STAT3在匹罗卡品致痫鼠星形胶质细胞增生中的作用
摘要
目的:研究匹罗卡品致痫状态下大鼠海马内活化的信号转导与转录激活因子3(p-STAT3)表达规律及星形胶质细胞增生的情况,探讨STAT3信号转导通路在癫痫时星形胶质细胞增生中的作用。
方法:采用氯化锂-匹罗卡品腹腔注射方法建立大鼠颞叶癫痫模型,腹腔注射STAT3特异性抑制剂AG490建立干预组模型,对照组以生理盐水代替匹罗卡品腹腔注射;免疫组织化学方法对照观察阻滞JAK/STAT通路前后大鼠海马p-STAT3与胶质原纤维酸性蛋白(GFAP)阳性细胞表达的变化规律,并用双重免疫荧光方法观察p-STAT3与GFAP阳性细胞间的关系。
结果:
1.行为学观察:生理盐水对照组大鼠无任何痫性发作。PILO模型组有85.00%(34/40)的动物达Racine分级III级以上发作;7.50%(3/40)的大鼠死亡;7.50%(3/40)的大鼠未达III级发作;动物反复自发性发作(SRS)为4.52±1.49次/只。AG490干预组大鼠III级以上发作的发生率为82.50%(33/40);死亡率为15.00%(6/40);2.50%(3/40)的大鼠未达III级发作;SRS仅为1.26±0.78次/只。
2.组织病理学观察:对照组海马各区神经元无明显变化。PILO模型组大鼠SE后3h,海马门区、CA1、CA3区开始散在出现神经元变性、坏死,细胞排列不整齐,少量神经细胞脱失;至SE3d时,上述病理改变达到高峰,齿状回颗粒细胞也开始出现变性;SE15d时,神经元受损状况渐恢复,细胞排列渐整齐。AG490干预组与PILO模型组比较,各时间点神经细胞损伤情况明显减轻。
3.免疫组化结果:生理盐水对照组中,p-STAT3在大鼠脑组织呈胞浆浅染色,极少有胞核免疫阳性反应;而PILO模型组中,p-STAT3则主要在胞核表达,其阳性细胞数目在SE3h时即开始增多,以CA1、CA3和齿状回门区为主,于SE3d时达到高峰,之后渐下降,至SE30d时仍比正常水平略高;AG490干预组各时间点p-STAT3胞核阳性表达均较PILO组明显减少。生理盐水对照组GFAP阳性细胞数量很少,胞体小,突起少而细小;PILO模型组GFAP阳性细胞胞体截面积增大、突起及其分支增多,且其细胞数量变化规律与p-STAT3阳性细胞类似; AG490干预组各时间点的GFAP阳性表达均较PILO组明显减弱。
4.双重免疫荧光结果:GFAP阳性细胞胞浆呈绿色星状,p-STAT3阳性细胞胞核呈红色圆形或椭圆形,且可以发现p-STAT3阳性胞核位于GFAP阳性细胞胞浆中,提示STAT3的激活发生于反应性增生的星形胶质细胞内。
结论:氯化锂-匹罗卡品慢性癫痫模型能够复制出与人类颞叶癫痫相似的行为学和病理学改变。海马星形胶质细胞增生在癫痫发作早期是对痫性发作和神经元损伤的适应性反应,而晚期则可能促进癫痫的复发。STAT3信号通路在癫痫后海马星形胶质细胞内被激活,提示其活化可能促进星形胶质细胞的反应性增生。AG490可阻断STAT3的激活,同时影响癫痫大鼠行为学改变、病理学变化及星形胶质细胞的增生,提示其对癫痫发作可能有抑制作用。
Objective: To investigate the spatiotemporal distribution pattern of phospho-STAT3 (p-STAT3) and reactive astrocytes in rats hippocampus following pilocarpine-induced seizures,and to infer the role of STAT3 signaling pathway in gliosis of rats with epilepsy.
Methods: Rat temporal lobe epilepsy models were established by intraperitoneal injection of pilocarpine (PILO) , and specific STAT3 inhibitor-AG490 was used to set up pretreated models,saline was insteaded in the contral group. The expression pattern of p-STAT3 and glial fibrillary acidic protein (GFAP)-positive cells was observed immunohistochemically before and after blockage of the JAK/STAT pathway in rat hippocampus. Double immunofluorescence assay was used to investigate the relationship between p-STAT3 and GFAP-positive cells.
Results:
1. Ethology observation: No seizures were observed in the saline-treated group.Among the pilocarpine-treated rats, 85.00% (34/40) rats presented seizures more than III stage (Racine classifacation),7.50% (3/40) rats died, and 7.50% (3/40) rats were expelled because of no epileptic attack arrived to III stage; in this group, the rate of spontaneous recurrent seizure (SRS) is 4.52±1.49 times per rat. Among the AG490-pretreated rats, 82.50% (33/40) rats presented seizures above III stage, 15% (7/40) rats died and 2.50% were expelled, while SRS rate (1.26±0.78 times per rat ) decreased remarkably compared with pilocarpine-treated groups.
2. Histopathology observation: Neurons of hippocampus had no marked changes in saline-treated rats. While in pilocarpine-treated group, neuronal degeneration,necrosis and slightly cell loss can be observed in the CA1,CA3 and hilar region of hippocampus since 3 hours after SE. These patho-changes became most serious at 3 days after SE. Granular cells in the dentate gyrus (DG) preserved integrited cell structure at 3h while showed degeneration at 3d. After 15d necrosis of neurons lessened gradually. Compared with the pilocarpine-treated group, necrosis of neurons lessened in the AG490-pretreated rats.
3. Immunohistochemistry Results: Few pale-staining p-STAT3 kytoplasm- positive cells were observed in the hippocampus of saline-treated rats; Among pilocarpine-treated group, the p-STAT3 immunoreactivity was main observed in necleus, and the numerus of these p-STAT3 positive cells increased at 3h after seizure, reached peak at 3d, then graudually decreased, and kept at a higer level than the basic till 30d. All these immunoreactivity was especially strong in the CA1,CA3 and hilar regions of hippocampus. Compared with the pilocarpine-treated group, the immunoreactivity of p-STAT3 in AG490-pretreated rats was significantly blocked. The GFAP immunoreactivity was observed only in few cells in the contral group, with which have little cell body and tiny arborization. Among pilocarpine-treated group, the section area of GFAP-positive cells enlarged with its evection increased, and the distribution pattern of GFAP positive cells was smilar to the p-STAT3 expression. Compared with the pilocarepine-treated group, the immunoreactivity of GFAP in AG490-pretreated rats weakened obviously at most time course.
4. Double Immunoflourescence Assay: The GFAP positive cells were stained with green astro-kytoplasm, and the p-STAT3 positive cells were with red round or oval-shap necleus. Both of these two positive cells were main distributed in the CA1 and hilar regions of hippocampus. The p-STAT3 positive cells with red nucleus can also be observed in GFAP positive cells’kytoplasm, revealed that the GFAP immunoreactive astrocytes may accompany the activation of STAT3.
Conclusion: Rats model of chornic epilepsy induced by Lithium-pilocarpine can mimic features of human temporal epilepsy in seizure behaviors and histopathology findings. Gliosis in hippocampus was adaptive reaction to seizures and neuron necrosis, it might play an important role in recurrence of epilepsy. The STAT3 signaling pathway can be activated in reactive astrocytes of rats with seizures induced by pilocarpine, indicating that the phosphorylation of STAT3 might contribute to the reactive gliosis. AG490 could block the activation of STAT3, and also can effect the seizure behaviors and the histopathology changes as well as the reactive gliosis, indicating that it might have a negtive role in the epilpsy attacks.
方法:采用氯化锂-匹罗卡品腹腔注射方法建立大鼠颞叶癫痫模型,腹腔注射STAT3特异性抑制剂AG490建立干预组模型,对照组以生理盐水代替匹罗卡品腹腔注射;免疫组织化学方法对照观察阻滞JAK/STAT通路前后大鼠海马p-STAT3与胶质原纤维酸性蛋白(GFAP)阳性细胞表达的变化规律,并用双重免疫荧光方法观察p-STAT3与GFAP阳性细胞间的关系。
结果:
1.行为学观察:生理盐水对照组大鼠无任何痫性发作。PILO模型组有85.00%(34/40)的动物达Racine分级III级以上发作;7.50%(3/40)的大鼠死亡;7.50%(3/40)的大鼠未达III级发作;动物反复自发性发作(SRS)为4.52±1.49次/只。AG490干预组大鼠III级以上发作的发生率为82.50%(33/40);死亡率为15.00%(6/40);2.50%(3/40)的大鼠未达III级发作;SRS仅为1.26±0.78次/只。
2.组织病理学观察:对照组海马各区神经元无明显变化。PILO模型组大鼠SE后3h,海马门区、CA1、CA3区开始散在出现神经元变性、坏死,细胞排列不整齐,少量神经细胞脱失;至SE3d时,上述病理改变达到高峰,齿状回颗粒细胞也开始出现变性;SE15d时,神经元受损状况渐恢复,细胞排列渐整齐。AG490干预组与PILO模型组比较,各时间点神经细胞损伤情况明显减轻。
3.免疫组化结果:生理盐水对照组中,p-STAT3在大鼠脑组织呈胞浆浅染色,极少有胞核免疫阳性反应;而PILO模型组中,p-STAT3则主要在胞核表达,其阳性细胞数目在SE3h时即开始增多,以CA1、CA3和齿状回门区为主,于SE3d时达到高峰,之后渐下降,至SE30d时仍比正常水平略高;AG490干预组各时间点p-STAT3胞核阳性表达均较PILO组明显减少。生理盐水对照组GFAP阳性细胞数量很少,胞体小,突起少而细小;PILO模型组GFAP阳性细胞胞体截面积增大、突起及其分支增多,且其细胞数量变化规律与p-STAT3阳性细胞类似; AG490干预组各时间点的GFAP阳性表达均较PILO组明显减弱。
4.双重免疫荧光结果:GFAP阳性细胞胞浆呈绿色星状,p-STAT3阳性细胞胞核呈红色圆形或椭圆形,且可以发现p-STAT3阳性胞核位于GFAP阳性细胞胞浆中,提示STAT3的激活发生于反应性增生的星形胶质细胞内。
结论:氯化锂-匹罗卡品慢性癫痫模型能够复制出与人类颞叶癫痫相似的行为学和病理学改变。海马星形胶质细胞增生在癫痫发作早期是对痫性发作和神经元损伤的适应性反应,而晚期则可能促进癫痫的复发。STAT3信号通路在癫痫后海马星形胶质细胞内被激活,提示其活化可能促进星形胶质细胞的反应性增生。AG490可阻断STAT3的激活,同时影响癫痫大鼠行为学改变、病理学变化及星形胶质细胞的增生,提示其对癫痫发作可能有抑制作用。
Objective: To investigate the spatiotemporal distribution pattern of phospho-STAT3 (p-STAT3) and reactive astrocytes in rats hippocampus following pilocarpine-induced seizures,and to infer the role of STAT3 signaling pathway in gliosis of rats with epilepsy.
Methods: Rat temporal lobe epilepsy models were established by intraperitoneal injection of pilocarpine (PILO) , and specific STAT3 inhibitor-AG490 was used to set up pretreated models,saline was insteaded in the contral group. The expression pattern of p-STAT3 and glial fibrillary acidic protein (GFAP)-positive cells was observed immunohistochemically before and after blockage of the JAK/STAT pathway in rat hippocampus. Double immunofluorescence assay was used to investigate the relationship between p-STAT3 and GFAP-positive cells.
Results:
1. Ethology observation: No seizures were observed in the saline-treated group.Among the pilocarpine-treated rats, 85.00% (34/40) rats presented seizures more than III stage (Racine classifacation),7.50% (3/40) rats died, and 7.50% (3/40) rats were expelled because of no epileptic attack arrived to III stage; in this group, the rate of spontaneous recurrent seizure (SRS) is 4.52±1.49 times per rat. Among the AG490-pretreated rats, 82.50% (33/40) rats presented seizures above III stage, 15% (7/40) rats died and 2.50% were expelled, while SRS rate (1.26±0.78 times per rat ) decreased remarkably compared with pilocarpine-treated groups.
2. Histopathology observation: Neurons of hippocampus had no marked changes in saline-treated rats. While in pilocarpine-treated group, neuronal degeneration,necrosis and slightly cell loss can be observed in the CA1,CA3 and hilar region of hippocampus since 3 hours after SE. These patho-changes became most serious at 3 days after SE. Granular cells in the dentate gyrus (DG) preserved integrited cell structure at 3h while showed degeneration at 3d. After 15d necrosis of neurons lessened gradually. Compared with the pilocarpine-treated group, necrosis of neurons lessened in the AG490-pretreated rats.
3. Immunohistochemistry Results: Few pale-staining p-STAT3 kytoplasm- positive cells were observed in the hippocampus of saline-treated rats; Among pilocarpine-treated group, the p-STAT3 immunoreactivity was main observed in necleus, and the numerus of these p-STAT3 positive cells increased at 3h after seizure, reached peak at 3d, then graudually decreased, and kept at a higer level than the basic till 30d. All these immunoreactivity was especially strong in the CA1,CA3 and hilar regions of hippocampus. Compared with the pilocarpine-treated group, the immunoreactivity of p-STAT3 in AG490-pretreated rats was significantly blocked. The GFAP immunoreactivity was observed only in few cells in the contral group, with which have little cell body and tiny arborization. Among pilocarpine-treated group, the section area of GFAP-positive cells enlarged with its evection increased, and the distribution pattern of GFAP positive cells was smilar to the p-STAT3 expression. Compared with the pilocarepine-treated group, the immunoreactivity of GFAP in AG490-pretreated rats weakened obviously at most time course.
4. Double Immunoflourescence Assay: The GFAP positive cells were stained with green astro-kytoplasm, and the p-STAT3 positive cells were with red round or oval-shap necleus. Both of these two positive cells were main distributed in the CA1 and hilar regions of hippocampus. The p-STAT3 positive cells with red nucleus can also be observed in GFAP positive cells’kytoplasm, revealed that the GFAP immunoreactive astrocytes may accompany the activation of STAT3.
Conclusion: Rats model of chornic epilepsy induced by Lithium-pilocarpine can mimic features of human temporal epilepsy in seizure behaviors and histopathology findings. Gliosis in hippocampus was adaptive reaction to seizures and neuron necrosis, it might play an important role in recurrence of epilepsy. The STAT3 signaling pathway can be activated in reactive astrocytes of rats with seizures induced by pilocarpine, indicating that the phosphorylation of STAT3 might contribute to the reactive gliosis. AG490 could block the activation of STAT3, and also can effect the seizure behaviors and the histopathology changes as well as the reactive gliosis, indicating that it might have a negtive role in the epilpsy attacks.
引文
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