Targeting glutamate receptors with IEM-1925: A strategy against soman-induced status epilepticus and neurodegeneration

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology Pub Date : 2026-03-01 Epub Date: 2026-01-09 DOI:10.1016/j.neuro.2026.103389

Yuxin Lin, Qian Jin, Yuanqing Chen, Jingyan Wang, Yi Zhang, Manzhu Cao, Jingjing Shi, Liqin Li

{"title":"Targeting glutamate receptors with IEM-1925: A strategy against soman-induced status epilepticus and neurodegeneration","authors":"Yuxin Lin, Qian Jin, Yuanqing Chen, Jingyan Wang, Yi Zhang, Manzhu Cao, Jingjing Shi, Liqin Li","doi":"10.1016/j.neuro.2026.103389","DOIUrl":null,"url":null,"abstract":"<div><div>Exposure to organophosphorus nerve agents (OPNAs) like soman frequently develops status epilepticus (SE), leading to brain damage. Existing antiseizure medications (e.g., diazepam, DZP) often demonstrate insufficient efficacy. To develop more effective treatments for OPNA-induced seizures, this study evaluated the efficacy of glutamate receptor antagonists with distinct mechanisms of action in a soman-induced rat seizure model. After 5 min of subcutaneous exposure to 110 μg/kg soman, which induced SE, rats received intraperitoneal injections (10 mg/kg) of perampanel (PER), fanapanel (FNP), IEM-1925 (IEM), or DZP. The results showed that IEM significantly suppressed seizure activity and improved survival. The survival rate of the vehicle-treated control group was 31.25 %, whereas DZP, FNP, and IEM increased survival rates to 50 %, 43.75 %, and 56.25 % respectively. Electroencephalographic (EEG) recordings for 24 h indicated that both DZP and IEM controlled soman-induced SE. However, while DZP initially blocked the onset of seizures, they recurred after its transient anticonvulsant effect wore off. In contrast, IEM reduced behavioral convulsion intensity and total duration of SE. Histopathological examinations (HE, Nissl, immunohistochemistry, and immunofluorescence) showed that IEM attenuated hippocampal CA1, CA2, and DG neuronal damage. Behavioral tests (open field, novel object recognition, and Y maze) confirmed IEM outperformed DZP and the solvent-treated group in ameliorating soman-induced anxiety, cognitive dysfunction, and memory impairment. In conclusion, IEM demonstrates potent triple effects-antiseizure, neuroprotective, and cognitive improving in soman exposure model, providing a novel therapeutic strategy and candidate drug for the medical treatment of OPNAs poisoning.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103389"},"PeriodicalIF":3.9000,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurotoxicology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0161813X26000100","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2026/1/9 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Exposure to organophosphorus nerve agents (OPNAs) like soman frequently develops status epilepticus (SE), leading to brain damage. Existing antiseizure medications (e.g., diazepam, DZP) often demonstrate insufficient efficacy. To develop more effective treatments for OPNA-induced seizures, this study evaluated the efficacy of glutamate receptor antagonists with distinct mechanisms of action in a soman-induced rat seizure model. After 5 min of subcutaneous exposure to 110 μg/kg soman, which induced SE, rats received intraperitoneal injections (10 mg/kg) of perampanel (PER), fanapanel (FNP), IEM-1925 (IEM), or DZP. The results showed that IEM significantly suppressed seizure activity and improved survival. The survival rate of the vehicle-treated control group was 31.25 %, whereas DZP, FNP, and IEM increased survival rates to 50 %, 43.75 %, and 56.25 % respectively. Electroencephalographic (EEG) recordings for 24 h indicated that both DZP and IEM controlled soman-induced SE. However, while DZP initially blocked the onset of seizures, they recurred after its transient anticonvulsant effect wore off. In contrast, IEM reduced behavioral convulsion intensity and total duration of SE. Histopathological examinations (HE, Nissl, immunohistochemistry, and immunofluorescence) showed that IEM attenuated hippocampal CA1, CA2, and DG neuronal damage. Behavioral tests (open field, novel object recognition, and Y maze) confirmed IEM outperformed DZP and the solvent-treated group in ameliorating soman-induced anxiety, cognitive dysfunction, and memory impairment. In conclusion, IEM demonstrates potent triple effects-antiseizure, neuroprotective, and cognitive improving in soman exposure model, providing a novel therapeutic strategy and candidate drug for the medical treatment of OPNAs poisoning.

查看原文本刊更多论文

用IEM-1925靶向谷氨酸受体：对抗索曼诱导的癫痫持续状态和神经变性的策略。

暴露于有机磷神经毒剂（OPNAs）如索曼经常发展癫痫持续状态（SE），导致脑损伤。现有的抗癫痫药物（如地西泮、DZP）往往疗效不足。为了开发更有效的治疗opna诱导癫痫发作的方法，本研究在soman诱导的大鼠癫痫发作模型中评估了具有不同作用机制的谷氨酸受体拮抗剂的疗效。大鼠皮下暴露于110μg/kg索曼诱导SE 5min后，腹腔注射perampanel （PER）、fanapanel （FNP）、IEM-1925 （IEM）或DZP （10mg/kg）。结果显示，IEM显著抑制癫痫发作活动，提高生存率。对照组的存活率为31.25%，而DZP、FNP和IEM分别使存活率提高到50%、43.75%和56.25%。24小时的脑电图记录显示，DZP和IEM均能控制soman诱导的SE。然而，虽然DZP最初阻断了癫痫发作，但在其短暂抗惊厥作用消失后，癫痫发作再次发生。相比之下，IEM降低了行为惊厥的强度和SE的总持续时间。组织病理学检查（HE, Nissl，免疫组织化学和免疫荧光）显示IEM减轻了海马CA1， CA2和DG神经元损伤。行为测试（开放领域、新物体识别和Y迷宫）证实，IEM在改善人体诱发的焦虑、认知功能障碍和记忆障碍方面优于DZP和溶剂治疗组。综上所述，IEM在人体暴露模型中表现出抗癫痫、神经保护和认知改善的三重效应，为OPNAs中毒的医学治疗提供了一种新的治疗策略和候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Neurotoxicology 医学-毒理学

CiteScore

6.80

自引率

5.90%

发文量

161

审稿时长

70 days

期刊介绍： NeuroToxicology specializes in publishing the best peer-reviewed original research papers dealing with the effects of toxic substances on the nervous system of humans and experimental animals of all ages. The Journal emphasizes papers dealing with the neurotoxic effects of environmentally significant chemical hazards, manufactured drugs and naturally occurring compounds.