Inhibition of Gasdermin D-Mediated Pyroptosis Attenuates the Severity of Seizures and Astroglial Damage in Kainic Acid-Induced Epileptic Mice.
Inhibition of Gasdermin D-Mediated Pyroptosis Attenuates the Severity of Seizures and Astroglial Damage in Kainic Acid-Induced Epileptic Mice.
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抑制 Gasdermin D 介导的焦亡可减轻红藻氨酸诱导的癫痫小鼠癫痫发作和星形胶质细胞损伤的严重程度
DOI：
10.3389/fphar.2021.751644
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发表时间：
2021
影响因子：
5.6
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Xia L;Liu L;Cai Y;Zhang Y;Tong F;Wang Q;Ding J;Wang X
目的：探讨赤霉素D(Gasdermin D，GSDMD)介导的上睑下垂是否参与了红藻氨酸致痫的机制。方法：C57BL/6小鼠随机分为假手术组和癫痫组。癫痫组海马区注射海人酸致癫痫持续状态(SE)，假手术组注射等体积生理盐水。以富马酸二甲酯(DMF)作为GSDMD N-末端片段(GSDMD-N)抑制剂，悬浮于0.5%羧甲基纤维素钠(CMC)中口服。癫痫组分为SE+CMC组和SE+DMF组。SE+DMF组在SE诱导前口服DMF 1周，持续至实验结束。假手术组和SE+CMC组给予等体积的CMC。SE后21d监测反复自发性惊厥(SRSS)。Western印迹分析和免疫荧光染色。结果：SE后7~21d，GSDMD在同侧和对侧海马区表达均显著增加，GSDMD-N表达在SE后7d显著升高。GSDMD阳性细胞与星形胶质细胞共同标记，但不与神经元或小胶质细胞共同标记。癫痫持续状态(SE)后会出现星形胶质细胞损伤。SE后7~21d，受损星形胶质细胞在含有GSDMD强表达的CA1区出现典型的束状突起，并伴有激活的小胶质细胞。SE+DMF组GSDMD-N表达明显低于SE+CMC组。给予DMF后，SE后7~21d的SRSS明显减少，树突状突起星形胶质细胞、小胶质细胞数量及IL-1β、IL-18等炎症因子的表达明显减少。结论：GSDMD介导的上睑下垂参与了红藻氨酸致痫的机制。我们的研究为癫痫控制提供了一个新的潜在的治疗靶点。
Objective: Our study aimed to explore whether gasdermin D (GSDMD)-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures. Methods: C57BL/6 mice were randomly divided into sham and epilepsy groups. The epilepsy group was intrahippocampally injected with kainic acid to induce status epilepticus (SE), and the sham group was injected with an equal volume of saline. Dimethyl fumarate (DMF) was used as the GSDMD N-terminal fragments (GSDMD-N) inhibitor and suspended in 0.5% sodium carboxymethyl cellulose (CMC) for orally administration. The epilepsy group was divided into SE + CMC and SE + DMF groups. In the SE + DMF group, DMF was orally administered for 1 week before SE induction and was continued until the end of the experiment. An equal volume of CMC was administered to the sham and SE + CMC groups. Recurrent spontaneous seizures (SRSs) were monitored for 21 days after SE. Western blot analysis and immunofluorescent staining was performed. Results: The expression of GSDMD increased at 7–21 days post-SE, and GSDMD-N expression was significantly elevated 7 days after SE in both ipsilateral and contralateral hippocampus. GSDMD-positive cells were co-labeled with astrocytes, but not neurons or microglia. Astroglial damage occurs following status epilepticus (SE). Damaged astrocytes showed typical clasmatodendrosis in the CA1 region containing strong GSDMD expression at 7–21 days post-SE, accompanied by activated microglia. In the SE + DMF group, the expression of GSDMD-N was significantly inhibited compared to that in the SE + CMC group. After administration of DMF, SRSs at 7–21 days after SE were significantly decreased, and the number of clasmatodendritic astrocytes, microglia, and the expression of inflammatory factors such as IL-1β and IL-18 were significantly attenuated. Conclusion: GSDMD-mediated pyroptosis is involved in the mechanism of kainic acid-induced seizures. Our study provides a new potential therapeutic target for seizure control.
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影响因子：
5.6
作者：
Aronica E;Bauer S;Bozzi Y;Caleo M;Dingledine R;Gorter JA;Henshall DC;Kaufer D;Koh S;Löscher W;Louboutin JP;Mishto M;Norwood BA;Palma E;Poulter MO;Terrone G;Vezzani A;Kaminski RM
通讯作者：
Kaminski RM
影响因子：
3.3
作者：
Jiang, Zhenxiu;Chen, Jun;Yu, Qin
通讯作者：
Yu, Qin
影响因子：
6.2
作者：
Kang, Tae-Cheon;Kim, Duk-Soo;Kwon, Oh-Shin
通讯作者：
Kwon, Oh-Shin
DOI：
10.1073/pnas.1722041115
发表时间：
2018-06-26
影响因子：
11.1
作者：
McKenzie, Brienne A.;Mamik, Manmeet K.;Power, Christopher
通讯作者：
Power, Christopher
影响因子：
6.4
作者：
Hase, Yoshiki;Chen, Aiqing;Kalaria, Raj N.
通讯作者：
Kalaria, Raj N.