Spatiotemporal pattern of neuronal injury induced by DFP in rats: A model for delayed neuronal cell death following acute OP intoxication
Spatiotemporal pattern of neuronal injury induced by DFP in rats: A model for delayed neuronal cell death following acute OP intoxication
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DOI：
10.1016/j.taap.2011.03.026
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发表时间：
2011-06-15
影响因子：
3.8
通讯作者：
Ford, Byron D.
中科院分区：
文献类型：
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作者：
Li, Yonggang;Lein, Pamela J.;Ford, Byron D.
有机磷（OP）神经毒素引起急性胆碱能毒性和癫痫发作，导致迟发性脑损伤和持续的神经症状。由于缺乏适当的动物模型，测试防止急性OP中毒延迟效应的新策略受到阻碍。在这项研究中，我们描述了OP二异丙基氟磷酸（DFP）急性中毒后细胞损伤的时空模式。成年雄性sprap - dawley大鼠在DFP （9 mg/kg, ip）给药前分别给予吡哆斯的明（0.1 mg/kg, im）和甲基硝酸阿托品（20 mg/kg, im）。注射DFP后，所有DFP治疗的动物在几分钟内出现中度至重度癫痫发作，但存活了72小时。注射DFP后1小时，皮质、海马、皮质下脑组织和小脑的AChE活性明显下降，这种抑制持续了72小时。通过氟玉B （FJB）标记对神经元损伤的分析显示，海马、皮质、杏仁核和丘脑的神经元细胞死亡延迟，但小脑没有。从DFP治疗后4小时开始，持续到72小时，尽管大脑区域之间的时间分布有所不同。注射DFP后24小时，FJB标记模式在大多数脑区与TUNEL染色相一致，FJB阳性细胞显示NeuN免疫反应性降低，但对星形胶质细胞（GFAP）、少突胶质细胞（O4）或巨噬细胞/小胶质细胞（ED1）标志物的免疫反应不阳性，表明DFP引起部分由细胞凋亡介导的区域特异性延迟神经元损伤。这些发现表明该模型用于测试神经保护策略的可行性，并为急性OP中毒后有效药物干预的治疗窗口提供了见解。(C) 2011爱思唯尔公司版权所有。
Organophosphate (OP) neurotoxins cause acute cholinergic toxicity and seizures resulting in delayed brain damage and persistent neurological symptoms. Testing novel strategies for protecting against delayed effects of acute OP intoxication has been hampered by the lack of appropriate animal models. In this study, we characterize the spatiotemporal pattern of cellular injury after acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague-Dawley rats received pyridostigmine (0.1 mg/kg, im) and atropine methylnitrate (20 mg/kg, im) prior to DFP (9 mg/kg, ip) administration. All DFP-treated animals exhibited moderate to severe seizures within minutes after DFP injection but survived up to 72 h. AChE activity was significantly depressed in the cortex, hippocampus, subcortical brain tissue and cerebellum at 1 h post-DFP injection and this inhibition persisted for up to 72 h. Analysis of neuronal injury by Fluoro-Jade B (FJB) labeling revealed delayed neuronal cell death in the hippocampus, cortex, amygdala and thalamus, but not the cerebellum, starting at 4 h and persisting until 72 h after DFP treatment, although temporal profiles varied between brain regions. At 24 h post-DFP injection, the pattern of FJB labeling corresponded to TUNEL staining in most brain regions, and FJB-positive cells displayed reduced NeuN immunoreactivity but were not immunopositive for astrocytic (GFAP), oligodendroglial (O4) or macrophage/microglial (ED1) markers, demonstrating that DFP causes a region-specific delayed neuronal injury mediated in part by apoptosis. These findings indicate the feasibility of this model for testing neuroprotective strategies, and provide insight regarding therapeutic windows for effective pharmacological intervention following acute OP intoxication. (C) 2011 Elsevier Inc. All rights reserved.