小鼠癫痫模型建立的实验研究
摘要
癫痫是神经科的常见疾病。统计资料显示,我国癫痫患病率为7.0‰,据此估算我国现有癫痫患者约900万人。癫痫不仅给患者造成身体上的危害,还严重影响患者生活质量,导致一系列精神心理问题,给家庭和社会带来沉重负担。癫痫发作、认知功能、精神行为状态、社会功能、自信心及羞耻感等因素都可能影响患者的生活质量。学者们逐渐认识到,控制发作仅是癫痫患者综合管理的一部分,社会、生理、心理等因素可能对癫痫患者生活质量造成不同程度的影响。癫痫治疗的目标已从单纯控制和减少发作,转变为最大程度地提高患者的生活质量。
颞叶癫痫是成人中最常见的癫痫综合征,占部分性癫痫的1/3以上,难治性癫痫的半数以上。研究证实颞叶癫痫是受遗传因素和环境因素共同作用的复杂多因性疾病,易感基因在决定颞叶癫痫病因和临床表现型上发挥作用。颞叶癫痫分为内侧型和外侧型两种临床亚型。颞叶内侧癫痫是最常见的药物难治性癫痫之一,早期外科手术治疗对控制发作、提高认知功能和改善预后均有重要意义。
海人酸(kanic acid, KA)是脑内兴奋性氨基酸递质—谷氨酸的结构类似物。KA模型具有模拟人类颞叶癫痫的理想条件:1.海马杏仁核在癫痫表现中起核心作用;2.有人类颞叶癫痫相似的病理改变,如神经元缺失、胶质增生和苔藓纤维发芽;3.有如人类症状性颞叶癫痫的临床表现:初始的脑部损害后,经过一段无症状的静止期,最终出现反复自发性癫痫发作;4.抗癫痫药物对KA引起的癫痫作用差。因此海人酸癫痫模型能很好地模拟人类颞叶癫痫,是研究癫痫发展变化、致病机理的有效工具。海人酸模型已广泛用于癫痫发作的研究,许多学者将海人酸腹腔注射或立体定向海马内注射应用,成功地诱导出类似于人类皮质癫痫的动物模型,为癫痫的发病机制和治疗方法的研究提供了重要的手段。本实验旨在建立海人酸颞叶癫痫动物模型,观察其发展过程中症状、脑电图、病理改变及药物治疗的作用,探讨该模型的病理机制和致痫机理。
第一部分构建海人酸急性致痫小鼠模型的研究
目的建立海人酸诱导的小鼠急性癫痫模型,并探讨其特点。方法实验取健康雄性昆明小鼠99只,随机分为生理盐水组(n=33)和致痫组(n=66),致痫组腹腔注射海人酸10mg/kg,生理盐水组腹腔注射生理盐水35μl/g。注射后连续5h观察小鼠是否有痫性发作并分级。当小鼠持续痫性发作达1h时给予地西泮4mg/kg腹腔注射,对照组3只和致痫组9只同时描记脑电图,并取脑切片后苏木精-伊红染色法观察海马各区病理学改变。结果①行为学表现,模型组小鼠注射海人酸后可出现湿狗样抖动、头面部肌肉阵挛、肢体阵挛及全面强直阵挛发作。生理盐水对照组未见癫痫发作。②脑电图表现,癫痫持续状态小鼠表现为持续性节律性棘波、棘慢波或高波幅慢波。③病理学研究,双侧海马均可出现神经元变性,以CA1和门区为主。结论腹腔注射海人酸致痫小鼠急性模型同相应的大鼠模型一样,具有制作简便、痫性发作潜伏期短、致痫率高等特点,其所产生的急性癫痫模型具有与人类颞叶癫痫相似的行为、脑电图与神经病理改变。
第二部分青霉素与海人酸癫痫模型的比较的研究
目的通过用青霉素、海人酸2种药物制作癫痫模型,探讨2种致痫剂的作用特点及应用条件。方法实验取健康雄性昆明小鼠90只,随机分为3组,对照组(n=10)、青霉素致痫组(n=40)和海人酸致痫组(n=40),青霉素致痫组腹腔注射青霉素7×106 U/kg,海人酸致痫组腹腔注射海人酸10 mg/kg,生理盐水组腹腔注射生理盐水35μL/g。注射后连续5 h观察小鼠是否有痫性发作并分级,进行脑电图描记。结果空白对照组无痫性发作,两组模型均出现痫性发作,海人酸致痫组与青霉素致痫组按Racine分级0~Ⅴ级各级之间无明显差异(P>0.05),小鼠出现Ⅲ~V级癫痫行为潜伏期两组致痫组比较有显著差异(t0.05,78=1.990 P<0.05)。而死亡率低(χ2=36.473 P<0.05)。结论腹腔注射海人酸所致的动物模型具有与人类颞叶癫痫极为相似的癫痫发作行为学、病理学、脑电图等特征,是理想的人类颞叶癫痫的动物模型。
Epilepsy is a common neurological disorder.Statistics showed that the morbidity rate of epilepsy in China was about 7.0‰.So there are about 9 million patients affected by epilepsy in China.Epilepsy carries a substantial burden of illness,which is reflected in poor quality of life(QOL),psychosocial function and higher care resource use.The influence of epilepsy on patients’lives may be quite destructive and impaired QOL.Seizure,cognitive, emotional and behavioral status,social function, self-esteem, stigma seem to be crucial to QOL. It has been gradually recognized that seizure control is only one aspect of comprehensive management on epilepsy. It is widely pointed out that the purpose of treating epilepsy is not necessarily seizure eradiation rather the aim should be at obtaining maximal improvement of patients’quality of life.
Temporal lobe epilepsy is the most common epilepsy syndrome in adults, accouting for more than 30%of partial epilepsy.About half of temporal lobe epilepsy is medically intractable.Temporal lobe epilepsy is a heterogeneous disorder with complex genetics in which putative susceptibility genes and environmental factors are believed to contribute to the etiologic and phenotype of the diseases. According to the focus of seizure origin,temporal lobe epilepsy is subclassificated as mesial temporal lobe epilepsy and lateral lobe epilepsy. Mesial temporal lobe epilepsy is regarded as the most common medically intractable epilepsy and early surgery may not only reduce seizure,but also improve cognitive and prognosis outcome.
The kanic acid(KA)is a structural analogue of the aminoglutaminic acid,excitatory amino acid in the brain.KA model fulfils the perfect criteria of animal model of temporal epolepsy: 1.The hippocampus, amygdala and other limbic structures play a central role in its symptomatology; 2.The pattern of pathologic change is clearly reminiscent of Ammon’s horn sclerosis in temporal epoleptic patients, including the neuronal cell loss, glia hyperplasia and mossy fiber sprouting. 3.There are spontaneous recurrent serzures in chronic phase. 4.Available anticonvulsants are weakly against the seizures generated by KA. So KA model can stimulate temporal epilepsy in human vividly. It is a good tool that can be used to research development and mechanism of epilepsy. KA model is used generally for the study in the epilepsy. Many scholars induced successfully epileptic animanl model by intraperitoneal injection of KA to investigate its pathogeniesin and therapeutics.In this investigation, the objective is to establish the kainate-induced temporal lobe epilepsy(TLE) model, study the morphology and electrophysiology’s changement of hippocampal formation in the model mice, discuss the mechanism of pathologic changes and epileptogenesis in this model.
Part One Establishing the mouse models of acute epilepsy induced by kainic acid
Objective To establish the mouse models with acute epilepsy induced by kainic acid, and explore the characteristics. Methods 99 healthy male Kunming mice were selected and divided randomly into the saline group (n=33) and seizure-induced group (n=66). The seizure-induced group were treated with 10mg/kg kainic acid by intraperitoneal injection, and those in the saline group were treated with 35μl/g saline by intraperitoneal injection. After injection, the following 5 hours if there was seizure or not was observed continuously and was graded. When the seizure lasted for 1 hour, the mice were offered 4mg/kg diazepam by intraperitoneal injection. 3 in the control group and 9 in the seizure-induced group were monitored by electro encephalogram(EEG). The mice brains were sectioned and the pathologic change in the hippocampal area was checked by hemotoxylin-eosin (HE) staining. Results Totally 99 mice entered the final analysis.①On the praxiology, mice in model group showed wet dog shakes, the clonus of face, head and limbs, and generalized tonic-clonic convusions after injection of kainic acid.Epileptic seizure was not observed on mice in saline control group.②On the EEG, the mice of the status epilepticus could see the explosive slow wave of high amplitude of wave, spike wave or spike slow wave.③On the pathology, intraperitoneal injection could lead to neuronal degeneration in the bilateral hippocampus, mainly in the CA1 and hilar area. Conclusion The kainic acid induced mouse models with acute epilepsy is the same to the corresponding mice models with the characters of easy to make, short latency of seizure and high incidence mice etc. The developed acute epilepsy models have mimic features of human temparal lobe epilepsy, and the brain electric wave and neural pathology have changed.
Part Two The comparison of epilepsy model reproduced by penicillin and kainic acid
Ovjective To establish the mouse models with acute epilepsy induced by kainic acid and penicillin, and explore the characteristics and condition of application. Methods 90 healthy male Kunming mice were selected and divided randomly into the saline group (n=10) and penicillin-induced group (n=40) and kainic acid-induced group (n=40). The kainic acid-induced group were treated with 10 mg/kg kainic acid by intraperitoneal injection, the penicillin-induced group were treated with 7×106 U/kg penicillin by intraperitoneal injection, and those in the saline group were treated with 35μL/g saline by intraperitoneal injection. After injection, the following 5 hours if there was seizure or not was observed continuously and was graded and was monitored by electro encephalogram(EEG). Results Totally 80 mice entered the final analysis. It was noted that the latency of the appearance of the status epilepticus by kainic acid was shorter than that by penicillin (P<0.05). The mortality rate was lower as well (P<0.05). Conclusion Acute epilepsy model reproduced by kainic acid might be superior to penicillin.
颞叶癫痫是成人中最常见的癫痫综合征,占部分性癫痫的1/3以上,难治性癫痫的半数以上。研究证实颞叶癫痫是受遗传因素和环境因素共同作用的复杂多因性疾病,易感基因在决定颞叶癫痫病因和临床表现型上发挥作用。颞叶癫痫分为内侧型和外侧型两种临床亚型。颞叶内侧癫痫是最常见的药物难治性癫痫之一,早期外科手术治疗对控制发作、提高认知功能和改善预后均有重要意义。
海人酸(kanic acid, KA)是脑内兴奋性氨基酸递质—谷氨酸的结构类似物。KA模型具有模拟人类颞叶癫痫的理想条件:1.海马杏仁核在癫痫表现中起核心作用;2.有人类颞叶癫痫相似的病理改变,如神经元缺失、胶质增生和苔藓纤维发芽;3.有如人类症状性颞叶癫痫的临床表现:初始的脑部损害后,经过一段无症状的静止期,最终出现反复自发性癫痫发作;4.抗癫痫药物对KA引起的癫痫作用差。因此海人酸癫痫模型能很好地模拟人类颞叶癫痫,是研究癫痫发展变化、致病机理的有效工具。海人酸模型已广泛用于癫痫发作的研究,许多学者将海人酸腹腔注射或立体定向海马内注射应用,成功地诱导出类似于人类皮质癫痫的动物模型,为癫痫的发病机制和治疗方法的研究提供了重要的手段。本实验旨在建立海人酸颞叶癫痫动物模型,观察其发展过程中症状、脑电图、病理改变及药物治疗的作用,探讨该模型的病理机制和致痫机理。
第一部分构建海人酸急性致痫小鼠模型的研究
目的建立海人酸诱导的小鼠急性癫痫模型,并探讨其特点。方法实验取健康雄性昆明小鼠99只,随机分为生理盐水组(n=33)和致痫组(n=66),致痫组腹腔注射海人酸10mg/kg,生理盐水组腹腔注射生理盐水35μl/g。注射后连续5h观察小鼠是否有痫性发作并分级。当小鼠持续痫性发作达1h时给予地西泮4mg/kg腹腔注射,对照组3只和致痫组9只同时描记脑电图,并取脑切片后苏木精-伊红染色法观察海马各区病理学改变。结果①行为学表现,模型组小鼠注射海人酸后可出现湿狗样抖动、头面部肌肉阵挛、肢体阵挛及全面强直阵挛发作。生理盐水对照组未见癫痫发作。②脑电图表现,癫痫持续状态小鼠表现为持续性节律性棘波、棘慢波或高波幅慢波。③病理学研究,双侧海马均可出现神经元变性,以CA1和门区为主。结论腹腔注射海人酸致痫小鼠急性模型同相应的大鼠模型一样,具有制作简便、痫性发作潜伏期短、致痫率高等特点,其所产生的急性癫痫模型具有与人类颞叶癫痫相似的行为、脑电图与神经病理改变。
第二部分青霉素与海人酸癫痫模型的比较的研究
目的通过用青霉素、海人酸2种药物制作癫痫模型,探讨2种致痫剂的作用特点及应用条件。方法实验取健康雄性昆明小鼠90只,随机分为3组,对照组(n=10)、青霉素致痫组(n=40)和海人酸致痫组(n=40),青霉素致痫组腹腔注射青霉素7×106 U/kg,海人酸致痫组腹腔注射海人酸10 mg/kg,生理盐水组腹腔注射生理盐水35μL/g。注射后连续5 h观察小鼠是否有痫性发作并分级,进行脑电图描记。结果空白对照组无痫性发作,两组模型均出现痫性发作,海人酸致痫组与青霉素致痫组按Racine分级0~Ⅴ级各级之间无明显差异(P>0.05),小鼠出现Ⅲ~V级癫痫行为潜伏期两组致痫组比较有显著差异(t0.05,78=1.990 P<0.05)。而死亡率低(χ2=36.473 P<0.05)。结论腹腔注射海人酸所致的动物模型具有与人类颞叶癫痫极为相似的癫痫发作行为学、病理学、脑电图等特征,是理想的人类颞叶癫痫的动物模型。
Epilepsy is a common neurological disorder.Statistics showed that the morbidity rate of epilepsy in China was about 7.0‰.So there are about 9 million patients affected by epilepsy in China.Epilepsy carries a substantial burden of illness,which is reflected in poor quality of life(QOL),psychosocial function and higher care resource use.The influence of epilepsy on patients’lives may be quite destructive and impaired QOL.Seizure,cognitive, emotional and behavioral status,social function, self-esteem, stigma seem to be crucial to QOL. It has been gradually recognized that seizure control is only one aspect of comprehensive management on epilepsy. It is widely pointed out that the purpose of treating epilepsy is not necessarily seizure eradiation rather the aim should be at obtaining maximal improvement of patients’quality of life.
Temporal lobe epilepsy is the most common epilepsy syndrome in adults, accouting for more than 30%of partial epilepsy.About half of temporal lobe epilepsy is medically intractable.Temporal lobe epilepsy is a heterogeneous disorder with complex genetics in which putative susceptibility genes and environmental factors are believed to contribute to the etiologic and phenotype of the diseases. According to the focus of seizure origin,temporal lobe epilepsy is subclassificated as mesial temporal lobe epilepsy and lateral lobe epilepsy. Mesial temporal lobe epilepsy is regarded as the most common medically intractable epilepsy and early surgery may not only reduce seizure,but also improve cognitive and prognosis outcome.
The kanic acid(KA)is a structural analogue of the aminoglutaminic acid,excitatory amino acid in the brain.KA model fulfils the perfect criteria of animal model of temporal epolepsy: 1.The hippocampus, amygdala and other limbic structures play a central role in its symptomatology; 2.The pattern of pathologic change is clearly reminiscent of Ammon’s horn sclerosis in temporal epoleptic patients, including the neuronal cell loss, glia hyperplasia and mossy fiber sprouting. 3.There are spontaneous recurrent serzures in chronic phase. 4.Available anticonvulsants are weakly against the seizures generated by KA. So KA model can stimulate temporal epilepsy in human vividly. It is a good tool that can be used to research development and mechanism of epilepsy. KA model is used generally for the study in the epilepsy. Many scholars induced successfully epileptic animanl model by intraperitoneal injection of KA to investigate its pathogeniesin and therapeutics.In this investigation, the objective is to establish the kainate-induced temporal lobe epilepsy(TLE) model, study the morphology and electrophysiology’s changement of hippocampal formation in the model mice, discuss the mechanism of pathologic changes and epileptogenesis in this model.
Part One Establishing the mouse models of acute epilepsy induced by kainic acid
Objective To establish the mouse models with acute epilepsy induced by kainic acid, and explore the characteristics. Methods 99 healthy male Kunming mice were selected and divided randomly into the saline group (n=33) and seizure-induced group (n=66). The seizure-induced group were treated with 10mg/kg kainic acid by intraperitoneal injection, and those in the saline group were treated with 35μl/g saline by intraperitoneal injection. After injection, the following 5 hours if there was seizure or not was observed continuously and was graded. When the seizure lasted for 1 hour, the mice were offered 4mg/kg diazepam by intraperitoneal injection. 3 in the control group and 9 in the seizure-induced group were monitored by electro encephalogram(EEG). The mice brains were sectioned and the pathologic change in the hippocampal area was checked by hemotoxylin-eosin (HE) staining. Results Totally 99 mice entered the final analysis.①On the praxiology, mice in model group showed wet dog shakes, the clonus of face, head and limbs, and generalized tonic-clonic convusions after injection of kainic acid.Epileptic seizure was not observed on mice in saline control group.②On the EEG, the mice of the status epilepticus could see the explosive slow wave of high amplitude of wave, spike wave or spike slow wave.③On the pathology, intraperitoneal injection could lead to neuronal degeneration in the bilateral hippocampus, mainly in the CA1 and hilar area. Conclusion The kainic acid induced mouse models with acute epilepsy is the same to the corresponding mice models with the characters of easy to make, short latency of seizure and high incidence mice etc. The developed acute epilepsy models have mimic features of human temparal lobe epilepsy, and the brain electric wave and neural pathology have changed.
Part Two The comparison of epilepsy model reproduced by penicillin and kainic acid
Ovjective To establish the mouse models with acute epilepsy induced by kainic acid and penicillin, and explore the characteristics and condition of application. Methods 90 healthy male Kunming mice were selected and divided randomly into the saline group (n=10) and penicillin-induced group (n=40) and kainic acid-induced group (n=40). The kainic acid-induced group were treated with 10 mg/kg kainic acid by intraperitoneal injection, the penicillin-induced group were treated with 7×106 U/kg penicillin by intraperitoneal injection, and those in the saline group were treated with 35μL/g saline by intraperitoneal injection. After injection, the following 5 hours if there was seizure or not was observed continuously and was graded and was monitored by electro encephalogram(EEG). Results Totally 80 mice entered the final analysis. It was noted that the latency of the appearance of the status epilepticus by kainic acid was shorter than that by penicillin (P<0.05). The mortality rate was lower as well (P<0.05). Conclusion Acute epilepsy model reproduced by kainic acid might be superior to penicillin.
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