Organophosphate (OP) chemicals include pesticides such as parathion, and nerve gases such as sarin and soman and are considered major chemical threat agents. Acute OP exposure is associated with a cholinergic crisis and status epilepticus (SE). It is also known that the survivors of OP toxicity exhibit neurobehavioral deficits such as mood changes, depression, and memory impairment, and acquired epilepsy. Our research has focused on addressing the need to develop effective therapeutic agents that could be administered even after prolonged seizures and would prevent or lessen the chronic morbidity associated with OP-SE survival. We have developed rat survival models of OP pesticide metabolite paraoxon (POX) and nerve agent sarin surrogate diisopropyl fluorophosphate (DFP) induced SE that are being used to screen for medical countermeasures against an OP attack. Our research has focused on studying neuronal calcium (Ca2+) homeostatic mechanisms for identifying mechanisms and therapeutics for the expression of neurological morbidities associated with OP-SE survival. We have observed development of a "Ca2+ plateau" characterized by sustained elevations in neuronal Ca2+ levels in OP-SE surviving rats that coincided with the appearance of OP-SE chronic morbidities. These Ca2+ elevations had their origin in Ca2+ release from the intracellular stores such that blockade with antagonists like dantrolene, carisbamate, and levetiracetam lowered OP-SE mediated Ca2+ plateau and afforded significant neuroprotection. Since the Ca2+ plateau lasts for a prolonged period, our studies suggest that blocking it after the control of SE may represent a unique target for development of novel countermeasures to prevent long term Ca2+ mediated OP-SE neuropsychiatric comorbidities such as depression, anxiety, and acquired epilepsy (AE).

中文翻译：

---

基于钙稳态变化的新型疗法，用于治疗有机磷酸酯诱导的癫痫持续状态。

有机磷酸盐（OP）化学品包括对硫磷等杀虫剂，以及沙林和梭曼等神经气体，被认为是主要的化学威胁剂。急性OP暴露与胆碱能危机和癫痫持续状态（SE）相关。还已知OP毒性的幸存者表现出神经行为缺陷，例如情绪变化，抑郁和记忆障碍以及后天性癫痫。我们的研究集中在解决开发有效治疗剂的需求上，这些治疗剂即使在癫痫发作长时间后也可以给药，并且可以预防或减轻与OP-SE生存相关的慢性病。我们已经开发了OP农药代谢产物对氧磷（POX）和神经毒药沙林替代品二异丙基氟磷酸盐（DFP）诱导的SE的大鼠存活模型，这些模型用于筛选针对OP发作的医学对策。我们的研究集中在研究神经钙（Ca2 +）稳态机制，以鉴定与OP-SE存活相关的神经系统疾病的表达机制和治疗药物。我们已经观察到“ Ca2 +平台”的发展，其特征是在OP-SE存活的大鼠中神经元Ca2 +水平持续升高，与OP-SE慢性病的出现相吻合。这些Ca2 +升高的起因是来自细胞内存储区的Ca2 +释放，因此被拮抗剂如丹特林，卡立氨基甲酸酯，左乙拉西坦降低了OP-SE介导的Ca2 +平台并提供了显着的神经保护作用。由于Ca2 +平台持续时间较长，因此我们的研究表明，在SE控制后对其进行阻断可能代表了开发新对策的独特目标，该新对策可预防长期的Ca2 +介导的OP-SE神经精神病合并症，如抑郁症，焦虑症和获得性疾病。癫痫病（AE）。