不同中药对青霉素致痫大鼠干预作用的实验观察
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摘要
目的:癫痫是大脑神经元异常同步放电引起的以短暂中枢神经系统功能失调为特征的慢性脑部疾病,严重危害人类健康。无论单独或联合用药,目前抗癫痫药物治疗仅能使80%癫痫患者缓解,仍有20%患者因耐药或西药的严重副作用而未能有效控制,因此开发新的无毒副作用的抗癫痫药物迫在眉睫。随着新型抗癫痫西药研发步伐的放慢,且抗癫痫西药的副作用也已逐渐被重视,人们将目光投向了抗癫痫中药的研发上。临床研究证实,天麻、石菖蒲、胡椒、全蝎及蜈蚣均具有抗癫痫作用,且长期使用无明显毒副作用,但其作用机制尚不完全明确。本实验采用青霉素致痫大鼠模型,观察以上中药对模型大鼠的行为学、惊厥潜伏期及海马组织的GABA能神经元、尼氏小体的影响,探讨它们的抗癫痫机制,为临床应用提供理论基础。
方法:健康成年雄性SD大鼠(250g左右),随机分成八组:即正常对照组、青霉素致痫大鼠模型组(简称模型组)、丙戊酸钠组、天麻组、石菖蒲组、胡椒组、全蝎组及蜈蚣组,每组8只大鼠。后6组于腹腔注射青霉素(8×10~6u/kg)复制癫痫模型前给予药物(临床常用剂量灌胃)干预15天,然后观察癫痫大鼠的行为及痫性发作潜伏期(以造模至首次出现湿狗样抖动的时间计算痫性发作潜伏期)的改变。部分大鼠于造模2h后断头取脑,对大鼠海马组织进行HE染色、Nissl染色和GABA免疫组化染色,计算高倍镜下免疫反应阳性细胞百分率(阳性细胞百分率(%)=免疫组化显色阳性神经细胞数/所观察视野相关细胞总数×100%)及免疫阳性细胞评分(Immunes Histochemistry Positive Cell Score,IHS)值。
结果:1行为学改变:造模前大鼠活动灵活,饮食正常,反应敏捷,皮毛纯白光滑。腹腔注射青霉素后,动物逐渐变得安静,随后出现眼神呆滞、呼吸加快,继而出现点头,头部肌群抖动,或身体突然出现一下抽动。模型组大鼠痫性发作潜伏期为38.45±3.05min ,丙戊酸钠组大鼠为87.48±2.99min ,天麻组为65.15±2.07min ,石菖蒲组为60.87±2.47 min ,胡椒组为45.73±1.84min ,全蝎组为74.34±1.24min,蜈蚣组为79.64±1.64 min,两两比较后差别均有统计学意义。
2脑电图变化:正常对照组大鼠脑电图以8-10HZ的α波为主要表现,无明显阵发性节律出现,波幅<50uv;模型组大鼠脑电图明显异常放电,表现为高幅尖波、棘波或棘慢综合波,说明青霉素诱导的大鼠癫痫模型成功。各药物组大鼠脑电图痫性放电较模型组有所减弱,表现为波幅降低、癫痫波减少。
3病理学变化:
3.1 HE染色:正常对照组大鼠海马CA3、CA1区、齿状回神经元排列整齐,极向好,染色均匀。模型组、药物组大鼠海马CA3、CA1区及齿状回门区神经元数量减少,排列紊乱,极向不清。
3.2 Nissl染色:正常对照组大鼠海马神经元胞浆内可见蓝色的块状或颗粒状的尼氏小体,且数量多,染色深;模型组与药物组大鼠海马区的神经元胞浆内尼氏小体数量少,染色淡,呈现不同程度的溶解。大鼠海马尼氏小体染色IHS值:正常对照组为2.08±0.04,模型组为0.57±0.03,丙戊酸钠组为1.57±0.02,天麻组为1.31±0.02,石菖蒲组为1.37±0.03,胡椒组为0.73±0.03,全蝎组为1.39±0.02,蜈蚣组为1.26±0.03。石菖蒲组大鼠与全蝎组比较,差别无统计学意义,石菖蒲组或全蝎组及其他各组大鼠两两比较,差别均有统计学意义。
3.3 GABA免疫组化染色:正常组大鼠海马GABA免疫反应阳性细胞形态完整,排列密集,而模型组及药物组大鼠海马GABA免疫反应阳性细胞排列稀疏,并有不同程度的损伤。大鼠海马GABA免疫反应阳性细胞百分率:正常对照组为0.76±0.03,模型组为0.19±0.03,丙戊酸钠组为0.66±0.03,天麻组为0.49±0.02,石菖蒲组为0.44±0.02,胡椒组为0.31±0.02,全蝎组为0.54±0.03,蜈蚣组为0.55±0.03。全蝎组与蜈蚣组大鼠比较,差别无统计学意义;全蝎组或蜈蚣组及其他各组大鼠两两比较,差别均有统计学意义。
结论:
1成功复制了青霉素诱发的急性癫痫大鼠模型。
2天麻、石菖蒲、胡椒、全蝎及蜈蚣等五味中药均有抗癫痫作用,但作用比丙戊酸钠弱。
3五味中药中以蜈蚣的抗癫痫作用最强,其次为全蝎,而胡椒的抗癫痫作用最弱。
4天麻、石菖蒲、全蝎、蜈蚣等四味中药抗癫痫作用,可能是通过GABA能抑制系统及其他途径实现的;而胡椒的抗癫痫作用是主要通过增加单胺类神经递质、降低兴奋性氨基酸水平等途径实现的,而与GABA能抑制系统无关。
Objective: Epilepsy is a transient disturbance of cerebral function caused by an abnormal neuronal Discharge. It is a common disease in nervous system, which seriously endangers human health. Whether alone or in combination, at present clinical antiepileptic medicine makes only 80% of remission in patients with epilepsy, but there are still 20% of patients failed to effectively control, with drug resistance or because of the serious side effects of western medicine, so the development of new non-toxic side effects of antiepileptic Drug is imminent. With the new antiepileptic medicine slowed the pace of development, and the side effects of antiepileptic medicine also has been increasingly attention, people are eyeing the antiepileptic medicine research and development. With the pace of development of new antiepileptic medicine slowed down, and the side effects of antiepileptic medicine also has been increasingly drawed attention, people are eyeing the antiepileptic m edicine research and development. Clinical research has shown that gastrodiae elata, acorus tatarinowii schot, pepper, scorpion and scolopendra are all antiepileptic role, and the non-obvious side effects of long-term use, but its mechanism is not entirely clear.This study uses the epileptic model induced by penicillin, and observes impacts of these herbs on the behavior of rats, latency of epilepsy episode, GABA neurons of hippocampus and Nissl bodies of model rats, and explore the mechanisms of antiepileptic medicine for clinical practice to provide a theoretical basis.
Method: Healthy male adult Sprague-Dawley rats(weight 250g) were separated into eight groups, normal control group, epileptic pattern group (induced by penicillin), sodium valproate group, gastrodiae elata group, acorus tatarinowii schot group, pepper group, scorpion group, scolopendra group, and each group is composed of eight rats. Rats of posterior six groups in the drugs intervention group were interferenced by gastric perfusion with drugs (commonly clinical dose gavage) 15 days before intraperitoneal injection of penicillin. Two hours after the model were made, some rats were decapitated brain, and the sections in hippocampus were HE-stainde, Nissl-stained and immunohistochemistry-stained by GABA, and calculate the percentage of immunoreactive positive cells (percentage of positive cells(%) =numbers of positive cells displayed by immunohistochemistry/total number of cells under the view of observation×100%) and of immunoreactive cells positive score (Immunes Histochemistry Positive Cell Score, IHS) values under the high-power microscope.
Results:
1 Behavior changes: Rats activities before making model flexible, normal diet, agile reaction, smooth white fur. Intraperitoneal injection of penicillin, the animals gradually become quiet, and then a sluggish eyes, breathing speed up, and then there nodding, his head muscles jitter, or the body suddenly appeared to spasm. Latency of epilepsy episode of the epileptic pattern group, sodium valproate group, gastrodiae elata group, acorus tatarinowii schot group, pepper group, scorpion group and scolopendra group is respectively 38.45±3.05min, 87.48±2.99min, 65.15±2.07min, 2.47±60.87min, 45.73±1.84min, 74.34±1.24min and 79.64±1.64min, Any two means were compared statistically significant difference. 2 EEG changes: EEG of normal control group rats areαwave of 8 to 10HZ as the main performance, volatility<50uv, and no rhythm with paroxysmal. EEG of epileptic pattern group rats obvious discharge, it includes a higher rate of sharp wave, spikes or spike slow wave ,and that shows penicillin-induced epileptic pattern is successful. Compared to the epileptic pattern group, epileptic discharge of drug groups have slowed down, it shows amplitude is reduced and epilepsy wave is reduced.
3 Pathological changes:
3.1 HE staining: Hippocampal CA3 and CA1 and dentate gyrus neurons of the normal control group arranged in line, to the very good, dyeing uniform. Hippocampal CA3 and CA1 and dentate gyrus neurons of epileptic pattern group and drug groups decrease in the number, are disorders, to a very unclear. 3.2 Nissl staining: There are the massive blue or Coarse Nissl bodies, and a large number of dyeing deep in the neurons cytoplasm of normal control group; Nissl bodies in hippocampal neurons cytoplasm of epileptic pattern group and drug groups decrease in the number, dye desalination, show different levels of dissolved. HIS value of Nissl staining of the epileptic pattern group, sodium valproate group, gastrodiae elata group, acorus tatarinowii schot group, pepper group, scorpion group and scolopendra group is respectively 2.08±0.04, 0.57±0.03, 1.57±0.02, 1.31±0.02, 1.37±0.03, 0.73±0.03, 1.39±0.02 and 1.26±0.03. Acorus tatarinowii rats and Scorpion group, the difference was not statistically significant; acrous gramineus group or Scorpion group and other groups in any two groups comparison, the differences were statistically significant.
3.3 GABA immunohistochemistry staining: hippocampal GABA immunoreactive positive cells of normal control group are morphologically integrity, intensive, and hippocampal GABA immunoreactive positive cells of the epileptic pattern group and drug groups are sparse, and there are injury of different degrees. Hippocampal GABA immunoreactive positive cells percentage of the epileptic pattern group, sodium valproate group, gastrodiae elata group, acorus tatarinowii schot group, pepper group, scorpion group and scolopendra group is respectively 0.76±0.03, 0.19±0.03, 0.66±0.03, 0.49±0.02, 0.44±0.02, 0.31±0.02, 0.54±0.03 and 0.55±0.03. Compared the scorpion group with centipede group, the difference was not statistically significant; compared scorpion group or centipede group with other groups in any two groups, the differences were statistically significant.
Conclusion:
1 Successfully reproduce the penicillin-induced rat model of acute epilepsy.
2 gastrodiae elata,acorus tatarinowii schot, pepper, scorpion and scolopendra etc. five Chinese herbs are antiepileptic medicine, but these herbs are weaker than sodium valproate in the Antiepileptic role.
3 The antiepileptic role of centipede is the strongest, followed by scorpio, and pepper weakest in five Chinese herbs.
4 The antiepileptic role of gastrodiae elata, acorus tatarinowii schot, scorpion and scolopendra, may be through GABA suppression system and other means to achieve; and antiepileptic role of pepper is primarily through increasing monoamine neurotransmitters and reducing excitatory amino acid level to achieve, and has nothing to do with the GABA suppression system.
方法:健康成年雄性SD大鼠(250g左右),随机分成八组:即正常对照组、青霉素致痫大鼠模型组(简称模型组)、丙戊酸钠组、天麻组、石菖蒲组、胡椒组、全蝎组及蜈蚣组,每组8只大鼠。后6组于腹腔注射青霉素(8×10~6u/kg)复制癫痫模型前给予药物(临床常用剂量灌胃)干预15天,然后观察癫痫大鼠的行为及痫性发作潜伏期(以造模至首次出现湿狗样抖动的时间计算痫性发作潜伏期)的改变。部分大鼠于造模2h后断头取脑,对大鼠海马组织进行HE染色、Nissl染色和GABA免疫组化染色,计算高倍镜下免疫反应阳性细胞百分率(阳性细胞百分率(%)=免疫组化显色阳性神经细胞数/所观察视野相关细胞总数×100%)及免疫阳性细胞评分(Immunes Histochemistry Positive Cell Score,IHS)值。
结果:1行为学改变:造模前大鼠活动灵活,饮食正常,反应敏捷,皮毛纯白光滑。腹腔注射青霉素后,动物逐渐变得安静,随后出现眼神呆滞、呼吸加快,继而出现点头,头部肌群抖动,或身体突然出现一下抽动。模型组大鼠痫性发作潜伏期为38.45±3.05min ,丙戊酸钠组大鼠为87.48±2.99min ,天麻组为65.15±2.07min ,石菖蒲组为60.87±2.47 min ,胡椒组为45.73±1.84min ,全蝎组为74.34±1.24min,蜈蚣组为79.64±1.64 min,两两比较后差别均有统计学意义。
2脑电图变化:正常对照组大鼠脑电图以8-10HZ的α波为主要表现,无明显阵发性节律出现,波幅<50uv;模型组大鼠脑电图明显异常放电,表现为高幅尖波、棘波或棘慢综合波,说明青霉素诱导的大鼠癫痫模型成功。各药物组大鼠脑电图痫性放电较模型组有所减弱,表现为波幅降低、癫痫波减少。
3病理学变化:
3.1 HE染色:正常对照组大鼠海马CA3、CA1区、齿状回神经元排列整齐,极向好,染色均匀。模型组、药物组大鼠海马CA3、CA1区及齿状回门区神经元数量减少,排列紊乱,极向不清。
3.2 Nissl染色:正常对照组大鼠海马神经元胞浆内可见蓝色的块状或颗粒状的尼氏小体,且数量多,染色深;模型组与药物组大鼠海马区的神经元胞浆内尼氏小体数量少,染色淡,呈现不同程度的溶解。大鼠海马尼氏小体染色IHS值:正常对照组为2.08±0.04,模型组为0.57±0.03,丙戊酸钠组为1.57±0.02,天麻组为1.31±0.02,石菖蒲组为1.37±0.03,胡椒组为0.73±0.03,全蝎组为1.39±0.02,蜈蚣组为1.26±0.03。石菖蒲组大鼠与全蝎组比较,差别无统计学意义,石菖蒲组或全蝎组及其他各组大鼠两两比较,差别均有统计学意义。
3.3 GABA免疫组化染色:正常组大鼠海马GABA免疫反应阳性细胞形态完整,排列密集,而模型组及药物组大鼠海马GABA免疫反应阳性细胞排列稀疏,并有不同程度的损伤。大鼠海马GABA免疫反应阳性细胞百分率:正常对照组为0.76±0.03,模型组为0.19±0.03,丙戊酸钠组为0.66±0.03,天麻组为0.49±0.02,石菖蒲组为0.44±0.02,胡椒组为0.31±0.02,全蝎组为0.54±0.03,蜈蚣组为0.55±0.03。全蝎组与蜈蚣组大鼠比较,差别无统计学意义;全蝎组或蜈蚣组及其他各组大鼠两两比较,差别均有统计学意义。
结论:
1成功复制了青霉素诱发的急性癫痫大鼠模型。
2天麻、石菖蒲、胡椒、全蝎及蜈蚣等五味中药均有抗癫痫作用,但作用比丙戊酸钠弱。
3五味中药中以蜈蚣的抗癫痫作用最强,其次为全蝎,而胡椒的抗癫痫作用最弱。
4天麻、石菖蒲、全蝎、蜈蚣等四味中药抗癫痫作用,可能是通过GABA能抑制系统及其他途径实现的;而胡椒的抗癫痫作用是主要通过增加单胺类神经递质、降低兴奋性氨基酸水平等途径实现的,而与GABA能抑制系统无关。
Objective: Epilepsy is a transient disturbance of cerebral function caused by an abnormal neuronal Discharge. It is a common disease in nervous system, which seriously endangers human health. Whether alone or in combination, at present clinical antiepileptic medicine makes only 80% of remission in patients with epilepsy, but there are still 20% of patients failed to effectively control, with drug resistance or because of the serious side effects of western medicine, so the development of new non-toxic side effects of antiepileptic Drug is imminent. With the new antiepileptic medicine slowed the pace of development, and the side effects of antiepileptic medicine also has been increasingly attention, people are eyeing the antiepileptic medicine research and development. With the pace of development of new antiepileptic medicine slowed down, and the side effects of antiepileptic medicine also has been increasingly drawed attention, people are eyeing the antiepileptic m edicine research and development. Clinical research has shown that gastrodiae elata, acorus tatarinowii schot, pepper, scorpion and scolopendra are all antiepileptic role, and the non-obvious side effects of long-term use, but its mechanism is not entirely clear.This study uses the epileptic model induced by penicillin, and observes impacts of these herbs on the behavior of rats, latency of epilepsy episode, GABA neurons of hippocampus and Nissl bodies of model rats, and explore the mechanisms of antiepileptic medicine for clinical practice to provide a theoretical basis.
Method: Healthy male adult Sprague-Dawley rats(weight 250g) were separated into eight groups, normal control group, epileptic pattern group (induced by penicillin), sodium valproate group, gastrodiae elata group, acorus tatarinowii schot group, pepper group, scorpion group, scolopendra group, and each group is composed of eight rats. Rats of posterior six groups in the drugs intervention group were interferenced by gastric perfusion with drugs (commonly clinical dose gavage) 15 days before intraperitoneal injection of penicillin. Two hours after the model were made, some rats were decapitated brain, and the sections in hippocampus were HE-stainde, Nissl-stained and immunohistochemistry-stained by GABA, and calculate the percentage of immunoreactive positive cells (percentage of positive cells(%) =numbers of positive cells displayed by immunohistochemistry/total number of cells under the view of observation×100%) and of immunoreactive cells positive score (Immunes Histochemistry Positive Cell Score, IHS) values under the high-power microscope.
Results:
1 Behavior changes: Rats activities before making model flexible, normal diet, agile reaction, smooth white fur. Intraperitoneal injection of penicillin, the animals gradually become quiet, and then a sluggish eyes, breathing speed up, and then there nodding, his head muscles jitter, or the body suddenly appeared to spasm. Latency of epilepsy episode of the epileptic pattern group, sodium valproate group, gastrodiae elata group, acorus tatarinowii schot group, pepper group, scorpion group and scolopendra group is respectively 38.45±3.05min, 87.48±2.99min, 65.15±2.07min, 2.47±60.87min, 45.73±1.84min, 74.34±1.24min and 79.64±1.64min, Any two means were compared statistically significant difference. 2 EEG changes: EEG of normal control group rats areαwave of 8 to 10HZ as the main performance, volatility<50uv, and no rhythm with paroxysmal. EEG of epileptic pattern group rats obvious discharge, it includes a higher rate of sharp wave, spikes or spike slow wave ,and that shows penicillin-induced epileptic pattern is successful. Compared to the epileptic pattern group, epileptic discharge of drug groups have slowed down, it shows amplitude is reduced and epilepsy wave is reduced.
3 Pathological changes:
3.1 HE staining: Hippocampal CA3 and CA1 and dentate gyrus neurons of the normal control group arranged in line, to the very good, dyeing uniform. Hippocampal CA3 and CA1 and dentate gyrus neurons of epileptic pattern group and drug groups decrease in the number, are disorders, to a very unclear. 3.2 Nissl staining: There are the massive blue or Coarse Nissl bodies, and a large number of dyeing deep in the neurons cytoplasm of normal control group; Nissl bodies in hippocampal neurons cytoplasm of epileptic pattern group and drug groups decrease in the number, dye desalination, show different levels of dissolved. HIS value of Nissl staining of the epileptic pattern group, sodium valproate group, gastrodiae elata group, acorus tatarinowii schot group, pepper group, scorpion group and scolopendra group is respectively 2.08±0.04, 0.57±0.03, 1.57±0.02, 1.31±0.02, 1.37±0.03, 0.73±0.03, 1.39±0.02 and 1.26±0.03. Acorus tatarinowii rats and Scorpion group, the difference was not statistically significant; acrous gramineus group or Scorpion group and other groups in any two groups comparison, the differences were statistically significant.
3.3 GABA immunohistochemistry staining: hippocampal GABA immunoreactive positive cells of normal control group are morphologically integrity, intensive, and hippocampal GABA immunoreactive positive cells of the epileptic pattern group and drug groups are sparse, and there are injury of different degrees. Hippocampal GABA immunoreactive positive cells percentage of the epileptic pattern group, sodium valproate group, gastrodiae elata group, acorus tatarinowii schot group, pepper group, scorpion group and scolopendra group is respectively 0.76±0.03, 0.19±0.03, 0.66±0.03, 0.49±0.02, 0.44±0.02, 0.31±0.02, 0.54±0.03 and 0.55±0.03. Compared the scorpion group with centipede group, the difference was not statistically significant; compared scorpion group or centipede group with other groups in any two groups, the differences were statistically significant.
Conclusion:
1 Successfully reproduce the penicillin-induced rat model of acute epilepsy.
2 gastrodiae elata,acorus tatarinowii schot, pepper, scorpion and scolopendra etc. five Chinese herbs are antiepileptic medicine, but these herbs are weaker than sodium valproate in the Antiepileptic role.
3 The antiepileptic role of centipede is the strongest, followed by scorpio, and pepper weakest in five Chinese herbs.
4 The antiepileptic role of gastrodiae elata, acorus tatarinowii schot, scorpion and scolopendra, may be through GABA suppression system and other means to achieve; and antiepileptic role of pepper is primarily through increasing monoamine neurotransmitters and reducing excitatory amino acid level to achieve, and has nothing to do with the GABA suppression system.
引文
1 王维治.神经病学 [M].第 4 版.北京:民卫生出版社,2002.224
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