CREB Protects against Temporal Lobe Epilepsy Associated with Cognitive Impairment by Controlling Oxidative Neuronal Damage
CREB Protects against Temporal Lobe Epilepsy Associated with Cognitive Impairment by Controlling Oxidative Neuronal Damage
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CREB 通过控制氧化神经元损伤来预防与认知障碍相关的颞叶癫痫
DOI：
10.1159/000507023
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发表时间：
2020-05
影响因子：
3
通讯作者：
Sun Lichao
中科院分区：
文献类型：
--
作者：
Xing Jihong;Han Dongfeng;Xu Dahai;Li Xingliang;Sun Lichao
背景：认知功能障碍是癫痫的常见合并症，常表现为颞叶癫痫（TLE）患者的学习和记忆障碍。癫痫相关认知功能障碍的发病分子机制尚不完全清楚。我们研究了cAMP反应元件结合蛋白（CREB）及其下游信号通路在TLE小鼠认知功能障碍发病机制中的作用。方法：制备CREB特异性短发夹rna和CREB cDNA质粒载体，转染原代神经元。流式细胞术检测神经元凋亡和线粒体氧化应激。在体内研究中，匹罗卡品注射诱导小鼠TLE，并在CREB抑制剂666-15（含或不含线粒体特异性抗氧化剂MitoQ）治疗后，使用Morris水迷宫评估TLE相关的记忆衰退。采用Western blotting和定量逆转录聚合酶链反应检测CREB及其下游介质。结果：CREB敲低诱导原代神经元线粒体活性氧产生和凋亡，而CREB过表达则相反。TLE小鼠表现出氧化应激升高和神经元凋亡，CREB及其下游介质PKA、CaMKIV、arc和c-fos的表达降低。CREB抑制加剧了tle相关的氧化神经元凋亡和记忆衰退。MitoQ处理恢复了CREB及其下游介质的表达，并防止了因CREB抑制而加重的tle相关的氧化神经元损伤和记忆缺陷。结论：CREB在tle相关的氧化神经元损伤和记忆障碍中起重要作用。这一新发现为CREB与线粒体氧化应激和癫痫认知功能障碍之间的关系提供了证据。线粒体特异性抗氧化剂如MitoQ可能通过激活CREB及其下游信号通路来减轻与tle相关的认知功能障碍。
Background: Cognitive dysfunction as a common comorbidity of epilepsy often manifests as learning and memory impairments in patients with temporal lobe epilepsy (TLE). The pathogenetic molecular mechanisms underlying epilepsy-associated cognitive dysfunction are incompletely understood. We investigated the role of cAMP response element binding protein (CREB) and its downstream signaling pathways in the pathogenesis of cognitive impairment in mice with TLE. Methods: Plasmid vectors of CREB-specific short-hairpin RNAs and CREB cDNA were prepared and transfected into primary neurons. Neuronal apoptosis and mitochondrial oxidative stress were assessed by flow cytometry. For in vivo studies, TLE in mice was induced by pilocarpine injection, and TLE-associated memory decline was evaluated using the Morris water maze after treatment with the CREB inhibitor 666-15, with or without the mitochondria-specific antioxidant MitoQ. CREB and its downstream mediators were examined by Western blotting analysis and quantitative reverse transcription polymerase chain reaction. Results: CREB knockdown induced mitochondrial reactive oxygen species production and apoptosis in primary neurons whereas CREB overexpression brought the opposite effects. The TLE mice exhibited elevated oxidative stress and neuronal apoptosis with decreased expression of CREB and its downstream mediators including PKA, CaMKIV, arc, and c-fos. CREB inhibition exacerbated TLE-associated oxidative neuronal apoptosis and memory decline. MitoQ treatment restored the expression of CREB and its downstream mediators, and prevented TLE-associated oxidative neuronal damage and memory deficits aggravated by CREB inhibition. Conclusion: CREB plays a significant role in TLE-associated oxidative neuronal damage and memory impairment. This novel finding provides the evidence of the relationship between CREB and mitochondrial oxidative stress and cognitive dysfunction in epilepsy. Mitochondria-specific antioxidants such as MitoQ may alleviate TLE-associated cognitive dysfunction through activation of CREB and its downstream signaling pathways.
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影响因子：
4.7
作者：
Sakamoto K;Karelina K;Obrietan K
通讯作者：
Obrietan K
影响因子：
2.7
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2.4
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Bading H
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4.7
作者：
Lee B;Cao R;Choi YS;Cho HY;Rhee AD;Hah CK;Hoyt KR;Obrietan K
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Obrietan K
影响因子：
5.1
作者：
Du, Lai-Ling;Wang, Lin;Zhou, Xin-Wen
通讯作者：
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