Protective Activity of Novel Hydrophilic Synthetic Neurosteroids on Organophosphate Status Epilepticus-induced Chronic Epileptic Seizures, Non-Convulsive Discharges, High-Frequency Oscillations, and Electrographic Ictal Biomarkers.
Protective Activity of Novel Hydrophilic Synthetic Neurosteroids on Organophosphate Status Epilepticus-induced Chronic Epileptic Seizures, Non-Convulsive Discharges, High-Frequency Oscillations, and Electrographic Ictal Biomarkers.
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DOI：
10.1124/jpet.123.001817
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发表时间：
2024-01-17
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影响因子：
--
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神经毒剂和有机磷酸酯 (OP) 是神经毒性化学物质，可诱发急性癫痫发作、癫痫持续状态 (SE) 和死亡。长期神经系统和神经退行性影响会在 OP 暴露后数月至数年显现。目前的苯二氮卓类抗惊厥药无法有效预防这种长期的神经行为和神经病理学变化。 OP中毒需要新型有效的抗惊厥药，特别是为了减轻急性暴露后的长期后遗症。我们在 OP 暴露模型中开发了神经类固醇作为新型抗惊厥药和神经保护剂。在这项研究中，我们评估了新型合成神经类固醇在 SE 大鼠 OP 模型中预防慢性癫痫和过度兴奋性发作事件发展的长期疗效。大鼠暴露于 OP 神经毒剂替代二异丙基氟磷酸酯 (DFP)，实验组在暴露后 40 分钟使用合成神经类固醇伐拉沙诺龙 (VX) 或赖沙沙诺龙 (LX) 与咪达唑仑联合治疗。监测视频脑电图两个月，以评估自发性复发性癫痫发作（SRS）、癫痫样放电、发作间期尖峰和高频振荡（HFO）。在接触 DFP 的 60 天内，大鼠出现慢性癫痫，其特征是频繁的 SRS、癫痫样放电和 HFO。 LX 治疗与癫痫发生率和总体癫痫负担的剂量依赖性减少相关，同时 SRS 和癫痫样放电显着减少。它还显着减少了 HFO 癫痫生物标志物和发作间期尖峰的发生，表明潜在的疾病缓解活性。同样，神经类固醇类似物 VX 也显着减弱 SRS、放电、HFO 和发作事件。这些结果证明了合成神经类固醇在 OP 暴露后 SE 模型中的长期保护作用，表明它们具有预防癫痫和发作异常的改善疾病的潜力。神经毒剂和有机磷 (OP) 暴露的影响是持久的，幸存者会遭受许多毁灭性的慢性神经功能障碍。目前，尚无特定疗法可预防 OP 暴露带来的灾难性影响。我们建议激活强直抑制的合成神经类固醇为预防OP中毒的长期神经系统影响提供了可行的选择。这项研究的结果揭示了两种新型合成神经类固醇在预防 OP 诱发 SE 后癫痫发生和慢性癫痫发作方面具有改善疾病的潜力。
Nerve agents and organophosphates (OP) are neurotoxic chemicals that induce acute seizures, status epilepticus (SE), and mortality. Long-term neurologic and neurodegenerative effects manifest months to years after OP exposure. Current benzodiazepine anticonvulsants are ineffective in preventing such long-term neurobehavioral and neuropathological changes. New and effective anticonvulsants are needed for OP intoxication, especially for mitigating the long-term sequelae after acute exposure. We developed neurosteroids as novel anticonvulsants and neuroprotectants in OP exposure models. In this study, we evaluated the long-term efficacy of novel synthetic neurosteroids in preventing the development of chronic epilepsy and hyperexcitable ictal events in a rat OP model of SE. Rats were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP), and the experimental groups were treated with the synthetic neurosteroid valaxanolone (VX) or lysaxanolone (LX) 40 minutes post-exposure in conjunction with midazolam. Video-electroencephalography was monitored for two months to assess spontaneous recurrent seizures (SRS), epileptiform discharges, interictal spikes, and high-frequency oscillations (HFOs). Within 60 days of DFP exposure, rats developed chronic epilepsy characterized by frequent SRS, epileptiform discharges, and HFOs. LX treatment was associated with a dose-dependent reduction of epilepsy occurrence and overall seizure burden with a significant decrease in SRS and epileptiform discharges. It also significantly reduced the occurrence of epileptic biomarkers of HFOs and interictal spikes, indicating potential disease-modifying activity. Similarly, the neurosteroid analog VX also significantly attenuated SRS, discharges, HFOs, and ictal events. These results demonstrate the long-term protective effects of synthetic neurosteroids in the OP-exposed post-SE model, indicating their disease-modifying potential to prevent epilepsy and ictal abnormalities. The effects of nerve agents and organophosphate (OP) exposure are persistent, and survivors suffer from a number of devastating, chronic neurological dysfunctions. Currently, there is no specific therapy for preventing this disastrous impact of OP exposure. We propose synthetic neurosteroids that activate tonic inhibition provide viable options for preventing the long-term neurological effects of OP intoxication. The results from this study reveal the disease-modifying potential of two novel synthetic neurosteroids in preventing epileptogenesis and chronic epileptic seizures after OP-induced SE.
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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
年轻墨西哥裔美国儿童的有机磷酸农药暴露和神经发育。
影响因子：
10.4
作者：
Eskenazi, Brenda;Marks, Amy R.;Bradman, Asa;Harley, Kim;Barr, Dana B.;Johnson, Caroline;Morga, Norma;Jewell, Nicholas A.
通讯作者：
Jewell, Nicholas A.
影响因子：
7.7
作者：
Ewell, Laura A.;Fischer, Kyle B.;Leutgeb, Jill K.
通讯作者：
Leutgeb, Jill K.
DOI：
10.1111/j.1749-6632.2010.05445.x
发表时间：
2010-01-01
期刊：
YEAR IN COGNITIVE NEUROSCIENCE 2010
影响因子：
--
作者：
Adolphs, Ralph
通讯作者：
Adolphs, Ralph
影响因子：
6.6
作者：
Kennedy, Sidney H.;Milev, Roumen;Ravindran, Arun V.
通讯作者：
Ravindran, Arun V.