Department of Neurology and Neuroscience Center, First Hospital of Jilin University, Changchun, Jilin, People's Republic of China.
Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China.
CNS Neurosci Ther. 2022 Dec;28(12):2032-2043. doi: 10.1111/cns.13934. Epub 2022 Jul 31.
Epileptic seizures or status epilepticus (SE) can cause hippocampal neuronal death, which has detrimental effects. Parthanatos, a new form of programmed cell death, is characterized by hyperactivation of poly (ADP-ribose) polymerase-1 (PARP-1), excessive synthesis of poly ADP-ribose polymer, mitochondrial depolarization, and nuclear translocation of apoptosis-inducing factor, observed in various neurodegenerative disorders but rarely reported in epilepsy. We aimed to investigate whether parthanatos participates in the mechanism of seizure-induced hippocampal neuronal death.
Glutamate-mediated excitotoxicity cell model was used to study the mechanism of seizure-induced cell injury. Injection of kainic acid into the amygdala was used to establish the epileptic rat model. Corresponding biochemical tests were carried out on hippocampal tissues and HT22 cells following indicated treatments.
In vitro, glutamate time-dependently induced HT22 cell death, accompanied by parthanatos-related biochemical events. Pretreatment with PJ34 (PARP-1 inhibitor) or small interfering RNA-mediated PARP-1 knockdown effectively protected HT22 cells against glutamate-induced toxic effects and attenuated parthanatos-related biochemical events. Application of the antioxidant N-acetylcysteine (NAC) rescued HT22 cell death and reversed parthanatos-related biochemical events. In vivo, PJ34 and NAC afforded protection against SE-induced hippocampal neuronal damage and inhibited parthanatos-related biochemical events.
Parthanatos participates in glutamate-induced HT22 cell injury and hippocampal neuronal damage in rats following epileptic seizures. ROS might be the initiating factor during parthanatos.
癫痫发作或癫痫持续状态（SE）可导致海马神经元死亡，从而产生有害影响。细胞程序性死亡的一种新形式——PARP-1 过度激活的 parthanatos，其特征是多聚（ADP-核糖）聚合酶-1（PARP-1）过度激活、多聚 ADP-核糖聚合物过度合成、线粒体去极化以及凋亡诱导因子的核转位，在各种神经退行性疾病中均有观察到，但在癫痫中鲜有报道。我们旨在研究 parthanatos 是否参与癫痫发作引起的海马神经元死亡的机制。
采用谷氨酸介导的兴奋性毒性细胞模型研究癫痫发作引起细胞损伤的机制。采用杏仁核注射海人酸建立癫痫大鼠模型。对海马组织和 HT22 细胞进行相应的生化检测。
体外，谷氨酸可时间依赖性诱导 HT22 细胞死亡，并伴有 parthanatos 相关的生化事件。PARP-1 抑制剂 PJ34 预处理或 PARP-1 小干扰 RNA 敲低可有效保护 HT22 细胞免受谷氨酸诱导的毒性作用，并减弱 parthanatos 相关的生化事件。抗氧化剂 N-乙酰半胱氨酸（NAC）的应用可挽救 HT22 细胞死亡并逆转 parthanatos 相关的生化事件。体内，PJ34 和 NAC 可防止 SE 引起的海马神经元损伤，并抑制 parthanatos 相关的生化事件。
PARP-1 过度激活的 parthanatos 参与了谷氨酸诱导的 HT22 细胞损伤和癫痫发作后大鼠海马神经元损伤。ROS 可能是 parthanatos 发生的起始因素。
