Development of a Prolonged Calcium Plateau in Hippocampal Neurons in Rats Surviving Status Epilepticus Induced by the Organophosphate Diisopropylfluorophosphate
Development of a Prolonged Calcium Plateau in Hippocampal Neurons in Rats Surviving Status Epilepticus Induced by the Organophosphate Diisopropylfluorophosphate
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DOI：
10.1093/toxsci/kfq157
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发表时间：
2010-08-01
影响因子：
3.8
通讯作者：
DeLorenzo, Robert J.
中科院分区：
文献类型：
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作者：
Deshpande, Laxmikant S.;Carter, Dawn S.;DeLorenzo, Robert J.
有机磷（OP）化合物是有史以来最致命的化学武器之一，是乙酰胆碱酯酶的不可逆抑制剂。暴露于大多数OP会产生癫痫持续状态（SE）和严重的胆碱能症状，如果不进行治疗，这些症状是致命的。OP中毒的幸存者往往遭受不可逆的脑损伤和慢性神经系统疾病。尽管毛果芸香碱已被用于模拟OP暴露后的SE，但仍需要建立一种使用OP化合物的SE模型，以真实地模拟神经毒剂中毒的急性和长期影响。在这里，我们描述了一个OP诱导的SE使用二异丙基氟磷酸盐（DFP）的大鼠模型的发展。DFP诱导SE（4 mg/kg，sc）的死亡率、行为表现和脑电图（EEG）特征与神经毒剂报告的相同。然而，使用改进的DFP剂量方案和氯解磷定（25 mg/kg，im）、阿托品（2 mg/kg，ip）和地西泮（5 mg/kg，ip）治疗，获得了显著更高的存活率，使该模型成为研究OP暴露慢性效应的理想模型。此外，DFP处理产生N-甲基-D-天冬氨酸（NMDA）受体介导的海马神经元[Ca 2 +]（i）显著升高，在初始SE后持续数周。这些结果提供了直接的证据表明，DFP诱导的SE改变了Ca 2+动力学，这可能是与OP毒性相关的一些长期可塑性变化的基础。该模型非常适合于测试OP暴露的有效对策，并研究OP中毒后神经系统疾病的分子机制。
Organophosphate (OP) compounds are among the most lethal chemical weapons ever developed and are irreversible inhibitors of acetylcholinesterase. Exposure to majority of OP produces status epilepticus (SE) and severe cholinergic symptoms that if left untreated are fatal. Survivors of OP intoxication often suffer from irreversible brain damage and chronic neurological disorders. Although pilocarpine has been used to model SE following OP exposure, there is a need to establish a SE model that uses an OP compound in order to realistically mimic both acute and long-term effects of nerve agent intoxication. Here we describe the development of a rat model of OP-induced SE using diisopropylfluorophosphate (DFP). The mortality, behavioral manifestations, and electroencephalogram (EEG) profile for DFP-induced SE (4 mg/kg, sc) were identical to those reported for nerve agents. However, significantly higher survival rates were achieved with an improved dose regimen of DFP and treatment with pralidoxime chloride (25 mg/kg, im), atropine (2 mg/kg, ip), and diazepam (5 mg/kg, ip) making this model ideal to study chronic effects of OP exposure. Further, DFP treatment produced N-methyl-D-aspartate (NMDA) receptor-mediated significant elevation in hippocampal neuronal [Ca2+](i) that lasted for weeks after the initial SE. These results provided direct evidence that DFP-induced SE altered Ca2+ dynamics that could underlie some of the long-term plasticity changes associated with OP toxicity. This model is ideally suited to test effective countermeasures for OP exposure and study molecular mechanisms underlying neurological disorders following OP intoxication.