胡椒碱/五味子甲素对海马神经元网络抑制作用研究
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摘要
癫痫是神经内科最常见的疾病之一。由于癫痫的长期反复发作,严重影响了患者的生活质量和社会工作能力,对个人及社会都造成很大的危害。然而目前临床使用的抗癫痫药物只能使70-80%左右的患者病情得到控制,20-30%的患者会发展为难治性癫痫。并且药物也往往只是对痫性发作的抑制,不能防止癫痫灶的形成,不能影响癫痫病进程。同时,大量长期服药还伴随有各种毒副作用对身体的伤害,因此对新的抗癫痫药物的研制具有重要的现实意义。中药治疗癫痫具有悠久的历史并有显著的疗效,但是由于中药的成分复杂,具体药理学机制的实验证据缺乏,阻碍了它的国际化和标准化。本论文选取了两种传统中药(胡椒和五味子)的主要有效成分(胡椒碱和五味子甲素、乙素),结合钙成像和膜片钳技术,以体外培养的海马神经元网络为实验模型,深入研究了它们对神经元网络兴奋性的调节作用,并分析其可能的机制,得到以下结论:
1.一定浓度的胡椒碱和五味子甲素、乙素能够有效抑制体外培养的海马神经元网络自发同步钙振荡,并且都呈浓度依赖关系;
2.胡椒碱对海马神经元电压激活的钠离子、钾离子、钙离子通道电流没有抑制作用,但对谷氨酸兴奋毒性造成的神经元凋亡有一定的保护作用;五味子甲素对海马神经元电压激活钠离子和钙离子通道电流有显著抑制作用,但不影响电压激活钾离子通道电流;
3.胡椒碱能够有效抑制海马神经元的自发放电和sEPSC频率,但是对KA、NMDA和Na2ATP引起的突触后电流没有抑制作用;五味子甲素对海马神经元sEPSC的频率没有影响,但是抑制了sIPSC的频率;
4.五味子甲素与乙素在低于各自有效浓度时的混合物即可有效抑制海马神经元网络的钙振荡频率,并且以不同比例混合,抑制能力不同;
5.胡椒碱和五味子甲素在低于各自有效浓度时的混合物对钙振荡频率有轻微的加快作用。以高浓度混合时,不同比例的混合物对钙振荡频率的抑制率不同。
Epilepsy is one of the most common diseases in neurology department. It’s caused by many different kinds of perturbances of normal balance of excitation and inhibition within the central nervous system. Given its chronic and recurrent properties, epilepsy damages patients’life qualities and social work abilities and bring heavy burden to the sufferers and the society. Current clinical antiepileptic drugs could control about 70-80% of the patients’symptoms; 20-30% patients develop to be intractable epilepsy sufferers. Moreover, antiepileptic drugs could not prevent formation of foci and disease process, but only alleviate symptoms of seizures at risk of different adverse effects as the consequences of large doses. The call for less negative and more effective antiepileptic drugs is brought forward to the fundamental researches. Chinese medicine is a promising candidate as clinical anticonvulsive drugs for its long history and therapeutic effectiveness of epilepsy. However, the complication of effective components and underlying elusive mechanism of the Chinese medicines hinder their internationalization and standardization. Here we choose the effective components of two traditional Chinese medicines-piperine (PIP) , deoxyschisandrin (DS) and schisandrin B (Sch B)-to investigate their respective modulation and possible mechanisms on primarily cultured hippocampal neurons, using calcium imaging combined with patch clamp technologies. We get the following conclusions:
1. Appropriate concentration of PIP, DS or Sch B respectively and effectively inhibit the frequencies of spontaneous and synchronized calcium oscillations in primarily cultured hippocampal neuronal networks. The inhibitory effects are both dose dependent;
2. PIP has no effect on voltage-gated sodium, potassium and calcium channels currents, but has neuroprotective effect on glutamate-induced excitotoxicity; DS decreases voltage-gated sodium and calcium channels currents with no effect on voltage-gated potassium channel currents;
3. PIP remarkably decreases the frequencies of spontaneous synaptic and spontaneous excitatory postsynaptic currents. However, PIP can not block KA、NMDA、Na2ATP induced postsynaptic currents; DS effectively inhibits the frequencies of spontaneous inhibitory postsynaptic currents with no effect on spontaneous excitatory postsynaptic currents;
4. The mixtures of DS and Sch B with concentrations lower than respective minimal effective dose remarkably inhibite calcium oscillations. The mixtures of DS and Sch B with different ratios have different effects on the changes of frequencies.
5. The mixtures of PIP and DS with concentrations lower than respective minimal effective dose slightly increase the frequencies of calcium oscillations; The mixtures of higher concentions of PIP and DS remarkably decrease the frequencies of calcium oscillations. Mixtures with different ratios of PIP and DS have different effect on the changes of calcium oscillation frequencies.
1.一定浓度的胡椒碱和五味子甲素、乙素能够有效抑制体外培养的海马神经元网络自发同步钙振荡,并且都呈浓度依赖关系;
2.胡椒碱对海马神经元电压激活的钠离子、钾离子、钙离子通道电流没有抑制作用,但对谷氨酸兴奋毒性造成的神经元凋亡有一定的保护作用;五味子甲素对海马神经元电压激活钠离子和钙离子通道电流有显著抑制作用,但不影响电压激活钾离子通道电流;
3.胡椒碱能够有效抑制海马神经元的自发放电和sEPSC频率,但是对KA、NMDA和Na2ATP引起的突触后电流没有抑制作用;五味子甲素对海马神经元sEPSC的频率没有影响,但是抑制了sIPSC的频率;
4.五味子甲素与乙素在低于各自有效浓度时的混合物即可有效抑制海马神经元网络的钙振荡频率,并且以不同比例混合,抑制能力不同;
5.胡椒碱和五味子甲素在低于各自有效浓度时的混合物对钙振荡频率有轻微的加快作用。以高浓度混合时,不同比例的混合物对钙振荡频率的抑制率不同。
Epilepsy is one of the most common diseases in neurology department. It’s caused by many different kinds of perturbances of normal balance of excitation and inhibition within the central nervous system. Given its chronic and recurrent properties, epilepsy damages patients’life qualities and social work abilities and bring heavy burden to the sufferers and the society. Current clinical antiepileptic drugs could control about 70-80% of the patients’symptoms; 20-30% patients develop to be intractable epilepsy sufferers. Moreover, antiepileptic drugs could not prevent formation of foci and disease process, but only alleviate symptoms of seizures at risk of different adverse effects as the consequences of large doses. The call for less negative and more effective antiepileptic drugs is brought forward to the fundamental researches. Chinese medicine is a promising candidate as clinical anticonvulsive drugs for its long history and therapeutic effectiveness of epilepsy. However, the complication of effective components and underlying elusive mechanism of the Chinese medicines hinder their internationalization and standardization. Here we choose the effective components of two traditional Chinese medicines-piperine (PIP) , deoxyschisandrin (DS) and schisandrin B (Sch B)-to investigate their respective modulation and possible mechanisms on primarily cultured hippocampal neurons, using calcium imaging combined with patch clamp technologies. We get the following conclusions:
1. Appropriate concentration of PIP, DS or Sch B respectively and effectively inhibit the frequencies of spontaneous and synchronized calcium oscillations in primarily cultured hippocampal neuronal networks. The inhibitory effects are both dose dependent;
2. PIP has no effect on voltage-gated sodium, potassium and calcium channels currents, but has neuroprotective effect on glutamate-induced excitotoxicity; DS decreases voltage-gated sodium and calcium channels currents with no effect on voltage-gated potassium channel currents;
3. PIP remarkably decreases the frequencies of spontaneous synaptic and spontaneous excitatory postsynaptic currents. However, PIP can not block KA、NMDA、Na2ATP induced postsynaptic currents; DS effectively inhibits the frequencies of spontaneous inhibitory postsynaptic currents with no effect on spontaneous excitatory postsynaptic currents;
4. The mixtures of DS and Sch B with concentrations lower than respective minimal effective dose remarkably inhibite calcium oscillations. The mixtures of DS and Sch B with different ratios have different effects on the changes of frequencies.
5. The mixtures of PIP and DS with concentrations lower than respective minimal effective dose slightly increase the frequencies of calcium oscillations; The mixtures of higher concentions of PIP and DS remarkably decrease the frequencies of calcium oscillations. Mixtures with different ratios of PIP and DS have different effect on the changes of calcium oscillation frequencies.
引文
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