IL1β通过上调CB1R促进幼鼠热惊厥后成年癫痫易感性
发布时间：2018-08-13 21:05
【摘要】：癫痫是发作性的大脑神经功能障碍,是常见的神经系统慢性病；约30%的癫痫患者对多种抗癫痫药物耐受,最终发展为难治性癫痫。目前癫痫的发病机制尚不清楚,外科手术及药物治疗都有其局限性。因此,急需进一步探讨癫痫的发病机制并寻找有效的防治策略。癫痫发病机制极为复杂,儿童和青少年是癫痫发病率最高的群体,癫痫新发病例中未成年人占一半以上。未成人还处于智能发育阶段,癫痫发作对他们的危害程度较成年人更为严重。发育早期是大脑神经环路形成和突触可塑性发育的关键时期,因此,发育早期的关键事件可能严重影响癫痫的形成。小儿热惊厥(Febrile seizures, FS)高发于6个月至5岁的婴幼儿,是婴幼儿时期常见的惊厥发作类型。尽管大部分热惊厥被认为是良性／简单热惊厥发作(发作时间15min),但是约有25-30%的热惊厥发作为复杂性的(发作时间15 min或24 h内多次反复发作,Prolonged/complex FS, FSs),FSs会在很大程度上增加海马损伤、认知障碍及成年癫痫发作的风险。尽管流行病学研究发现仅有3-5%的FS患者会发展为癫痫,临床回顾性研究却表明相当一部分颞叶癫痫病人具有FS病史(约30-50%)；并且具有FS病史的颞叶癫痫患者会伴随更加严重的中央颞叶硬化。以上研究结果提示了FS可能与癫痫发生密切相关。此外,动物实验研究表明,FS大鼠在亚剂量(5mg/kg)海人藻酸(Kainic acid, KA)的作用下有癫痫发作；且约有35%的FS动物成年后出现自发性癫痫发作,提示FS可能增加了成年罹患癫痫的风险,那么FS如何引起成年后癫痫发生?另一方面,目前治疗FS主要采用传统的抗癫痫药物,如苯巴比妥,苯妥英等,这些抗癫痫药物只能控制惊厥发作,而对于FS引起的成年癫痫发生则没有效果；此外,传统抗癫痫药物对儿童智力发育有较大影响。因此,有必要寻找有效的控制FS后癫痫发生的药物治疗手段。炎症因子作为一种神经调质在癫痫异常神经环路的形成和不断巩固中的作用日益受到关注。白介素1β (Interleukin-1β, IL-1β)作为重要的炎症因子在癫痫发生早期激活并参与调节神经元兴奋性和突触可塑性。最近临床研究发现,具有IL1β-511C/T基因多态性的儿童更加容易发生FS；同时有研究报道FS后IL-1β的表达水平增加,提示IL-1β可能参与FS后的癫痫发生,但其作用机制尚不清楚。因此,本课题采用不同发作程度的FS模型,探讨其对成年癫痫发生的影响,并进一步研究IL-1β对FS后癫痫发生的作用及其作用机制。将出生8-10天(P8-10)的SD大鼠放入环境温度为44±2℃的烘箱中诱导简单热惊厥发作(惊厥发作后立即从烘箱取出)和复杂热惊厥发作(FSs,发作时间大于30 min),并记录发作期特征性脑电(EEG)。采用最大电休克(Maximal electroshock, MES)和KA诱导的癫痫发作模型检测成年癫痫易感性。实验结果发现幼年动物经历FSs后其海马内IL-1β的表达水平一过性增加(惊厥发作后12h内增加,其后恢复至正常水平),并且FSs动物成年后癫痫易感性增加；而经历简单热惊厥的动物海马内IL-1β的表达水平无变化,其成年后癫痫易感性也没有改变。动物经历FSs后12h内给予IL1受体拮抗剂(IL1Ra)可剂量依赖性的逆转其成年癫痫易感性的改变,12h后给予IL1Ra却没有效果,提示IL1Ra具有“治疗时间窗”。同时,如果幼年动物(P8)单独给予IL-1β,其成年后癫痫易感性增加。IL1R1敲除(IL1R1-/-)小鼠无论经历FSs或者给予IL-1p处理,其成年后癫痫易感性均无变化。此外,幼年动物经FSs或IL-1p处理后,其海马中内源性大麻素I型受体(CB1R)的表达水平在处理后第3天开始增加,并持续到成年。上调的CB1R的表达水平及其功能能够被IL1Ra所逆转。CB1R拮抗剂、小RNA干扰CBlR或者抑制内源性大麻素合成均可逆转FSs后增加的癫痫易感性。进一步,我们发现具有FS病史的颞叶癫痫患者病灶区CB1R表达水平显著高于无FS病史的颞叶癫痫患者。总之,本课题发现复杂性而非简单的小儿热惊厥能够引起成年癫痫易感性增加；FSs后一过性增加的IL-1β作用于IL1R1,通过上调内源性大麻素系统参与FSs后的癫痫发生机制。此外,IL1Ra对FSs后癫痫发生具有“治疗时间窗”作用,提示及时有效的控制幼儿FS后的炎症是预防其成年后癫痫发生的关键,并可能是一种预防成年癫痫发生的新的治疗策略。
[Abstract]:Epilepsy is a kind of paroxysmal cerebral neurological dysfunction and a common chronic neurological disease. About 30% of epileptic patients tolerate a variety of antiepileptic drugs and eventually develop into intractable epilepsy. The pathogenesis of epilepsy is extremely complex. Children and adolescents are the group with the highest incidence of epilepsy. More than half of the new cases of epilepsy occur among minors. Febrile seizures (FS) are common seizures in infants aged 6 months to 5 years, although most febrile seizures are considered benign / simple febrile seizures. (Fifteen minutes), but about 25-30% of febrile seizures are complex (repeated attacks within 15 minutes or 24 hours, Prolonged / complex FS, FSs), FSs significantly increase the risk of hippocampal damage, cognitive impairment, and adult seizures. Although epidemiological studies have found that only 3-5% of FS patients develop epilepsy. Epilepsy, clinical retrospective studies have shown that a considerable number of patients with temporal lobe epilepsy have a history of FS (about 30-50%); and patients with temporal lobe epilepsy with a history of FS are associated with more severe central temporal lobe sclerosis. These findings suggest that FS may be closely related to epilepsy. In addition, animal studies have shown that FS rats at a sub-dose (5mg/g). Kg) kainic acid (KA) acts on epileptic seizures; and about 35% of FS animals develop spontaneous seizures in adulthood, suggesting that FS may increase the risk of adult epilepsy, then how does FS cause adult epilepsy? On the other hand, the current treatment of FS mainly uses traditional antiepileptic drugs, such as phenobarbital, benzene. These antiepileptic drugs can only control convulsive seizures, but have no effect on adult epilepsy induced by FS. In addition, traditional antiepileptic drugs have a greater impact on children's intellectual development. Therefore, it is necessary to find effective drug treatment to control epilepsy after FS. Inflammatory factors as a neuromodulator in epilepsy. Interleukin-1 beta (IL-1 beta), as an important inflammatory factor, activates early in epilepsy and regulates neuronal excitability and synaptic plasticity. At the same time, some studies reported that the expression of IL-1 beta increased after FS, suggesting that IL-1 beta may participate in the occurrence of epilepsy after FS, but its mechanism is still unclear. Simple febrile seizures (immediately removed from the oven after the seizure) and complex febrile seizures (FSs) were induced in SD rats born 8-10 days (P8-10) in ovens with ambient temperature of 44 6550 The results showed that the expression of IL-1 beta in the hippocampus of young animals increased temporarily after FSs (increased within 12 hours after seizures, then returned to normal level), and the susceptibility to epilepsy increased in adult FSs animals, while that of hippocampus of simple febrile seizures animals increased. There was no change in the level of IL-1 receptor antagonist (IL-1Ra) and the susceptibility to adult epilepsy was reversed in a dose-dependent manner within 12 hours after FSs. However, IL-1Ra had no effect after 12 hours, suggesting that IL-1Ra had a "therapeutic window". At the same time, if the young animals (P8) were given IL-1Ra alone, the susceptibility to adult epilepsy would be reversed in a dose-dependent manner. The susceptibility to epilepsy increased after adulthood in IL1R1 knockout (IL1R1-/-) mice. There was no change in susceptibility to epilepsy after adulthood in IL1R1 knockout (IL1R1-/-) mice treated with FSs or IL-1p. CB1R expression and function can be reversed by IL1Ra. CB1R antagonists, small RNAs interfering with CBlR or inhibiting endocannabinoid synthesis can reverse the increased susceptibility to epilepsy after FSs. Further, we found that CB1R expression in temporal lobe epilepsy patients with FS history was significantly higher than that in temporal lobe epilepsy patients without FS history. In summary, we found that complex rather than simple febrile convulsions in children can increase the susceptibility to adult epilepsy; transient increased IL-1beta after FSs acts on IL-1R1 and participates in the epileptic mechanism after FSs by up-regulating the endocannabinoid system. In addition, IL1Ra has a "therapeutic window" effect on post-FSs epilepsy, suggesting timely action. Effective control of inflammation after FS is the key to prevent adult epilepsy and may be a new therapeutic strategy to prevent adult epilepsy.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R742.1
本文编号：2182186
[Abstract]:Epilepsy is a kind of paroxysmal cerebral neurological dysfunction and a common chronic neurological disease. About 30% of epileptic patients tolerate a variety of antiepileptic drugs and eventually develop into intractable epilepsy. The pathogenesis of epilepsy is extremely complex. Children and adolescents are the group with the highest incidence of epilepsy. More than half of the new cases of epilepsy occur among minors. Febrile seizures (FS) are common seizures in infants aged 6 months to 5 years, although most febrile seizures are considered benign / simple febrile seizures. (Fifteen minutes), but about 25-30% of febrile seizures are complex (repeated attacks within 15 minutes or 24 hours, Prolonged / complex FS, FSs), FSs significantly increase the risk of hippocampal damage, cognitive impairment, and adult seizures. Although epidemiological studies have found that only 3-5% of FS patients develop epilepsy. Epilepsy, clinical retrospective studies have shown that a considerable number of patients with temporal lobe epilepsy have a history of FS (about 30-50%); and patients with temporal lobe epilepsy with a history of FS are associated with more severe central temporal lobe sclerosis. These findings suggest that FS may be closely related to epilepsy. In addition, animal studies have shown that FS rats at a sub-dose (5mg/g). Kg) kainic acid (KA) acts on epileptic seizures; and about 35% of FS animals develop spontaneous seizures in adulthood, suggesting that FS may increase the risk of adult epilepsy, then how does FS cause adult epilepsy? On the other hand, the current treatment of FS mainly uses traditional antiepileptic drugs, such as phenobarbital, benzene. These antiepileptic drugs can only control convulsive seizures, but have no effect on adult epilepsy induced by FS. In addition, traditional antiepileptic drugs have a greater impact on children's intellectual development. Therefore, it is necessary to find effective drug treatment to control epilepsy after FS. Inflammatory factors as a neuromodulator in epilepsy. Interleukin-1 beta (IL-1 beta), as an important inflammatory factor, activates early in epilepsy and regulates neuronal excitability and synaptic plasticity. At the same time, some studies reported that the expression of IL-1 beta increased after FS, suggesting that IL-1 beta may participate in the occurrence of epilepsy after FS, but its mechanism is still unclear. Simple febrile seizures (immediately removed from the oven after the seizure) and complex febrile seizures (FSs) were induced in SD rats born 8-10 days (P8-10) in ovens with ambient temperature of 44 6550 The results showed that the expression of IL-1 beta in the hippocampus of young animals increased temporarily after FSs (increased within 12 hours after seizures, then returned to normal level), and the susceptibility to epilepsy increased in adult FSs animals, while that of hippocampus of simple febrile seizures animals increased. There was no change in the level of IL-1 receptor antagonist (IL-1Ra) and the susceptibility to adult epilepsy was reversed in a dose-dependent manner within 12 hours after FSs. However, IL-1Ra had no effect after 12 hours, suggesting that IL-1Ra had a "therapeutic window". At the same time, if the young animals (P8) were given IL-1Ra alone, the susceptibility to adult epilepsy would be reversed in a dose-dependent manner. The susceptibility to epilepsy increased after adulthood in IL1R1 knockout (IL1R1-/-) mice. There was no change in susceptibility to epilepsy after adulthood in IL1R1 knockout (IL1R1-/-) mice treated with FSs or IL-1p. CB1R expression and function can be reversed by IL1Ra. CB1R antagonists, small RNAs interfering with CBlR or inhibiting endocannabinoid synthesis can reverse the increased susceptibility to epilepsy after FSs. Further, we found that CB1R expression in temporal lobe epilepsy patients with FS history was significantly higher than that in temporal lobe epilepsy patients without FS history. In summary, we found that complex rather than simple febrile convulsions in children can increase the susceptibility to adult epilepsy; transient increased IL-1beta after FSs acts on IL-1R1 and participates in the epileptic mechanism after FSs by up-regulating the endocannabinoid system. In addition, IL1Ra has a "therapeutic window" effect on post-FSs epilepsy, suggesting timely action. Effective control of inflammation after FS is the key to prevent adult epilepsy and may be a new therapeutic strategy to prevent adult epilepsy.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R742.1
【参考文献】
相关博士学位论文 前1条
1 闫海静;组胺H3受体拮抗剂对缺血性脑损伤的神经保护作用及机制研究[D];浙江大学;2013年
，本文编号：2182186
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