宁痫颗粒联合卡马西平对难治性癫痫大鼠的相关性研究
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摘要
目的：
本研究通过建立海人酸难治性癫痫大鼠模型,采用宁痫颗粒、卡马西平单独或联合治疗,观察海人酸难治性癫痫大鼠行为学和脑电图变化,从炎症因子、凋亡及耐药基因探讨宁痫颗粒抗癫痫作用机制,为中西医结合治疗难治性癫痫提供了新的治疗方法。
方法：
第一部分：采用海人酸海马CA3区微量注射的化学点燃方法制作模型,通过苯妥英钠及脑电图筛选成功制作慢性难治性癫痫模型36只,随机分为模型组、卡马西平组、宁痫颗粒组、宁痫颗粒低、中、高剂量联合卡马西平组,再加假手术组,共7组,每组6只。
第二部分：观察各组大鼠治疗前后体重、癫痫发作的次数、发作平均持续时间、被抓时平均防卫级别、发作级别、SRS发作总时间,并对各组大鼠治疗前后进行脑电图监测。
第三部分：难治性癫痫大鼠模型每组6只,分组治疗后与假手术组6只,予心尖灌注生理盐水后取脑,在4%多聚甲醛中固定,常规制备石蜡切片(含皮层和海马)。HE染色观察海马各区及颞叶皮层神经元形态结构的改变,免疫组化观察海马及颢叶皮层c-fos、caspase-3的表达。
第四部分：按上述治疗分组后股动脉采血,收集各实验组大鼠血清采用免疫酶联法(Elisa法)测定各实验组大鼠血清IL-1β、IL-6、TNF-α水平。
第五部分：按上述治疗分组后大鼠在10%水合氯醛麻醉下取脑,实时荧光定量PCR法检测各组大鼠脑内海马MDR1mRNA表达,western-blot法检测其相应P-gp表达。
结果：
第一部分：采用海马局部注射海人酸及药物筛选后成功制作成难治性癫痫大鼠模型。
第二部分：治疗后大鼠体重比较：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组体重明显增加,有显著性差异(P<0.05)：大鼠治疗前后发作平均持续时间比较：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平发作平均持续时间明显减少,有极显著性差异(P<0.01)：大鼠治疗前后被抓时的平均防卫反应评分：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组被抓时平均防卫反应评分明显减少,有极显著性差异(P<0.01)；大鼠治疗前后平均发作级别的变化：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组平均发作级别减少,有极显著性差异(P<0.01); SRS发作总时间变化：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组SRS发作总时间明显减少,有极显著性差异(P<0.01)。脑电图显示宁痫颗粒中、高剂量联合卡马西平组大鼠痫性放电受到抑制。
第三部分：c-fos表达：假手术组大鼠海马区组织切片中可见少量c-fos阳性细胞表达,模型组海马区c-fos阳性细胞的表达明显增多。与卡马西平组比较,宁痫颗粒低、中、高剂量组联合卡马西表达明显减少,有极显著性差异(氏0.01)；caspase-3表达：与卡马西平组比较,宁痫颗粒低、中、高剂量联合卡马西组表达减少,有显著性差异(P<0.05)。
第四部分：IL-1p表达：与卡马西平组比较,宁痫颗粒低剂量联合卡马西平组大鼠血清IL-1p含量显著降低(P<0.05),宁痫颗粒中、高剂量组联合卡马西平大鼠血清IL-6含量极显著降低(P<0.01)；IL-6表达：与卡马西平组比较,宁痫颗粒低剂量联合卡马西平组大鼠血清IL-6含量显著降低(尸<0.05)；宁痫颗粒中、高剂量联合卡马西平组大鼠血清IL-6含量极显著降低护<0.01)；TNF-α表达：与卡马西平组比较,宁痫颗粒低、中、高剂量联合卡马西平组大鼠血清TNF-α含量极显著降低(P<0.01)。
第五部分：MDR1mRNA表达：与模型组比较,其余各组大鼠脑组织MDRI含量极显著降低(P<0.01)；与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组大鼠脑组织MDRI含量极显著降低(P<0.01); P-gp表达：与模型组比较,宁痫颗粒高剂量联合卡马西平组大鼠脑组织P-gp蛋白表达极显著降低(P<0.01),宁痫颗粒低、中剂量联合卡马西平组表达显著降低∽<0.05)。
结论：
1.本研究成功建立了大鼠海马局部注射微量海人酸后经癫痫持续状态及药物筛选成为难治性癫痫模型,操作相对简单,成功率高,节约成本,为后续研究打下较好的基础。
2.宁痫颗粒低、中、高剂量联合卡马西平组能明显减少各组致痫大鼠的痫性发作平均持续时间、被抓时的防卫反应评分、SRS发作总时间,并降低痫性发作程度,比单用中药或西药有明显改善。脑电图显示宁痫颗粒中、高剂量组联合卡马西平组大鼠痫性放电明显受到抑制,只见少量棘波或尖波,而以宁痫颗粒高剂量联合卡马西平组出现最少。
3.宁痫颗粒低、中、高剂量联合卡马西平组可以明显降低c-fos、caspase-3基因的表达,抑制细胞凋亡,达到保护神经细胞的作用；推测宁痫颗粒可能作用于细胞凋亡途径的多个靶点,与卡马西平有协同增效的作用,但凋亡基因的表达并未随中药剂量的增加而下调。
4.IL-1β、IL-6、TNF-α共同参与了免疫反应,其水平的变化间接反映了脑组织损伤程度。宁痫颗粒中、高剂量联合卡马西平组炎症因子的表达明显低于卡马西平组(P<0.01),表明宁痫颗粒联合卡马西平具有一定的免疫抑制作用,比单用卡马西平疗效显著,进而说明两者联合具有协同作用,对癫痫有一定的治疗作用。
5.宁痫颗粒联合卡马西平具有一定的抑制MDR1mRNA/P-gp的药物转运体功能,可以下调MDR1mRNA/P-gp表达,且存在一定的量效关系。
Objective
This paper attempts to study the possible antiepileptic mechanism of Ningxian Particles by the inflammation factors, apoptosis and drug-resistance gene, based on the kainic acid refractory epilepsy rats model by the Ningxian particles, CBZ alone or integrated therapy, observing the kainic acid refractory epilepsy rats behavior and EEG epileptic wave in order to provide a new therapeutic method for combing traditional Chinese and western medicine treatment of refractory epilepsy.
Method
Part1:36chronic refractory epilepsy models were made by microinjection of kainic acid hippocampal CA3chemic igniting and PHT and EEG screening, and they were divided randomly into7groups, such as model, CBZ, Ningxian particles, Ningxian particles low, medium and high dose combination CBZ and sham-operated group, and these are6rats each group.
Part2:The rats before and after being treated were observed by the weight, the number of seizures, the average duration of seizures, the defense levels, the seizures levels, the spontaneous recurrent seizures total times, and EEG monitoring.
Part3:Refractory epilepsy rat model (n=6), each group after treatment with the sham group (n=6), the apical perfusion normal saline before removal of brain, fixed in4%paraformaldehyde, conventional preparation of paraffin sections (containing the cerebral cortex and hippocampus). HE staining was used to observe the changes in the hippocampus and temporal cortex neurons morphology, immunohistochemical observation hippocampus and temporal cortex of c-fos and caspase-3expression.
Part4:The experimental group rats serum IL-1β, IL-6, TNF-α content were detected by using the enzyme-linked immunosorbent assay method (Elisa method) after femoral artery blood collected in each experimental group therapy.
Part5:The rats were under anaesthesia by10%chloral hydrate to be removed their brains. The MDR1mRNA expression of rats was detected by Real-time quantitative polymerase chain reaction. The P-gp expression was detected by western-blot.
Result
Part1:Refractory epilepsy rat model was successfully made by hippocampal local injection of kainic acid and drug screening.
Part2:The weight of the rats by combining medium and high-dose Ningxian particles with CBZ group drastically increased, comparing with CBZ group. There was a significant difference (P<0.05). The seizures mean duration of the rats before and after being treated by combining medium and high-dose Ningxian particles with CBZ group were drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01). The mean defense response of the rats before and after being treated by combining medium and high-dose Ningxian particles with CBZ group were drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01). The average seizure changes in the level of rats before and after being treated by combining medium and high-dose Ningxian particles with CBZ group drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01).The spontaneous recurrent seizures total time of the rats being treated by combining medium and high-dose Ningxian particles with CBZ drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01). The EEG showed the Ningxian particles medium and high-dose combination CBZ group epileptic discharge was inhibited.
Part3:Minimum c-fos positive cells expression was seen in sham-operated rats' hippocampus tissue sections. The c-fos positive cells expression in the hippocampus increased significantly in model group. The expression of combining low, medium and high-dose Ningxian particles with CBZ group drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01). The caspase-3 expression of combining low, medium and high-dose Ningxian particles with CBZ group drastically decreased, comparing with CBZ group. There was a significant difference (P<0.05).
Part4:Comparing with CBZ group,the Ningxian particles low dose combination CBZ rats serum IL-1β levels were significantly lower (P<0.05).The Ningxian particles medium and high-dose combination CBZ rats serum IL-1β levels were very significantly decreased (P<0.01); Comparing with CBZ group, the Ningxian particles low dose combination CBZ rats serum IL-6levels were significantly lower (P<0.05); The Ningxian particles medium and high dose combination CBZ rats serum IL-6levels very significantly decreased (P<0.01); Comparing with CBZ group, the Ningxian particles low, medium and high-dose combination CBZ rats serum TNF-a levels were very significantly decreased (P<0.01).
Part5:Comparing with model group, the remaining groups of rat brain tissue MDR1mRNA was very significantly decreased (P<0.01). Comparison with CBZ group, the Ningxian particles medium and high dose combination CBZ group of rats brain tissue MDR1mRNA content was significantly decreased (P<0.01); Comparing with model group, the Ningxian particles high dose combination CBZ group rats brain P-gp protein expression was very significantly decreased (P<0.01); the Ningxian particles low and medium dose combination CBZ rats brain P-gp protein expression was significantly decreased (P<0.05).
Conclusion
1. The study successfully establishes refractory epilepsy rat model by microinjecting kainic acid in rats'hippocampal CA3with epilepticus status and by drug screening. The model was easily, economically, relatively simply set up in order to lay a good foundation for the further research.
2. The Ningxian particle low, medium and high-dose combined CBZ group can significantly reduce the epileptic rats in each group of seizure average duration, the defense responses score, the spontaneous recurrent seizures total time and the degree of seizures.The Ningxian Particles combined CBZ use better than single effect.The EEG show the Ningxian particles medium and high dose combined CBZ group of rats epileptic discharge was significantly inhibited, only a small amount of spikes or sharp waves, while the Ningxian particles high dose combined CBZ group appeared at least.
3. The Ningxian particles low, medium and high-dose combination CBZ group can significantly reduce c-fos and caspase-3gene expression, inhibit apoptosis, to protect nerve cells; Speculated the Ningxian particles may act on multiple targets in the apoptotic pathway synergistic role with CBZ, but apoptotic gene expression did not downward trend in the increase of herb dose.
4.IL-1P, IL-6, TNF-a inflamatory cytokines participate in the immune response, the changes in their levels indirectly reflect the degree of the brain tissue damage.The Ningxian particles medium and high doses combination CBZ group of inflammatory cytokines was significantly lower than the CBZ group (P<0.01). The Ningxian particles medium and high-dose combination CBZ have some immunosuppressive effects than with CBZ efficacy significantly, then explain the combination has a synergistic effect on epilepsy treatment, have a certain role in the treatment of epilepsy.
5. The Ningxian particles joint CBZ can certainly inhibit MDR1mRNA/P-gp drug transporter function, reduce MDR1mRNA/P-gp expression, and there was a dose-effect relationship.
本研究通过建立海人酸难治性癫痫大鼠模型,采用宁痫颗粒、卡马西平单独或联合治疗,观察海人酸难治性癫痫大鼠行为学和脑电图变化,从炎症因子、凋亡及耐药基因探讨宁痫颗粒抗癫痫作用机制,为中西医结合治疗难治性癫痫提供了新的治疗方法。
方法：
第一部分：采用海人酸海马CA3区微量注射的化学点燃方法制作模型,通过苯妥英钠及脑电图筛选成功制作慢性难治性癫痫模型36只,随机分为模型组、卡马西平组、宁痫颗粒组、宁痫颗粒低、中、高剂量联合卡马西平组,再加假手术组,共7组,每组6只。
第二部分：观察各组大鼠治疗前后体重、癫痫发作的次数、发作平均持续时间、被抓时平均防卫级别、发作级别、SRS发作总时间,并对各组大鼠治疗前后进行脑电图监测。
第三部分：难治性癫痫大鼠模型每组6只,分组治疗后与假手术组6只,予心尖灌注生理盐水后取脑,在4%多聚甲醛中固定,常规制备石蜡切片(含皮层和海马)。HE染色观察海马各区及颞叶皮层神经元形态结构的改变,免疫组化观察海马及颢叶皮层c-fos、caspase-3的表达。
第四部分：按上述治疗分组后股动脉采血,收集各实验组大鼠血清采用免疫酶联法(Elisa法)测定各实验组大鼠血清IL-1β、IL-6、TNF-α水平。
第五部分：按上述治疗分组后大鼠在10%水合氯醛麻醉下取脑,实时荧光定量PCR法检测各组大鼠脑内海马MDR1mRNA表达,western-blot法检测其相应P-gp表达。
结果：
第一部分：采用海马局部注射海人酸及药物筛选后成功制作成难治性癫痫大鼠模型。
第二部分：治疗后大鼠体重比较：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组体重明显增加,有显著性差异(P<0.05)：大鼠治疗前后发作平均持续时间比较：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平发作平均持续时间明显减少,有极显著性差异(P<0.01)：大鼠治疗前后被抓时的平均防卫反应评分：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组被抓时平均防卫反应评分明显减少,有极显著性差异(P<0.01)；大鼠治疗前后平均发作级别的变化：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组平均发作级别减少,有极显著性差异(P<0.01); SRS发作总时间变化：与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组SRS发作总时间明显减少,有极显著性差异(P<0.01)。脑电图显示宁痫颗粒中、高剂量联合卡马西平组大鼠痫性放电受到抑制。
第三部分：c-fos表达：假手术组大鼠海马区组织切片中可见少量c-fos阳性细胞表达,模型组海马区c-fos阳性细胞的表达明显增多。与卡马西平组比较,宁痫颗粒低、中、高剂量组联合卡马西表达明显减少,有极显著性差异(氏0.01)；caspase-3表达：与卡马西平组比较,宁痫颗粒低、中、高剂量联合卡马西组表达减少,有显著性差异(P<0.05)。
第四部分：IL-1p表达：与卡马西平组比较,宁痫颗粒低剂量联合卡马西平组大鼠血清IL-1p含量显著降低(P<0.05),宁痫颗粒中、高剂量组联合卡马西平大鼠血清IL-6含量极显著降低(P<0.01)；IL-6表达：与卡马西平组比较,宁痫颗粒低剂量联合卡马西平组大鼠血清IL-6含量显著降低(尸<0.05)；宁痫颗粒中、高剂量联合卡马西平组大鼠血清IL-6含量极显著降低护<0.01)；TNF-α表达：与卡马西平组比较,宁痫颗粒低、中、高剂量联合卡马西平组大鼠血清TNF-α含量极显著降低(P<0.01)。
第五部分：MDR1mRNA表达：与模型组比较,其余各组大鼠脑组织MDRI含量极显著降低(P<0.01)；与卡马西平组比较,宁痫颗粒中、高剂量联合卡马西平组大鼠脑组织MDRI含量极显著降低(P<0.01); P-gp表达：与模型组比较,宁痫颗粒高剂量联合卡马西平组大鼠脑组织P-gp蛋白表达极显著降低(P<0.01),宁痫颗粒低、中剂量联合卡马西平组表达显著降低∽<0.05)。
结论：
1.本研究成功建立了大鼠海马局部注射微量海人酸后经癫痫持续状态及药物筛选成为难治性癫痫模型,操作相对简单,成功率高,节约成本,为后续研究打下较好的基础。
2.宁痫颗粒低、中、高剂量联合卡马西平组能明显减少各组致痫大鼠的痫性发作平均持续时间、被抓时的防卫反应评分、SRS发作总时间,并降低痫性发作程度,比单用中药或西药有明显改善。脑电图显示宁痫颗粒中、高剂量组联合卡马西平组大鼠痫性放电明显受到抑制,只见少量棘波或尖波,而以宁痫颗粒高剂量联合卡马西平组出现最少。
3.宁痫颗粒低、中、高剂量联合卡马西平组可以明显降低c-fos、caspase-3基因的表达,抑制细胞凋亡,达到保护神经细胞的作用；推测宁痫颗粒可能作用于细胞凋亡途径的多个靶点,与卡马西平有协同增效的作用,但凋亡基因的表达并未随中药剂量的增加而下调。
4.IL-1β、IL-6、TNF-α共同参与了免疫反应,其水平的变化间接反映了脑组织损伤程度。宁痫颗粒中、高剂量联合卡马西平组炎症因子的表达明显低于卡马西平组(P<0.01),表明宁痫颗粒联合卡马西平具有一定的免疫抑制作用,比单用卡马西平疗效显著,进而说明两者联合具有协同作用,对癫痫有一定的治疗作用。
5.宁痫颗粒联合卡马西平具有一定的抑制MDR1mRNA/P-gp的药物转运体功能,可以下调MDR1mRNA/P-gp表达,且存在一定的量效关系。
Objective
This paper attempts to study the possible antiepileptic mechanism of Ningxian Particles by the inflammation factors, apoptosis and drug-resistance gene, based on the kainic acid refractory epilepsy rats model by the Ningxian particles, CBZ alone or integrated therapy, observing the kainic acid refractory epilepsy rats behavior and EEG epileptic wave in order to provide a new therapeutic method for combing traditional Chinese and western medicine treatment of refractory epilepsy.
Method
Part1:36chronic refractory epilepsy models were made by microinjection of kainic acid hippocampal CA3chemic igniting and PHT and EEG screening, and they were divided randomly into7groups, such as model, CBZ, Ningxian particles, Ningxian particles low, medium and high dose combination CBZ and sham-operated group, and these are6rats each group.
Part2:The rats before and after being treated were observed by the weight, the number of seizures, the average duration of seizures, the defense levels, the seizures levels, the spontaneous recurrent seizures total times, and EEG monitoring.
Part3:Refractory epilepsy rat model (n=6), each group after treatment with the sham group (n=6), the apical perfusion normal saline before removal of brain, fixed in4%paraformaldehyde, conventional preparation of paraffin sections (containing the cerebral cortex and hippocampus). HE staining was used to observe the changes in the hippocampus and temporal cortex neurons morphology, immunohistochemical observation hippocampus and temporal cortex of c-fos and caspase-3expression.
Part4:The experimental group rats serum IL-1β, IL-6, TNF-α content were detected by using the enzyme-linked immunosorbent assay method (Elisa method) after femoral artery blood collected in each experimental group therapy.
Part5:The rats were under anaesthesia by10%chloral hydrate to be removed their brains. The MDR1mRNA expression of rats was detected by Real-time quantitative polymerase chain reaction. The P-gp expression was detected by western-blot.
Result
Part1:Refractory epilepsy rat model was successfully made by hippocampal local injection of kainic acid and drug screening.
Part2:The weight of the rats by combining medium and high-dose Ningxian particles with CBZ group drastically increased, comparing with CBZ group. There was a significant difference (P<0.05). The seizures mean duration of the rats before and after being treated by combining medium and high-dose Ningxian particles with CBZ group were drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01). The mean defense response of the rats before and after being treated by combining medium and high-dose Ningxian particles with CBZ group were drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01). The average seizure changes in the level of rats before and after being treated by combining medium and high-dose Ningxian particles with CBZ group drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01).The spontaneous recurrent seizures total time of the rats being treated by combining medium and high-dose Ningxian particles with CBZ drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01). The EEG showed the Ningxian particles medium and high-dose combination CBZ group epileptic discharge was inhibited.
Part3:Minimum c-fos positive cells expression was seen in sham-operated rats' hippocampus tissue sections. The c-fos positive cells expression in the hippocampus increased significantly in model group. The expression of combining low, medium and high-dose Ningxian particles with CBZ group drastically decreased, comparing with CBZ group. There were very significant differences (P<0.01). The caspase-3 expression of combining low, medium and high-dose Ningxian particles with CBZ group drastically decreased, comparing with CBZ group. There was a significant difference (P<0.05).
Part4:Comparing with CBZ group,the Ningxian particles low dose combination CBZ rats serum IL-1β levels were significantly lower (P<0.05).The Ningxian particles medium and high-dose combination CBZ rats serum IL-1β levels were very significantly decreased (P<0.01); Comparing with CBZ group, the Ningxian particles low dose combination CBZ rats serum IL-6levels were significantly lower (P<0.05); The Ningxian particles medium and high dose combination CBZ rats serum IL-6levels very significantly decreased (P<0.01); Comparing with CBZ group, the Ningxian particles low, medium and high-dose combination CBZ rats serum TNF-a levels were very significantly decreased (P<0.01).
Part5:Comparing with model group, the remaining groups of rat brain tissue MDR1mRNA was very significantly decreased (P<0.01). Comparison with CBZ group, the Ningxian particles medium and high dose combination CBZ group of rats brain tissue MDR1mRNA content was significantly decreased (P<0.01); Comparing with model group, the Ningxian particles high dose combination CBZ group rats brain P-gp protein expression was very significantly decreased (P<0.01); the Ningxian particles low and medium dose combination CBZ rats brain P-gp protein expression was significantly decreased (P<0.05).
Conclusion
1. The study successfully establishes refractory epilepsy rat model by microinjecting kainic acid in rats'hippocampal CA3with epilepticus status and by drug screening. The model was easily, economically, relatively simply set up in order to lay a good foundation for the further research.
2. The Ningxian particle low, medium and high-dose combined CBZ group can significantly reduce the epileptic rats in each group of seizure average duration, the defense responses score, the spontaneous recurrent seizures total time and the degree of seizures.The Ningxian Particles combined CBZ use better than single effect.The EEG show the Ningxian particles medium and high dose combined CBZ group of rats epileptic discharge was significantly inhibited, only a small amount of spikes or sharp waves, while the Ningxian particles high dose combined CBZ group appeared at least.
3. The Ningxian particles low, medium and high-dose combination CBZ group can significantly reduce c-fos and caspase-3gene expression, inhibit apoptosis, to protect nerve cells; Speculated the Ningxian particles may act on multiple targets in the apoptotic pathway synergistic role with CBZ, but apoptotic gene expression did not downward trend in the increase of herb dose.
4.IL-1P, IL-6, TNF-a inflamatory cytokines participate in the immune response, the changes in their levels indirectly reflect the degree of the brain tissue damage.The Ningxian particles medium and high doses combination CBZ group of inflammatory cytokines was significantly lower than the CBZ group (P<0.01). The Ningxian particles medium and high-dose combination CBZ have some immunosuppressive effects than with CBZ efficacy significantly, then explain the combination has a synergistic effect on epilepsy treatment, have a certain role in the treatment of epilepsy.
5. The Ningxian particles joint CBZ can certainly inhibit MDR1mRNA/P-gp drug transporter function, reduce MDR1mRNA/P-gp expression, and there was a dose-effect relationship.
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