Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University.
Institute of Clinical Pharmacology and Department of Engineering Research Center of Applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha.
Neuroreport. 2024 Dec 4;35(17):1090-1097. doi: 10.1097/WNR.0000000000002103. Epub 2024 Sep 30.
The objective of this study is to explore whether sodium valproate (VPA) alleviates epileptic seizures via suppressing lysyl oxidase (Lox)-mediated ferroptosis. Epileptic seizure mouse model was prepared via intrahippocampal injection of kainic acid (250 ng/μl). After treatment with kainic acid, VPA was injected intraperitoneally by the dose of 250 mg/kg twice daily for 4 days. Ferroptosis-associated indices including lipid peroxides (LPO) level and Ptgs2 mRNA in hippocampal tissue samples were detected. Additionally, effects of VPA on Lox mRNA and enzymatic activity were assessed by quantitative real-time PCR and a commercial kit, respectively. Neuronal survival was assessed by Nissl staining. In kainic acid-induced epileptic seizure mouse model, VPA significantly suppressed LPO level and Ptgs2 mRNA and the suppression of ferroptosis was positively correlated with its anti-seizure effect. Lox mRNA and enzymatic activity were also found to decrease in hippocampus of epileptic seizure mice after VPA treatment. Furthermore, overexpression of Lox via adeno-associated virus infection remarkably abrogated the inhibitory effect of VPA on ferroptosis and neuronal impairment together with its anti-seizure effect. VPA suppresses Lox-mediated ferroptosis process, which can provide the explanation for its anti-seizure property.
本研究旨在探讨丙戊酸钠（VPA）是否通过抑制赖氨酰氧化酶（Lox）介导的铁死亡来缓解癫痫发作。通过向海马内注射海人酸（250ng/μl）制备癫痫发作小鼠模型。在海人酸处理后，通过腹腔内注射 250mg/kg 的剂量每天两次，共 4 天，给予 VPA 治疗。检测海马组织样本中与铁死亡相关的指标，包括脂质过氧化物（LPO）水平和 Ptgs2 mRNA。此外，通过定量实时 PCR 和商业试剂盒分别评估 VPA 对 Lox mRNA 和酶活性的影响。通过尼氏染色评估神经元存活情况。在海人酸诱导的癫痫发作小鼠模型中，VPA 显著抑制 LPO 水平和 Ptgs2 mRNA，铁死亡的抑制与抗惊厥作用呈正相关。VPA 治疗后，癫痫发作小鼠海马中 Lox mRNA 和酶活性也降低。此外，通过腺相关病毒感染过表达 Lox 可显著消除 VPA 对铁死亡和神经元损伤的抑制作用及其抗惊厥作用。VPA 抑制 Lox 介导的铁死亡过程，这可以解释其抗惊厥特性。
