A Pediatric Rat Model of Organophosphate-Induced Refractory Status Epilepticus: Characterization of Long-Term Epileptic Seizure Activity, Neurologic Dysfunction and Neurodegeneration.
A Pediatric Rat Model of Organophosphate-Induced Refractory Status Epilepticus: Characterization of Long-Term Epileptic Seizure Activity, Neurologic Dysfunction and Neurodegeneration.
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DOI：
10.1124/jpet.123.001794
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发表时间：
2024-01-17
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影响因子：
--
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儿童非常容易受到有机磷的神经毒性影响，这可能会导致神经元发育缺陷，包括智力残疾、自闭症、癫痫和相关的合并症。不幸的是，目前还没有专门的儿科OP神经毒性模型。在这项研究中，我们建立了一种由OP二异丙基氟磷酸盐(DFP)诱导的儿童大鼠癫痫持续状态(SE)模型，并对其对长期神经预后的影响进行了研究。出生后第21天，大鼠接受含有标准解毒剂的DFP方案。对进行性行为恶化进行了为期三个月的评估。通过视频脑电记录监测癫痫发作、发作性放电、高频振荡(HFO)和发作间期棘波的发展。组织学−体视学分析评估神经变性、神经炎症和形态异常。暴露于DFP的SE后动物在暴露后1、2和3个月表现出显著高于年龄匹配的对照组的焦虑和抑郁水平。接触DFP的动物表现出攻击性行为和物体识别记忆的显著下降，以及空间学习和记忆的显著损害。暴露于DFP的动物有显著的电信号异常，表现为癫痫发作、发作性放电、HFO和发作间歇性棘波，提示慢性癫痫。神经病理学分析显示，主神经元和抑制性中间神经元明显减少，反应性小胶质细胞和海马区和其他脑区的神经炎症明显增加。接触DFP的动物也表现出苔藓纤维发芽，表明网络形成受损。DFP所致的长期癫痫发作和神经精神功能障碍与神经病理缺陷相一致。总的来说，这个儿科模型显示了许多慢性后遗症的特征，让人想起儿童暴露在OP中，这表明它将是一个有价值的工具，用于研究病理机制和潜在的治疗策略，以减轻OP的长期神经毒性。数以百万计的儿童暴露在农业或化学事故中使用的有机磷(OP)。这项研究调查了新生儿长期接触OP化学物质二异丙基氟磷酸盐(DFP)对成年后神经行为和神经发育结果的影响。接触DFP导致了长期的行为异常、癫痫发作和双侧脑缺陷，并在儿童OP神经毒性中出现了一系列神经后遗症。因此，该模型提供了一种新的工具来探索治疗干预措施，以减轻暴露在OP诱导的癫痫发作和癫痫持续状态下的儿童的长期神经毒性效应。
Children are highly vulnerable to the neurotoxic effects of organophosphates (OPs), which can cause neuronal developmental defects, including intellectual disability, autism, epilepsy, and related comorbidities. Unfortunately, no specific pediatric OP neurotoxicity model currently exists. In this study, we developed and characterized a pediatric rat model of status epilepticus (SE) induced by the OP diisopropylfluorophosphate (DFP) and examined its impact on long-term neurological outcomes. Postnatal day 21 rats were exposed to a DFP regimen with standard antidotes. Progressive behavioral deteriorations were assessed over a three-month period. Development of epileptic seizures, ictal discharges, high-frequency oscillations (HFOs), and interictal spikes were monitored by video-electroencephalography recordings. Histology−stereology analysis was performed to assess neurodegeneration, neuroinflammation, and morphologic abnormalities. DFP-exposed, post-SE animals exhibited significantly elevated levels of anxiety and depression than age-matched controls at 1, 2, and 3 months post-exposure. DFP-exposed animals displayed aggressive behavior and a marked decline in object recognition memory, as well as prominent impairment in spatial learning and memory. DFP-exposed animals had striking electrographic abnormalities with the occurrence of displayed epileptic seizures, ictal discharges, HFOs, and interictal spikes, suggesting chronic epilepsy. Neuropathological analysis showed substantially fewer principal neurons and inhibitory interneurons with a marked increase in reactive microglia and neuroinflammation in the hippocampus and other brain regions. DFP-exposed animals also exhibited mossy fiber sprouting indicating impaired network formations. Long-term epileptic seizures and neuropsychiatric functional deficits induced by DFP were consistent with neuropathological defects. Collectively, this pediatric model displays many hallmarks of chronic sequelae reminiscent of children exposed to OPs, suggesting that it will be a valuable tool for investigating pathologic mechanisms and potential treatment strategies to attenuate long-term OP neurotoxicity. Millions of children are exposed to organophosphates (OPs) used in agriculture or chemical incidents. This study investigated the long-term impact of neonatal exposure to the OP chemical diisopropylfluorophosphate (DFP) on neurobehavioral and neurodevelopmental outcomes in adulthood. DFP exposure caused long-lasting behavioral abnormalities, epileptic seizures, and bilateral brain defects with an array of neurological sequelae seen in children’s OP neurotoxicity. Thus, this model provides a novel tool to explore therapeutic interventions that mitigate long-term neurotoxic effects of children exposed to OP-induced seizures and status epilepticus.
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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
影响因子：
2.7
作者：
ENNACEUR, A;DELACOUR, J
通讯作者：
DELACOUR, J
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
DOI：
10.1124/jpet.114.217299
发表时间：
2014-11-01
影响因子：
3.5
作者：
Apland, James P.;Aroniadou-Anderjaska, Vassiliki;Braga, Maria F. M.
通讯作者：
Braga, Maria F. M.