all of which may contribute to its anticonvulsant action.
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