Role of the calcium plateau in neuronal injury and behavioral morbidities following organophosphate intoxication.
Role of the calcium plateau in neuronal injury and behavioral morbidities following organophosphate intoxication.
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DOI：
10.1111/nyas.13122
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发表时间：
2016-06
影响因子：
5.2
通讯作者：
DeLorenzo RJ
中科院分区：
文献类型：
--
作者：
Deshpande LS;Blair RE;Phillips KF;DeLorenzo RJ
有机磷化学品包括神经毒剂和杀虫剂，人们越来越担心有机磷对平民发动化学袭击。目前的解毒剂对于限制与OP接触相关的立即死亡至关重要。然而，为了开发有效的治疗方法，需要进一步的研究来确定OP毒性存活后长期神经功能障碍的分子机制。我们开发了OP诱导的大鼠癫痫持续状态（SE）的生存模型，模拟OP中毒后的慢性死亡率和发病率。我们观察到OP SE后海马钙水平显著升高，这种升高在初始存活后持续数周。抑制细胞内钙诱导的钙释放的药物，如丹曲林、左乙莱西坦和carisbamate，降低了OP se介导的持续性钙升高。考虑到钙信号在调节行为和细胞死亡机制中的关键作用，靶向预防钙平台发展的药物可以增强神经保护，帮助降低发病率，改善OP SE存活后的预后。
Organophosphate (OP) chemicals include nerve agents and pesticides, and there is a growing concern of OP-based chemical attacks against civilians. Current antidotes are essential in limiting immediate mortality associated with OP exposure. However, further research is needed to identify molecular mechanisms underlying long-term neurological deficits following survival of OP toxicity in order to develop effective therapeutics. We have developed rat survival models of OP-induced status epilepticus (SE) that mimic chronic mortality and morbidity following OP intoxication. We have observed significant elevations in hippocampal calcium levels after OP SE that persisted for weeks following initial survival. Drugs inhibiting intracellular calcium–induced calcium release, such as dantrolene, levetiracetam, and carisbamate, lowered OP SE–mediated protracted calcium elevations. Given the critical role of calcium signaling in modulating behavior and cell death mechanisms, drugs targeted at preventing the development of the calcium plateau could enhance neuroprotection, help reduce morbidity, and improve outcomes following survival of OP SE.