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.

中文翻译：

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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

背景：认知功能障碍作为癫痫的常见合并症，通常表现为颞叶癫痫 (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。通过流式细胞术评估神经元凋亡和线粒体氧化应激。对于体内研究，毛果芸香碱注射诱导小鼠 TLE，在用 CREB ​​抑制剂 666-15 处理后，使用莫里斯水迷宫评估与 TLE 相关的记忆衰退，有或没有线粒体特异性抗氧化剂 MitoQ。通过蛋白质印迹分析和定量逆转录聚合酶链反应检查 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的产生和凋亡，而 CREB ​​过表达则产生相反的效果。TLE 小鼠表现出氧化应激和神经元凋亡升高，CREB ​​及其下游介质包括 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力下降。MitoQ 处理恢复了 CREB ​​及其下游介质的表达，并防止 CREB ​​抑制加剧的 TLE 相关氧化神经元损伤和记忆缺陷。结论：CREB ​​在 TLE 相关的氧化性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 可以通过激活 CREB ​​及其下游信号通路来缓解 TLE 相关的认知功能障碍。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 可以通过激活 CREB ​​及其下游信号通路来缓解 TLE 相关的认知功能障碍。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 可以通过激活 CREB ​​及其下游信号通路来缓解 TLE 相关的认知功能障碍。