基于PET分子影像的生酮饮食改善癫痫共患认知障碍的表观遗传机制研究

Cognitive impairment, one of the most common comorbidities of epilepsy, can have an even greater impact on quality of life than do seizures. Since conventional antiepileptic drugs may also impair cognitive function, it is urgent to explore new methods of antiepileptic therapy with protective effects on cognition. Ketogenic diet (KD) is a well-established treatment for epilepsy, and recently, it has been reported to protect cognitive function. However, as an endogenous histone deacetylase inhibitor, the mechanism of ketone body regulating synaptic plasticity by activating cAMP response element binding protein (CREB) is still controversial. Our pilot study suggested that the down-regulated dopamine D1 receptor recovered accompanied by the improvement of cognitive function after KD treatment in the epileptic rat model with comorbid cognitive impairment. In order to further clarify the effects of KD on cognitive function in rat model, and the epigenetic mechanism of KD regulating AC/cAMP/PKA/CREB signaling pathway mediated by dopamine D1 receptor, this study intends to use ketone metabolism and dopamine D1 receptor PET molecular imaging combined with in vitro detection, which may provide important theoretical and experimental basis for exploring new methods of antiepileptic therapy with protective effects on cognition.

认知障碍是癫痫最常见的共患病之一，较癫痫发作本身对患者生活质量的影响更为严重。常规的抗癫痫药物也可损害认知功能，因此亟需探索具有认知保护作用的新型抗癫痫治疗手段。生酮饮食（KD）是一种疗效确切的癫痫治疗手段，近期也被发现具有认知保护作用。然而作为内源性组蛋白去乙酰基酶抑制剂，酮体通过激活cAMP反应元件结合蛋白（CREB）调节突触可塑性的具体机制尚存在争议。本课题组前期研究发现：癫痫共患认知障碍大鼠模型下调的多巴胺D1受体在KD治疗后有所恢复，并且与其改善认知功能的作用有关。本项目拟基于酮体代谢及多巴胺D1受体PET分子影像，结合离体检测技术探究KD对于大鼠模型认知功能的影响，阐明KD调控多巴胺D1受体介导的AC/cAMP/PKA/CREB信号通路的表观遗传机制，旨在为研发具有认知保护作用的新型抗癫痫治疗手段提供重要的理论和实验依据。

癫痫是最常见的神经系统疾病之一。此外，认知障碍等癫痫的共患病，较癫痫发作本身对患者生活质量的影响更为严重。目前针对癫痫患者共患的认知障碍尚无确切有效的防治措施，因此，探索具有认知保护作用的新型抗癫痫治疗手段已被列为癫痫研究领域的前沿热点之一。生酮饮食(KD)已被用于难治性癫痫的临床治疗，并且具有一定的认知保护作用，考虑到KD疗法在临床应用中尚存在的一些局限性，本课题旨在探究KD改善癫痫共患认知障碍的分子机制。本研究的主要内容为分析癫痫共患认知障碍大鼠模型的D1R基因启动子区组蛋白乙酰化水平及表达水平的改变，基于D1R受体PET分子影像并结合离体检测技术探究KD改善癫痫共患认知障碍的表观遗传机制。本研究结果表明D1R及其介导的AC/cAMP/PKA/CREB信号通路在KD改善癫痫共患认知障碍中具有关键作用。本项研究成果为研发具有认知保护作用的新型抗癫痫治疗手段提供重要的理论和实验依据。