Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA; Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Department of Neurology, Virginia Commonwealth University, Richmond, VA 23298, USA; Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Neurobiol Dis. 2020 Jan;133:104418. doi: 10.1016/j.nbd.2019.03.006. Epub 2019 Mar 12.
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 (Ca) homeostatic mechanisms for identifying mechanisms and therapeutics for the expression of neurological morbidities associated with OP-SE survival. We have observed development of a "Ca plateau" characterized by sustained elevations in neuronal Ca levels in OP-SE surviving rats that coincided with the appearance of OP-SE chronic morbidities. These Ca elevations had their origin in Ca release from the intracellular stores such that blockade with antagonists like dantrolene, carisbamate, and levetiracetam lowered OP-SE mediated Ca plateau and afforded significant neuroprotection. Since the Ca 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 Ca mediated OP-SE neuropsychiatric comorbidities such as depression, anxiety, and acquired epilepsy (AE).
有机磷（OP）化学物质包括杀虫剂如对硫磷，以及神经毒气如沙林和梭曼，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）有关。已知 OP 毒性的幸存者表现出神经行为缺陷，如情绪变化、抑郁和记忆障碍，以及获得性癫痫。我们的研究重点是开发有效的治疗剂，即使在长时间发作后也可以给药，并预防或减轻与 OP-SE 存活相关的慢性发病率。我们已经开发了 OP 农药代谢物对氧磷（POX）和神经毒剂沙林替代品二异丙基氟膦（DFP）诱导 SE 的大鼠存活模型，这些模型正在被用于筛选针对 OP 攻击的医疗对策。我们的研究重点是研究神经元钙（Ca）稳态机制，以确定与 OP-SE 存活相关的神经病理学表达的机制和治疗方法。我们观察到在 OP-SE 幸存大鼠中出现了“钙平台”，其特征是神经元 Ca 水平持续升高，这与 OP-SE 慢性发病率的出现相吻合。这些 Ca 升高起源于细胞内储存的 Ca 释放，因此用拮抗剂如丹曲林、卡马西平、和左乙拉西坦阻断，可降低 OP-SE 介导的 Ca 平台，并提供显著的神经保护作用。由于 Ca 平台持续时间较长，我们的研究表明，在控制 SE 后阻断它可能代表开发预防长期 Ca 介导的 OP-SE 神经精神合并症（如抑郁、焦虑和获得性癫痫（AE））的新型对策的独特目标。
