Zhang Zhijuan, Zhang Hui, Zhang Peng, Li Rong, Zhou Jinyu, Li Jiyuan, Hu Danmei, Huang Rui, Tang Fenglin, Liu Jie, Xu Demei, Zhang Chenlu, Tian Xin, Ma Yuanlin, Kwan Patrick
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, 400016, China.
Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, 400010, China.
Adv Sci (Weinh). 2025 Apr;12(13):e2404488. doi: 10.1002/advs.202404488. Epub 2024 Dec 30.
Current antiepileptic drugs are ineffective in one-third of patients with epilepsy; however, identification of genes involved in epilepsy can enable a precision medicine approach. Here, it is demonstrated that downregulating D-2-hydroxyglutarate dehydrogenase (D2HGDH) enhances susceptibility to epilepsy. Furthermore, its potential involvement in the seizure network through synaptic function modulation is investigated. D2HGDH knockdown reduces the glutathione reduced (GSH)/glutathione oxidized (GSSG) ratio and elevates reactive oxygen species (ROS) levels within neurons. Oxidative stress may play a crucial role in the pathogenesis of epilepsy. The specific contribution of each pathway varies among patients, highlighting the complexity of this disease. In this study, downregulation of D2HGDH affects modulation of ROS levels, synaptic transmission, and seizure susceptibility. Furthermore, the acid calcium-independent phospholipase A2 (aiPLA2) inhibitor, MJ33, restores the GSH/GSSG balance and reverses the increase in ROS levels caused by D2HGDH knockdown, resulting in remission of epilepsy-related behaviors. The results demonstrate that downregulation of D2HGDH affects synaptic function by regulating ROS production. These findings support the use of targeted gene therapy as a potential alternative to antioxidant-based treatments for refractory epilepsy.
目前的抗癫痫药物对三分之一的癫痫患者无效；然而，确定与癫痫相关的基因能够实现精准医疗。在此，研究表明下调D-2-羟基戊二酸脱氢酶（D2HGDH）会增加癫痫易感性。此外，还研究了其通过调节突触功能在癫痫网络中的潜在作用。敲低D2HGDH会降低神经元内还原型谷胱甘肽（GSH）/氧化型谷胱甘肽（GSSG）的比值，并提高活性氧（ROS）水平。氧化应激可能在癫痫发病机制中起关键作用。每条途径的具体作用在不同患者中有所不同，凸显了这种疾病的复杂性。在本研究中，D2HGDH的下调会影响ROS水平的调节、突触传递和癫痫易感性。此外，酸性钙非依赖性磷脂酶A2（aiPLA2）抑制剂MJ33可恢复GSH/GSSG平衡，并逆转由D2HGDH敲低引起的ROS水平升高，从而缓解癫痫相关行为。结果表明，D2HGDH的下调通过调节ROS生成来影响突触功能。这些发现支持将靶向基因治疗作为难治性癫痫基于抗氧化剂治疗的潜在替代方法。
