IL1β通過上調(diào)CB1R促進幼鼠熱驚厥后成年癲癇易感性
發(fā)布時間：2018-08-13 21:05
【摘要】：癲癇是發(fā)作性的大腦神經(jīng)功能障礙,是常見的神經(jīng)系統(tǒng)慢性�。患s30%的癲癇患者對多種抗癲癇藥物耐受,最終發(fā)展為難治性癲癇。目前癲癇的發(fā)病機制尚不清楚,外科手術(shù)及藥物治療都有其局限性。因此,急需進一步探討癲癇的發(fā)病機制并尋找有效的防治策略。癲癇發(fā)病機制極為復(fù)雜,兒童和青少年是癲癇發(fā)病率最高的群體,癲癇新發(fā)病例中未成年人占一半以上。未成人還處于智能發(fā)育階段,癲癇發(fā)作對他們的危害程度較成年人更為嚴重。發(fā)育早期是大腦神經(jīng)環(huán)路形成和突觸可塑性發(fā)育的關(guān)鍵時期,因此,發(fā)育早期的關(guān)鍵事件可能嚴重影響癲癇的形成。小兒熱驚厥(Febrile seizures, FS)高發(fā)于6個月至5歲的嬰幼兒,是嬰幼兒時期常見的驚厥發(fā)作類型。盡管大部分熱驚厥被認為是良性／簡單熱驚厥發(fā)作(發(fā)作時間15min),但是約有25-30%的熱驚厥發(fā)作為復(fù)雜性的(發(fā)作時間15 min或24 h內(nèi)多次反復(fù)發(fā)作,Prolonged/complex FS, FSs),FSs會在很大程度上增加海馬損傷、認知障礙及成年癲癇發(fā)作的風(fēng)險。盡管流行病學(xué)研究發(fā)現(xiàn)僅有3-5%的FS患者會發(fā)展為癲癇,臨床回顧性研究卻表明相當一部分顳葉癲癇病人具有FS病史(約30-50%)；并且具有FS病史的顳葉癲癇患者會伴隨更加嚴重的中央顳葉硬化。以上研究結(jié)果提示了FS可能與癲癇發(fā)生密切相關(guān)。此外,動物實驗研究表明,FS大鼠在亞劑量(5mg/kg)海人藻酸(Kainic acid, KA)的作用下有癲癇發(fā)作；且約有35%的FS動物成年后出現(xiàn)自發(fā)性癲癇發(fā)作,提示FS可能增加了成年罹患癲癇的風(fēng)險,那么FS如何引起成年后癲癇發(fā)生?另一方面,目前治療FS主要采用傳統(tǒng)的抗癲癇藥物,如苯巴比妥,苯妥英等,這些抗癲癇藥物只能控制驚厥發(fā)作,而對于FS引起的成年癲癇發(fā)生則沒有效果；此外,傳統(tǒng)抗癲癇藥物對兒童智力發(fā)育有較大影響。因此,有必要尋找有效的控制FS后癲癇發(fā)生的藥物治療手段。炎癥因子作為一種神經(jīng)調(diào)質(zhì)在癲癇異常神經(jīng)環(huán)路的形成和不斷鞏固中的作用日益受到關(guān)注。白介素1β (Interleukin-1β, IL-1β)作為重要的炎癥因子在癲癇發(fā)生早期激活并參與調(diào)節(jié)神經(jīng)元興奮性和突觸可塑性。最近臨床研究發(fā)現(xiàn),具有IL1β-511C/T基因多態(tài)性的兒童更加容易發(fā)生FS；同時有研究報道FS后IL-1β的表達水平增加,提示IL-1β可能參與FS后的癲癇發(fā)生,但其作用機制尚不清楚。因此,本課題采用不同發(fā)作程度的FS模型,探討其對成年癲癇發(fā)生的影響,并進一步研究IL-1β對FS后癲癇發(fā)生的作用及其作用機制。將出生8-10天(P8-10)的SD大鼠放入環(huán)境溫度為44±2℃的烘箱中誘導(dǎo)簡單熱驚厥發(fā)作(驚厥發(fā)作后立即從烘箱取出)和復(fù)雜熱驚厥發(fā)作(FSs,發(fā)作時間大于30 min),并記錄發(fā)作期特征性腦電(EEG)。采用最大電休克(Maximal electroshock, MES)和KA誘導(dǎo)的癲癇發(fā)作模型檢測成年癲癇易感性。實驗結(jié)果發(fā)現(xiàn)幼年動物經(jīng)歷FSs后其海馬內(nèi)IL-1β的表達水平一過性增加(驚厥發(fā)作后12h內(nèi)增加,其后恢復(fù)至正常水平),并且FSs動物成年后癲癇易感性增加；而經(jīng)歷簡單熱驚厥的動物海馬內(nèi)IL-1β的表達水平無變化,其成年后癲癇易感性也沒有改變。動物經(jīng)歷FSs后12h內(nèi)給予IL1受體拮抗劑(IL1Ra)可劑量依賴性的逆轉(zhuǎn)其成年癲癇易感性的改變,12h后給予IL1Ra卻沒有效果,提示IL1Ra具有“治療時間窗”。同時,如果幼年動物(P8)單獨給予IL-1β,其成年后癲癇易感性增加。IL1R1敲除(IL1R1-/-)小鼠無論經(jīng)歷FSs或者給予IL-1p處理,其成年后癲癇易感性均無變化。此外,幼年動物經(jīng)FSs或IL-1p處理后,其海馬中內(nèi)源性大麻素I型受體(CB1R)的表達水平在處理后第3天開始增加,并持續(xù)到成年。上調(diào)的CB1R的表達水平及其功能能夠被IL1Ra所逆轉(zhuǎn)。CB1R拮抗劑、小RNA干擾CBlR或者抑制內(nèi)源性大麻素合成均可逆轉(zhuǎn)FSs后增加的癲癇易感性。進一步,我們發(fā)現(xiàn)具有FS病史的顳葉癲癇患者病灶區(qū)CB1R表達水平顯著高于無FS病史的顳葉癲癇患者。總之,本課題發(fā)現(xiàn)復(fù)雜性而非簡單的小兒熱驚厥能夠引起成年癲癇易感性增加；FSs后一過性增加的IL-1β作用于IL1R1,通過上調(diào)內(nèi)源性大麻素系統(tǒng)參與FSs后的癲癇發(fā)生機制。此外,IL1Ra對FSs后癲癇發(fā)生具有“治療時間窗”作用,提示及時有效的控制幼兒FS后的炎癥是預(yù)防其成年后癲癇發(fā)生的關(guān)鍵,并可能是一種預(yù)防成年癲癇發(fā)生的新的治療策略。
[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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R742.1
本文編號：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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R742.1
【參考文獻】
相關(guān)博士學(xué)位論文 前1條
1 閆海靜;組胺H3受體拮抗劑對缺血性腦損傷的神經(jīng)保護作用及機制研究[D];浙江大學(xué);2013年
，本文編號：2182186
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