Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, PR China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, PR China; National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, 410008, Hunan, PR China.
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, China.
Free Radic Biol Med. 2022 Feb 1;179:109-118. doi: 10.1016/j.freeradbiomed.2021.12.268. Epub 2021 Dec 22.
Posttraumatic epilepsy (PTE) is a prevalent complication of brain trauma. Current anti-epileptic drugs available do not have satisfactory response to PTE. It is of desperate need to explore novel therapeutic approaches for curing PTE. Our prior work revealed that ferroptosis, a recently discovered mode of cell death, occurs in rodent model of PTE. In the present study, we aimed to further investigate the effect of ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, on seizure behavior and cognitive deficit in a mouse model of PTE. The preparation of PTE was performed by stereotaxical injection in the somatosensory cortex region of 50 mM FeCl. Seizure activity was assessed via Racine scoring and electroencephalogram analysis. PTE-related cognitive function was evaluated by novel object recognition and Morris water maze tests. Ferroptosis-related indices including glutathione peroxidase (GPx) activity and protein expressions of 4-hydroxynonenal (4-HNE) were detected using a commercial kit and immunofluorescence, respectively. It was found that treatment with Fer-1 significantly exerted protective effects against acute seizure and memory decline, although no evident effect on epileptic progression. Fer-1 also exhibited good tolerability and safety as we observed that it hardly influenced the body weight. Furthermore, it was noted that administration of Fer-1 suppressed ferroptosis-related indices including GPx activity and protein expressions of 4-HNE in hippocampus. These data altogether indicate that Fer-1 has potent therapeutic effects against seizures and cognitive impairment following PTE-induced brain insult. Fer-1 may act as a promising drug for curing PTE patients.
创伤后癫痫（PTE）是脑外伤的一种常见并发症。目前可用的抗癫痫药物对 PTE 的反应并不理想。迫切需要探索治疗 PTE 的新治疗方法。我们之前的工作表明，铁死亡，一种新发现的细胞死亡模式，发生在 PTE 的啮齿动物模型中。在本研究中，我们旨在进一步研究铁死亡抑制剂 Ferrostatine-1（Fer-1）对 PTE 小鼠模型中癫痫发作行为和认知缺陷的影响。通过立体定向注射 50mMFeCl 在体感皮层区域制备 PTE。通过 Racine 评分和脑电图分析评估癫痫发作活动。通过新物体识别和 Morris 水迷宫测试评估与 PTE 相关的认知功能。使用商业试剂盒和免疫荧光分别检测谷胱甘肽过氧化物酶 (GPx) 活性和 4-羟基壬烯醛 (4-HNE) 的蛋白表达等铁死亡相关指标。结果发现，Fer-1 治疗可显著对抗急性癫痫发作和记忆减退，但对癫痫进展无明显影响。Fer-1 还表现出良好的耐受性和安全性，因为我们观察到它几乎不影响体重。此外，还注意到 Fer-1 给药可抑制海马中与铁死亡相关的指标，包括 GPx 活性和 4-HNE 的蛋白表达。这些数据表明 Fer-1 对 PTE 引起的脑损伤后的癫痫发作和认知障碍具有潜在的治疗作用。Fer-1 可能是治疗 PTE 患者的有希望的药物。
