Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island, USA.
Department of Neurology, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.
Epilepsia. 2021 Feb;62 Suppl 1(Suppl 1):S32-S48. doi: 10.1111/epi.16796. Epub 2021 Jan 4.
Extensive study has demonstrated that epilepsy occurs with greater frequency at certain times in the 24-h cycle. Although these findings implicate an overlap between the circadian rhythm and epilepsy, the molecular and cellular mechanisms underlying this circadian regulation are poorly understood. Because the 24-h rhythm is generated by the circadian molecular system, it is not surprising that this system comprised of many circadian genes is implicated in epilepsy. We summarized evidence in the literature implicating various circadian genes such as Clock, Bmal1, Per1, Rev-erb⍺, and Ror⍺ in epilepsy. In various animal models of epilepsy, the circadian oscillation and the steady-state level of these genes are disrupted. The downstream pathway of these genes involves a large number of metabolic pathways associated with epilepsy. These pathways include pyridoxal metabolism, the mammalian target of rapamycin pathway, and the regulation of redox state. We propose that disruption of these metabolic pathways could mediate the circadian regulation of epilepsy. A greater understanding of the cellular and molecular mechanism of circadian regulation of epilepsy would enable us to precisely target the circadian disruption in epilepsy for a novel therapeutic approach.
大量研究表明，癫痫在 24 小时周期的某些时间发生的频率更高。尽管这些发现暗示了昼夜节律和癫痫之间存在重叠，但昼夜节律调节的分子和细胞机制尚不清楚。由于 24 小时节律是由昼夜节律分子系统产生的，因此毫不奇怪，由许多昼夜节律基因组成的这个系统与癫痫有关。我们总结了文献中的证据，这些证据表明各种昼夜节律基因，如 Clock、Bmal1、Per1、Rev-erbα 和 Rorα，与癫痫有关。在各种癫痫动物模型中，这些基因的昼夜振荡和稳态水平都被打乱了。这些基因的下游途径涉及与癫痫相关的大量代谢途径。这些途径包括吡哆醛代谢、雷帕霉素靶蛋白途径和氧化还原状态的调节。我们提出，这些代谢途径的破坏可能介导了癫痫的昼夜节律调节。更深入地了解癫痫昼夜节律调节的细胞和分子机制，将使我们能够针对癫痫的昼夜节律失调进行精确的靶向治疗，从而开辟一种新的治疗方法。
