PDF(Pubmed)
Abstract：
OBJECTIVE: Synaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure-induced neuronal programmed death, parthanatos was rarely reported in PRE. Apoptosis-inducing factor (AIF), which has been implicated in parthanatos, shares a common cytoprotective function with SV2A. We aimed to investigate whether parthanatos participates in PRE and is mitigated by SV2A via AIF.
METHODS: An intraperitoneal injection of lithium chloride-pilocarpine was used to establish an epileptic rat model, and phenytoin and phenobarbital sodium were utilized to select PRE and pharmacosensitive rats. The expression of SV2A was manipulated via lentivirus delivery into the hippocampus. Video surveillance was used to assess epileptic ethology. Biochemical tests were employed to test hippocampal tissues following a successful SV2A infection. Molecular dynamic calculations were used to simulate the interaction between SV2A and AIF.
RESULTS: Parthanatos core index, PARP1, PAR, nuclear AIF and MIF, γ-H2AX, and TUNEL staining were all increased in PRE. SV2A is bound to AIF to form a stable complex, successfully inhibiting AIF and MIF nuclear translocation and parthanatos and consequently mitigating spontaneous recurrent seizures in PRE. Moreover, parthanatos deteriorated after the SV2A reduction.
CONCLUSIONS: SV2A protected hippocampal neurons and mitigated epileptic seizures by inhibiting parthanatos via binding to AIF in PRE.
METHODS: An intraperitoneal injection of lithium chloride-pilocarpine was used to establish an epileptic rat model, and phenytoin and phenobarbital sodium were utilized to select PRE and pharmacosensitive rats. The expression of SV2A was manipulated via lentivirus delivery into the hippocampus. Video surveillance was used to assess epileptic ethology. Biochemical tests were employed to test hippocampal tissues following a successful SV2A infection. Molecular dynamic calculations were used to simulate the interaction between SV2A and AIF.
RESULTS: Parthanatos core index, PARP1, PAR, nuclear AIF and MIF, γ-H2AX, and TUNEL staining were all increased in PRE. SV2A is bound to AIF to form a stable complex, successfully inhibiting AIF and MIF nuclear translocation and parthanatos and consequently mitigating spontaneous recurrent seizures in PRE. Moreover, parthanatos deteriorated after the SV2A reduction.
CONCLUSIONS: SV2A protected hippocampal neurons and mitigated epileptic seizures by inhibiting parthanatos via binding to AIF in PRE.
摘要：
目的：突触小泡蛋白2A（SV2A）是药物抵抗癫痫（PRE）的独特治疗靶点。作为癫痫诱发的神经元程序性死亡，pre中很少报道parthanatos。凋亡诱导因子(AIF),与parthanatos有牵连，与SV2A具有共同的细胞保护功能。我们旨在调查parthanatos是否参与PRE并通过AIF通过SV2A缓解。
方法：采用氯化锂-毛果芸香碱腹腔注射建立癫痫大鼠模型，用苯妥英钠和苯巴比妥钠选择PRE和药敏大鼠。SV2A的表达通过慢病毒递送到海马中进行操作。视频监控用于评估癫痫行为学。在成功的SV2A感染后，采用生化测试来测试海马组织。使用分子动力学计算来模拟SV2A和AIF之间的相互作用。
结果：Parthanatos核心指数，PARP1,PAR,核AIF和MIF，γ-H2AX,PRE中TUNEL染色均增加。SV2A与AIF结合形成稳定的复合物，成功抑制AIF和MIF核易位和parthanatos，从而减轻PRE的自发性复发性癫痫发作。此外，Parthanatos在SV2A减少后恶化。
结论：SV2A通过与PRE中的AIF结合来抑制parthanatos，从而保护海马神经元并减轻癫痫发作。
方法：采用氯化锂-毛果芸香碱腹腔注射建立癫痫大鼠模型，用苯妥英钠和苯巴比妥钠选择PRE和药敏大鼠。SV2A的表达通过慢病毒递送到海马中进行操作。视频监控用于评估癫痫行为学。在成功的SV2A感染后，采用生化测试来测试海马组织。使用分子动力学计算来模拟SV2A和AIF之间的相互作用。
结果：Parthanatos核心指数，PARP1,PAR,核AIF和MIF，γ-H2AX,PRE中TUNEL染色均增加。SV2A与AIF结合形成稳定的复合物，成功抑制AIF和MIF核易位和parthanatos，从而减轻PRE的自发性复发性癫痫发作。此外，Parthanatos在SV2A减少后恶化。
结论：SV2A通过与PRE中的AIF结合来抑制parthanatos，从而保护海马神经元并减轻癫痫发作。
