本文選題：MyD88 + ST2825�。� 參考：《重慶醫(yī)科大學(xué)》2015年博士論文

【摘要】：第一部分 MyD88在難治性癲癇患者及癲癇動物中的表達(dá)目的：越來越多的證據(jù)表明腦內(nèi)的炎癥反應(yīng)是癲癇發(fā)生發(fā)展的重要病理生理機(jī)制。髓樣分化因子88(Myeloid differentiation factor 88, MyD88)是細(xì)胞內(nèi)的接頭分子,在機(jī)體免疫和炎癥反應(yīng)中起關(guān)鍵作用。本實驗首先在難治性顳葉癲癇(temporal lobe epilepsy, TLE)患者及急、慢性癲癇動物模型中測定MyD88的表達(dá)規(guī)律,以探討癲癇活動是否影響MyD88的表達(dá)。方法：1.從本課題組建立的癲癇腦庫中隨機(jī)抽取25例難治性TLE患者和15例對照組患者的顳葉新皮質(zhì)；使用免疫熒光、免疫組化、和免疫印跡法測定MyD88的表達(dá)規(guī)律。2.使用氯化鋰和皮羅卡品(25mg/kg)在SD大鼠中誘導(dǎo)急性癲癇發(fā)作模型,在癲癇發(fā)作后6h、24h、和72h,采用免疫熒光和免疫印跡法測定大鼠海馬及周圍皮質(zhì)中MyD88的表達(dá)規(guī)律；建立急性戊四氮(pentylenetetrazol, PTZ)模型(65mg/kg),在PTZ注射后3h、6h、和24h,采用免疫印跡法測定大鼠海馬中MyD88的表達(dá)規(guī)律。3.使用氯化鋰和皮羅卡品在SD大鼠中建立慢性TLE模型,在皮羅卡品注射2個月后,采用免疫組化和免疫印跡法在有慢性自發(fā)性癲癇發(fā)作(spontaneous recurrent seizures, SRS)大鼠的海馬及周圍皮質(zhì)中檢測MyD88的表達(dá)規(guī)律；建立慢性PTZ點燃模型,采用免疫印跡法在點燃大鼠腦組織中測定MyD88的表達(dá)規(guī)律。結(jié)果：1.MyD88在難治性TLE患者腦組織中表達(dá)升高,主要表達(dá)于神經(jīng)元的胞漿中。2.在急性皮羅卡品模型中,MyD88在癲癇發(fā)作后24h和72h表達(dá)升高,主要與神經(jīng)元共表達(dá),沒有與膠質(zhì)細(xì)胞共表達(dá)；在急性PTZ模型中,MyD88在癲癇發(fā)作后6h和24h表達(dá)升高。3.在慢性匹羅卡品模型中,在有SRS的大鼠海馬和皮質(zhì)中MyD88表達(dá)升高；在慢性PTZ點燃模型中,MyD88在點燃大鼠海馬中表達(dá)也升高。結(jié)論：MyD88在難治性TLE患者和急、慢性癲癇大鼠腦組織中表達(dá)均升高,說明癲癇活動可影響MyD88的表達(dá)。第二部分MyD88在癲癇大鼠發(fā)作中的作用目的：為了測定MyD88對癲癇發(fā)作的影響,本部分在急性匹羅卡品和急性PTZ模型中測定MyD88的小分子抑制劑ST2825及刺激分子IL-1p對癲癇發(fā)作的影響。方法：1.在急性皮羅卡品模型中,在皮羅卡品注射前20min側(cè)腦室注射不同劑量的MyD88抑制劑ST2825 (2.5μg、5μg、10μg),在皮羅卡品注射后90min,觀察ST2825對癲癇發(fā)作的行為學(xué)影響,評價指標(biāo)為SE發(fā)生率、SE潛伏期、癲癇發(fā)作嚴(yán)重程度、和累積發(fā)作評分。2.在急性皮羅卡品模型中,在皮羅卡品注射前20min給予10ggST2825,觀察其對腦電圖(electroencephalogram, EEG)上癲癇發(fā)作的影響,評價指標(biāo)為EEG上第一次癲癇發(fā)作潛伏期、總的癲癇發(fā)作次數(shù)、和總的癲癇發(fā)作時間；檢測10μg ST2825對小膠質(zhì)細(xì)胞活化的影響。3.在急性PTZ模型中,在PTZ(65mg/kg)注射前20min給予10μgST2825,觀察其對癲癇發(fā)作的影響,評價指標(biāo)為第一次陣攣發(fā)作的潛伏期、全身強直-陣攣發(fā)作的潛伏期、和全身強直-陣攣發(fā)作的持續(xù)時間。4.在急性皮羅卡品模型中,在皮羅卡品注射前20min給予ST2825,前10min給予重組大鼠IL-1β,實驗分為溶劑組、IL-1β組,ST+IL-1β組,觀察IL-1β是否有促驚厥作用,及ST2825對IL-1β促驚厥作用的影響。5.在急性PTZ模型中,在PTZ注射前20min給予ST2825,前10min給予重組大鼠IL-1β,實驗分為溶劑組、IL-1β組,ST+IL-1β組,觀察IL-1β是否有促驚厥作用,及ST2825對IL-1β促驚厥作用的影響。結(jié)果：1.在急性皮羅卡品模型中,側(cè)腦室注射5μg及10μg ST2825顯著延長SE潛伏期,減弱癲癇發(fā)作的嚴(yán)重程度,降低累積發(fā)作評分。2.在急性皮羅卡品模型中,側(cè)腦室注射10μg ST2825顯著延長EEG上第一次癲癇發(fā)作的潛伏期,減少癲癇發(fā)作的總次數(shù),縮短癲癇發(fā)作總的持續(xù)時間；此外,10μg ST2825顯著減輕由癲癇發(fā)作誘導(dǎo)的小膠質(zhì)細(xì)胞活化程度。3.在急性PTZ模型中,側(cè)腦室注射10μg ST2825顯著延長第一次陣攣發(fā)作的潛伏期、延長全身強直-陣攣發(fā)作的潛伏期、并縮短全身強直-陣攣發(fā)作的持續(xù)時間。4.在急性皮羅卡品模型中,側(cè)腦室注射lng IL-1β顯著縮短SE潛伏期,加重癲癇發(fā)作嚴(yán)重程度,增加累積發(fā)作評分；在IL-1β前10min給予ST2825, ST2825阻止IL-1β誘導(dǎo)的SE潛伏期縮短,減輕IL-1β誘導(dǎo)的癲癇發(fā)作程度加劇,減弱IL-1β誘導(dǎo)的累積發(fā)作評分增加。此外側(cè)腦室注射lng IL-1β顯著縮短EEG上第一次癲癇發(fā)作的潛伏期,增加總的癲癇發(fā)作時間；ST2825阻止IL-1β誘導(dǎo)的EEG上第一次發(fā)作潛伏期的縮短,減輕總的癲癇發(fā)作次數(shù),減少IL-1β誘導(dǎo)的癲癇發(fā)作時間的增加。5.在急性PTZ大鼠模型中,i.c.v. lng IL-1β顯著縮短全身強直-陣攣發(fā)作的潛伏期并延長全身強直-陣攣發(fā)作的持續(xù)時間。預(yù)先給予ST2825可阻斷IL-1β誘導(dǎo)的潛伏期縮短及全身強直-陣攣發(fā)作持續(xù)時間的增加。結(jié)論：1.MyD88的小分子抑制劑ST2825在急性匹羅卡品模型中可減少行為學(xué)上及EEG上的癲癇發(fā)作,減輕小膠質(zhì)細(xì)胞的活化；ST2825在急性PTZ模型中也能減少癲癇發(fā)作。2.IL-1β在急性皮羅卡品和急性PTZ模型中均具有促驚厥作用,ST2825能抑制IL-1β的促驚厥作用。第三部分MyD88參與癲癇發(fā)作的機(jī)制探討目的：NR2B酪氨酸位點的磷酸化在NMDA受體功能和神經(jīng)元興奮性中發(fā)揮重要作用。上部分的研究說明MyD88在癲癇活動中起重要作用,本部分對NR2B酪氨酸的磷酸化水平改變是否參與這個過程進(jìn)行探討。方法：1.采用免疫印跡法檢鋇NMD A亞基NR2B酪氨酸磷酸化位點1472(NR2B Tyr1472)在不同干預(yù)條件下的磷酸化水平改變,分組：vehicle組、Pilo組、IL-1β組、IL-1β+Pilo組、ST+IL-1β+Pilo組、和ST+Pilo組。2.在急性皮羅卡品模型中,在匹羅卡品注射前20min給予NR2BTyr1472的抑制劑艾芬地爾,在皮羅卡品10min前給予重組大鼠IL-1β,實驗分為vehicle組、IL-1β組、Ifen組、和Ifen+IL-1β組,觀察抑制NR2B Tyr1472后對IL-1β促驚厥作用的影響。3.在急性PTZ模型中,在PTZ注射前20min給予艾芬地爾,在PTZ 10min前給予重組大鼠IL-1β,實驗分為vehicle組、IL-1β組、Ifen組、和Ifen+IL-1β組,觀察抑制NR2B Tyr1472后對IL-1β促驚厥作用的影響。結(jié)果：1.單獨給予IL-1β或癲癇發(fā)作本身(僅皮羅卡品)增加NR2B Tyr1472位點的磷酸化,分別增加154%和134%(P0.05)。同時給予IL-1β和皮羅卡品時,與vehicle組相比,NR2B Tyr1472的磷酸化水平增加213%,說明IL-1β和癲癇發(fā)作對其磷酸化水平增加具有疊加效應(yīng)。10μgST2825顯著抑制由癲癇發(fā)作引起的NR2B Tyr1472磷酸化水平增高(P0.05)。此外,10μg ST2825有效阻止IL-1β+皮羅卡品誘導(dǎo)的NR2BTyr1472磷酸化水平增高(P0.01)。2.在急性皮羅卡品模型中,側(cè)腦室注射lng IL-1β顯著縮短SE潛伏期,加重癲癇發(fā)作嚴(yán)重程度,增加累積發(fā)作評分；在IL-1β前10min給予NR2B Tyr1472的抑制劑艾芬地爾,艾芬地爾阻止IL-1β誘導(dǎo)的SE潛伏期縮短,緩和IL-1β誘導(dǎo)的癲癇發(fā)作程度加劇,減弱IL-1p誘導(dǎo)的累積發(fā)作評分增加。3.在急性PTZ模型中,與vehicle組相比,IL-1β組顯著縮短全身強直-陣攣發(fā)作的潛伏期并延長全身強直-陣攣的持續(xù)時間。相反,與vehicle組相比,艾芬地爾顯著增加第一次陣攣發(fā)作和強直-陣攣發(fā)作的潛伏期,減少全身強直-陣攣的持續(xù)時間,具有抗驚厥作用。此外,艾芬地爾可阻斷IL-1β誘導(dǎo)的潛伏期縮短和全身強直-陣攣發(fā)作持續(xù)時間的延長。結(jié)論：1.在癲癇發(fā)作中,NR2B Tyr1472的磷酸化水平增高,IL-1β可使NR2B Tyr1472的磷酸化水平進(jìn)一步增高,ST2825可降低由癲癇發(fā)作誘導(dǎo)的NR2B Tyr1472磷酸化水平的增加。2.NR2B亞基的選擇性抑制劑艾芬地爾可抑制癲癇發(fā)作活動,并可抑制IL-1β的促驚厥作用。第四部分MyD88對癲癇形成的影響目的：越來越多的證據(jù)表明腦內(nèi)的炎癥反應(yīng)在癲癇形成中起重要作用,抗炎治療有可能成為抗癲癇形成治療的新策略。前部分的研究證實MyD88在癲癇發(fā)作中起重要作用,本部分進(jìn)一步研究MyD88對癲癇形成的影響。方法：1.在SD大鼠中每天給予亞驚厥劑量的PTZ (33mg/kg)建立慢性PTZ點燃模型,IL-1β在PTZ前10min給予,ST2825在PTZ前20min給予,分Con組、vehicle組、IL-1β組、和ST2825組,記錄每次PTZ注射后癲癇發(fā)作的最高級別和達(dá)到完全點燃的潛伏期,完全點燃是指大鼠在PTZ注射后連續(xù)3天達(dá)到4級或4級以上的癲癇發(fā)作。2.在慢性皮羅卡品模型中,在SE結(jié)束后24h,每天側(cè)腦室注射IL-1β和ST2825,每天一次,連續(xù)給予7天。實驗分為vehicle組、IL-1β組、和ST2825組。從SE后的第21-34天,使用高清視頻系統(tǒng)監(jiān)測SRS活動。分析指標(biāo)為SRS發(fā)生率、SRS發(fā)作次數(shù)、和SRS發(fā)作嚴(yán)重程度。結(jié)果：1.在慢性PTZ點燃模型中,IL-1β組完全點燃的潛伏期與vehicle組相比明顯縮短,IL-1β組的癲癇發(fā)作級別在第5、7-9、10、12天與vehicle組相比明顯加重。相反,ST2825組完全點燃的潛伏期與vehicle組相比明顯延長,ST2825組的癲癇發(fā)作級別在第6-8、13-18天明顯減輕。此外,Con組與vehicle組相比,達(dá)到完全點燃的潛伏期及癲癇發(fā)作嚴(yán)重程度沒有明顯差別。2.在慢性皮羅卡品模型中,SRS發(fā)生率在vehicle組、IL-1β組、和ST2825組沒有明顯差異。與vehicle組相比,IL-1β組SRS每天發(fā)作次數(shù)明顯增加,差異有統(tǒng)計學(xué)意義(p0.05),ST2825組SRS每天發(fā)作次數(shù)差別不顯著(p0.05)。與vehicle組相比,SRS的嚴(yán)重程度在IL-1β組明顯增加(p0.05),而在ST2825組差別不顯著(p0.05)。結(jié)論：1.在慢性PTZ點燃模型中,IL-1β可縮短PTZ完全點燃的潛伏期,并縮短點燃過程。相反,ST2825可顯著延長完全點燃的潛伏期并延緩點燃過程,具有一定的抗癲癇形成作用。2.在慢性皮羅卡品模型中,IL-1β可增加SRS發(fā)作頻率并加重SRS發(fā)作嚴(yán)重程度,而ST2825對SRS發(fā)作頻率及SRS發(fā)作嚴(yán)重程度沒有影響,說明post-SE誘導(dǎo)的癲癇形成過程更難被修飾,多階段或多藥聯(lián)合干預(yù)可能是未來的研究方向。
[Abstract]:Part one MyD88 expression in intractable epilepsy and epileptic animals: more and more evidence shows that the inflammatory reaction in the brain is an important pathophysiological mechanism in the development of epilepsy. Myeloid differentiation factor 88 (Myeloid differentiation factor 88, MyD88) is a cell joint molecule, in the immune and inflammatory response of the body. This experiment first measured the expression of MyD88 in intractable temporal lobe epilepsy (temporal lobe epilepsy, TLE) and acute and chronic epileptic animal models to investigate whether epileptic activity affects the expression of MyD88. Methods: 1. from the epileptic brain bank established in this group, 25 cases of refractory TLE patients and 15 cases of MyD88 were randomly selected. Group of patients with temporal Ye Xin cortex; using immunofluorescence, immunohistochemistry, and immunoblotting to determine the expression of MyD88.2. using lithium chloride and 25mg/kg to induce acute epileptic seizures in SD rats, 6h, 24h, and 72h after epileptic seizures, using immunofluorescence and Western blotting to determine My in the hippocampus and the surrounding cortex. The expression of D88, the establishment of an acute amyl four nitrogen (pentylenetetrazol, PTZ) model (65mg/kg), 3h, 6h, and 24h after PTZ injection, the expression of MyD88 in the hippocampus of rats was determined by immunoblotting.3. using lithium chloride and pilocarpine to establish a chronic TLE model in SD rats. After 2 months of injection, immunization and immunity were used. The expression of MyD88 in hippocampus and surrounding cortex of rats with chronic spontaneous seizures (spontaneous recurrent seizures, SRS) was detected by immunoblotting. A chronic PTZ kindling model was established. The expression of MyD88 in the brain tissue of kindled rats was determined by immunoblotting. Results: 1.MyD88 was in the brain tissue of refractory TLE patients. The expression of.2. in the cytoplasm of neurons was mainly expressed in the acute pilocarpine model, and the expression of 24h and 72h increased after epileptic seizures, and the expression of 24h and 72h was mainly co expressed with neurons. In the acute PTZ model, MyD88 increased.3. in the chronic pilocarpine model after epileptic seizures, and in the chronic pilocarpine model, there were SRS in the acute PTZ model. The expression of MyD88 in the hippocampus and cortex of rats increased. In the chronic PTZ kindling model, the expression of MyD88 in the hippocampus of the kindled rats also increased. Conclusion: the expression of MyD88 increased in the brain tissues of the refractory TLE patients and the acute and chronic epileptic rats, indicating that the epileptic activity could affect the expression of MyD88. Second part of the role of MyD88 in the seizure of epileptic rats Objective: to determine the effect of MyD88 on epileptic seizures, this part examines the effects of MyD88's small molecular inhibitor ST2825 and stimulator IL-1p on epileptic seizures in acute pilocarpine and acute PTZ models. Methods: 1. in the acute pilocarpine model, different doses of MyD88 inhibition were injected into the 20min lateral ventricle before the injection of pilocarpine. The effects of ST2825 on epileptic seizures were observed after injection of ST2825 (2.5, 5, 5, G, 10 g). The behavioral effects of ST2825 on epileptic seizures were observed. The evaluation indexes were SE incidence, SE latency, seizure severity, and cumulative episodes of.2. in acute pilocarpine models. Before injection, 20min was given 10ggST2825, and the electroencephalogram (electr) was observed. The effects of oencephalogram, EEG) on epileptic seizures, the evaluation index was the first seizure latency in EEG, the total number of epileptic seizures, and the total seizure time; the effects of 10 mu g ST2825 on the activation of microglia were detected in the acute PTZ model, and 10 micron gST2825 was 20min before PTZ (65mg/ kg) injection to observe its seizures. The evaluation index was the incubation period of the first clonic seizure, the latent period of the generalized tonic clonic seizure, and the duration of the generalized tonic clonic seizure.4. in the acute pilocarpine model, 20min was given to ST2825 before the injection of the pilocarpine, and the former 10min was given to the recombinant rat IL-1 beta, and the experiment was divided into the solvent group, the IL-1 beta group, ST+IL-1 beta group, and the view of the ST+IL-1 beta group. The effect of IL-1 beta on convulsion, and the effect of ST2825 on IL-1 beta convulsion,.5. in the acute PTZ model, 20min was given ST2825 before PTZ injection, and the anterior 10min was given to the recombinant rat IL-1 beta. The experiment was divided into solvent group, IL-1 beta group and ST+IL-1 beta group. 1. in the acute pilocarpine model, the lateral ventricle injection of 5 g and 10 mu g ST2825 significantly prolongs the SE latency, reduces the severity of the seizures, and reduces the cumulative attack score in the acute pilocarpine model. The lateral ventricle injection of 10 mu ST2825 significantly prolongs the incubation period of the first seizure on EEG, reducing the total number of epileptic seizures, and reducing the total number of seizures. In addition, 10 g ST2825 significantly alleviated the degree of activation of microglia induced by epileptic seizures in the acute PTZ model. The lateral ventricle injection of the lateral ventricle significantly prolonged the incubation period of the first clonic seizure, prolonged the latent period of the generalized tonic clonic seizure, and shortened the generalized tonic clonic seizure. Duration of.4. in the acute pilocarpine model, the lateral ventricle injection of LNG IL-1 beta significantly shortened the SE latency, aggravated the severity of epileptic seizures and increased the cumulative attack score; ST2825 prevented the IL-1 beta induced SE latency, reduced the severity of the IL-1 beta induced epileptic seizures, and reduced the involvement of IL-1 beta induced involvement in IL-1 beta 10min. LNG IL-1 beta injection in this lateral ventricle significantly shortened the incubation period of the first seizure on EEG and increased the total seizure time; ST2825 prevented the shortening of the first seizure latency on EEG induced by IL-1 beta, reduced the total number of epileptic seizures, and reduced the time of epileptic seizures induced by IL-1 beta.5. in acute PTZ In the rat model, i.c.v. LNG IL-1 beta significantly shortens the latent period of generalized tonic clonic seizures and prolongs the duration of generalized tonic clonic seizures. Pre administration of ST2825 can block the shortened latency induced by IL-1 beta and the duration of generalized tonic clonic seizures. Conclusion: the small molecular inhibitor of 1.MyD88, ST2825, is in the acute pion. In the card model, epileptic seizures on behavior and EEG can be reduced and the activation of microglia can be reduced; ST2825 can also reduce seizure.2.IL-1 beta in acute PTZ and acute PTZ models with convulsion, and ST2825 can inhibit the effect of IL-1 beta convulsion in acute PTZ model. Part MyD88 involved in epileptic seizures. Objective: the phosphorylation of NR2B tyrosine sites plays an important role in the function of NMDA receptor and neuronal excitability. The previous study shows that MyD88 plays an important role in epileptic activity. This part studies whether the phosphorylation level of NR2B tyrosine is involved in this process. Method: 1. by immunoblotting The phosphorylation level of barium NMD A subunit NR2B tyrosine phosphorylation site 1472 (NR2B Tyr1472) was changed under different intervention conditions. Groups: Vehicle Group, Pilo group, IL-1 beta group, IL-1 beta +Pilo group, ST+IL-1 beta +Pilo group, and in acute pilocarpine model, before pilocarpine injection, the inhibitor alfentil, The recombinant rat IL-1 beta was given before 10min, and the experiment was divided into vehicle group, IL-1 beta group, Ifen group, and Ifen+IL-1 beta group. The effect of NR2B Tyr1472 on IL-1 beta convulsion was observed..3. in the acute PTZ model was given before the PTZ injection. The effect of inhibition of NR2B Tyr1472 on IL-1 beta convulsion was observed in group beta, Ifen, and Ifen+IL-1 beta. Results: 1. the phosphorylation of IL-1 beta or epileptic seizures alone (only pilocarpine) increased the phosphorylation of NR2B Tyr1472 sites, increased by 154% and 134% (P0.05), respectively, while giving IL-1 beta and pilocarpine, compared with vehicle group, NR2B The level of phosphorylation increased by 213%, indicating that IL-1 beta and epileptic seizures had a superposition effect on its phosphorylation level, which significantly inhibited the increase of NR2B Tyr1472 phosphorylation level (P0.05) caused by epileptic seizures (P0.05). In addition, 10 mu g ST2825 effectively prevented IL-1 beta + pilocarpine induced NR2BTyr1472 phosphorylation level increased (P0.01).2. was in a hurry. In the sex pilocarpine model, the injection of LNG IL-1 beta in the lateral ventricle significantly shortened the SE latency, aggravated the severity of epileptic seizures, and increased the cumulative attack score. In the front of IL-1 beta, apifentel, a NR2B Tyr1472 inhibitor, prevented the SE latency induced by IL-1 beta, reducing the severity of epileptic seizures induced by IL-1 beta, weakening IL-1 and weakening IL-1. The P induced cumulative attack score increased.3. in the acute PTZ model. Compared with the vehicle group, the IL-1 beta group significantly shortened the latent period of the generalized tonic clonic seizure and prolonged the duration of the generalized tonic clonus. On the contrary, the latent period of the first clonic seizure and tonic clonic seizures increased significantly compared with the vehicle group, and decreased the total duration of the first clonic seizure and tonic clonic seizures. The duration of strong direct clonus has an anticonvulsant effect. In addition, Ifen can block the shortened latency induced by IL-1 beta and prolongation of the duration of generalized tonic clonic seizures. Conclusion: 1. in epileptic seizures, the level of phosphorylation of NR2B Tyr1472 increases, IL-1 beta can increase the level of phosphorylation of NR2B Tyr1472, ST2825 can be reduced. The low level of phosphorylation of NR2B Tyr1472 induced by epileptic seizures increased the activity of epileptic seizures by the selective inhibitor of.2.NR2B subunit and inhibited the convulsion of IL-1 beta. Fourth the effects of MyD88 on the formation of epilepsy: more and more evidence suggests that the inflammatory reaction in the brain plays an important role in the formation of epilepsy. Anti-inflammatory therapy may be a new strategy for antiepileptic therapy. Previous studies have confirmed that MyD88 plays an important role in epileptic seizures. This part further studies the effect of MyD88 on the formation of epilepsy. Methods: 1. a chronic PTZ kindling model was established in SD rats with PTZ (33mg /kg) every day in a dose of subconvulsive dose (33mg /kg), and IL-1 beta was in the PTZ pre 10m. In was given, ST2825 was given in pre PTZ 20min, Con group, vehicle group, IL-1 beta group, and ST2825 group, record the highest level of epileptic seizures and the latent period of complete kindling after each injection of PTZ. The complete kindling was the.2. in the chronic pilocarpine model in rats after 3 days of PTZ injection to 4 or more. After 24h, IL-1 beta and ST2825 were injected every day in the lateral ventricle for 7 days. The experiment was divided into vehicle, IL-1, and ST2825. SRS activity was monitored by HD video system on day 21-34 after SE. The analysis index was SRS incidence, SRS attack times, and SRS attack severity. Results 1. in chronic PTZ kindling model, 1. The latent period of complete kindling in the group was significantly shorter than that in the vehicle group. The level of epileptic seizures in the IL-1 beta group was significantly higher than that in the vehicle group on day 5,7-9,10,12. On the contrary, the latent period of the complete kindling in the ST2825 group was significantly longer than that in the vehicle group. The epileptic seizure level in the ST2825 group was significantly reduced on the day 6-8,13-18. In addition, the Con group and vehicle were observed. There was no significant difference in the incubation period and the severity of epileptic seizures in the group.2.. In the chronic pilocarpine model, the incidence of SRS was not significantly different in the vehicle group, in the IL-1 beta group and in the ST2825 group. Compared with the vehicle group, the number of SRS episodes in the IL-1 beta group increased significantly (P0.05), and the SRS of the ST2825 group was SRS every day. There was no significant difference in the number of episodes (P0.05). Compared with the vehicle group, the severity of SRS increased significantly in the IL-1 beta group (P0.05), but in the ST2825 group, the difference was not significant (P0.05). Conclusion: 1. in the chronic PTZ kindling model, IL-1 beta can shorten the incubation period of PTZ, and shorten the ignition process. On the contrary, ST2825 can significantly prolong the incubation period of complete kindling. And postpone the kindling process, with a certain antiepileptic effect of.2. in the chronic pilocarpine model, IL-1 beta can increase the frequency of SRS seizures and aggravate the severity of SRS seizures, and ST2825 has no effect on the frequency of SRS and the severity of SRS seizures, indicating that post-SE induced seizures are more difficult to be modified, multistage or multidrug combination Intervention may be the future research direction.

【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R742.1

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