Department of Neuroscience and Experimental Therapeutics (M.J.N., D.S.R.) and Institute of Pharmacology and Neurotherapeutics (M.J.N., D.S.R.), School of Medicine, Texas A&M University Health Science Center, Bryan, Texas.
Department of Neuroscience and Experimental Therapeutics (M.J.N., D.S.R.) and Institute of Pharmacology and Neurotherapeutics (M.J.N., D.S.R.), School of Medicine, Texas A&M University Health Science Center, Bryan, Texas
J Pharmacol Exp Ther. 2024 Jan 17;388(2):451-468. doi: 10.1124/jpet.123.001763.
Children are much more susceptible to the neurotoxic effects of organophosphate (OP) pesticides and nerve agents than adults. OP poisoning in children leads to acute seizures and neuropsychiatric sequela, including the development of long-term disabilities and cognitive impairments. Despite these risks, there are few chronic rodent models that use pediatric OP exposure for studying neurodevelopmental consequences and interventions. Here, we investigated the protective effect of the neurosteroid ganaxolone (GX) on the long-term developmental impact of neonatal exposure to the OP compound, diisopropyl-fluorophosphate (DFP). Pediatric postnatal day-28 rats were acutely exposed to DFP, and at 3 and 10 months after exposure, they were evaluated using a series of cognitive and behavioral tests with or without the postexposure treatment of GX. Analysis of the neuropathology was performed after 10 months. DFP-exposed animals displayed significant long-term deficits in mood, anxiety, depression, and aggressive traits. In spatial and nonspatial cognitive tests, they displayed striking impairments in learning and memory. Analysis of brain sections showed significant loss of neuronal nuclei antigen(+) principal neurons, parvalbumin(+) inhibitory interneurons, and neurogenesis, along with increased astrogliosis, microglial neuroinflammation, and mossy fiber sprouting. These detrimental neuropathological changes are consistent with behavioral dysfunctions. In the neurosteroid GX-treated cohort, behavioral and cognitive deficits were significantly reduced and were associated with strong protection against long-term neuroinflammation and neurodegeneration. In conclusion, this pediatric model replicates the salient features of children exposed to OPs, and the protective outcomes from neurosteroid intervention support the viability of developing this strategy for mitigating the long-term effects of acute OP exposure in children. SIGNIFICANCE STATEMENT: An estimated 3 million organophosphate exposures occur annually worldwide, with children comprising over 30% of all victims. Our understanding of the neurodevelopmental consequences in children exposed to organophosphates is limited. Here, we investigated the long-term impact of neonatal exposure to diisopropyl-fluorophosphate in pediatric rats. Neurosteroid treatment protected against major deficits in behavior and memory and was well correlated with neuropathological changes. Overall, this pediatric model is helpful to screen novel therapies to mitigate long-term developmental deficits of organophosphate exposure.
儿童比成年人更容易受到有机磷（OP）农药和神经毒剂的神经毒性影响。儿童 OP 中毒可导致急性癫痫发作和神经精神后遗症，包括长期残疾和认知障碍的发展。尽管存在这些风险，但很少有慢性啮齿动物模型使用儿科 OP 暴露来研究神经发育后果和干预措施。在这里，我们研究了神经甾体 ganaxolone（GX）对新生儿接触 OP 化合物二异丙基氟膦（DFP）的长期发育影响的保护作用。儿科出生后第 28 天的大鼠急性暴露于 DFP，在暴露后 3 个月和 10 个月时，使用一系列认知和行为测试评估它们，这些测试有或没有 GX 的暴露后治疗。在 10 个月后进行神经病理学分析。DFP 暴露的动物表现出明显的情绪、焦虑、抑郁和攻击性特征的长期缺陷。在空间和非空间认知测试中，它们表现出明显的学习和记忆障碍。大脑切片分析显示神经元核抗原（+）主神经元、parvalbumin（+）抑制性中间神经元和神经发生显著丧失，同时伴有星形胶质细胞增生、小胶质细胞神经炎症和苔藓纤维发芽。这些有害的神经病理学变化与行为功能障碍一致。在神经甾体 GX 处理组中，行为和认知缺陷显著减少，并与长期神经炎症和神经退行性变的强烈保护作用相关。总之，这种儿科模型复制了儿童暴露于 OP 后的显著特征，神经甾体干预的保护作用支持开发这种策略以减轻儿童急性 OP 暴露的长期影响的可行性。
据估计，全世界每年发生 300 万起有机磷暴露事件，其中儿童占所有受害者的 30%以上。我们对接触有机磷的儿童的神经发育后果的了解有限。在这里，我们研究了儿科大鼠中新生期接触二异丙基氟膦的长期影响。神经甾体治疗可预防行为和记忆的主要缺陷，并与神经病理学变化密切相关。总的来说，这种儿科模型有助于筛选新的治疗方法来减轻有机磷暴露的长期发育缺陷。
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