Chronic Epilepsy and Mossy Fiber Sprouting Following Organophosphate-Induced Status Epilepticus in Rats.
Chronic Epilepsy and Mossy Fiber Sprouting Following Organophosphate-Induced Status Epilepticus in Rats.
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DOI：
10.1124/jpet.123.001739
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发表时间：
2024-01-17
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有机磷酸盐（OP）化合物具有很高的毒性，包括杀虫剂和化学战神经毒剂。OP暴露抑制乙酰胆碱酯酶，引起胆碱能过度刺激，可演变为癫痫持续状态（SE）并产生致死性。此外，OP诱导的SE存活率与情绪和记忆功能障碍以及自发性复发性癫痫发作（SRS）相关。在雄性Sprague-Dawley大鼠中，我们评估了通过施用OP剂对氧磷（2 mg/kg，s.c.）氟磷酸二异丙酯（4 mg/kg，s.c.），或O-异丙基甲基氟膦酸酯（GB;沙林）（2 mg/kg，s.c.），紧接着注射阿托品和2-PAM在OP诱导SE发作后1小时，给予咪达唑仑以控制SE。在OP诱导SE后约6个月，使用视频和脑电图监测评估SRS。使用苏木精和伊红（H&E）进行组织学检查，而硫化银（Timm）染色用于评估苔藓纤维发芽（MFS）。在所有OP药物中，超过60%的OP诱导SE存活的大鼠发展为慢性SRS。H&E染色显示海马神经元明显丢失，而Timm染色显示齿状回内分子区域内存在广泛的MFS。这项研究表明，OP诱导的SE与海马神经元丢失，广泛的MFS，SRS的发展，所有慢性癫痫的标志。有机磷（OP）诱导的SE模型提供了一个独特的资源，以确定有助于神经病理学和慢性OP发病率的发展的分子机制。这些模型可以允许筛选针对OP毒性的有效治疗策略的靶向治疗剂。
Organophosphate (OP) compounds are highly toxic and include pesticides and chemical warfare nerve agents. OP exposure inhibits the acetylcholinesterase enzyme, causing cholinergic overstimulation that can evolve into status epilepticus (SE) and produce lethality. Furthermore, OP-induced SE survival is associated with mood and memory dysfunction and spontaneous recurrent seizures (SRS). In male Sprague–Dawley rats, we assessed hippocampal pathology and chronic SRS following SE induced by administration of OP agents paraoxon (2 mg/kg, s.c.), diisopropyl fluorophosphate (4 mg/kg, s.c.), or O-isopropyl methylphosphonofluoridate (GB; sarin) (2 mg/kg, s.c.), immediately followed by atropine and 2-PAM. At 1-hour post-OP–induced SE onset, midazolam was administered to control SE. Approximately 6 months after OP-induced SE, SRS were evaluated using video and electroencephalography monitoring. Histopathology was conducted using hematoxylin and eosin (H&E), while silver sulfide (Timm) staining was used to assess mossy fiber sprouting (MFS). Across all the OP agents, over 60% of rats that survived OP-induced SE developed chronic SRS. H&E staining revealed a significant hippocampal neuronal loss, while Timm staining revealed extensive MFS within the inner molecular region of the dentate gyrus. This study demonstrates that OP-induced SE is associated with hippocampal neuronal loss, extensive MFS, and the development of SRS, all hallmarks of chronic epilepsy. Models of organophosphate (OP)-induced SE offer a unique resource to identify molecular mechanisms contributing to neuropathology and the development of chronic OP morbidities. These models could allow the screening of targeted therapeutics for efficacious treatment strategies for OP toxicities.
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影响因子：
3.3
作者：
González EA;Calsbeek JJ;Tsai YH;Tang MY;Andrew P;Vu J;Berg EL;Saito NH;Harvey DJ;Supasai S;Gurkoff GG;Silverman JL;Lein PJ
通讯作者：
Lein PJ
影响因子：
3.4
作者：
Chao LL;Rothlind JC;Cardenas VA;Meyerhoff DJ;Weiner MW
通讯作者：
Weiner MW
影响因子：
3.4
作者：
Chapman, S;Kadar, T;Gilat, E
通讯作者：
Gilat, E
影响因子：
11.2
作者：
Bar-Klein, Guy;Klee, Rebecca;Loescher, Wolfgang
通讯作者：
Loescher, Wolfgang
影响因子：
5.6
作者：
Heng K;Haney MM;Buckmaster PS
通讯作者：
Buckmaster PS