Organophosphates (OPs) are valuable as pesticides in agriculture and for controlling deadly vector-borne illnesses; however, they are highly toxic and associated with many deleterious health effects in humans including long-term neurological impairments. Antidotal treatment regimens are available to combat the symptoms of acute OP toxicity, which result from the irreversible inhibition of acetylcholinesterase (AChE). However, there are no established treatments for the long-term neurological consequences of OP exposure. In addition to AChE, OPs can negatively affect multiple protein targets as well as biological processes such as axonal transport. Given the fundamental nature of axonal transport to neuronal health, we rationalized that this process might serve as a general focus area for novel therapeutic strategies against OP toxicity. In the studies described here, we employed a multi-target, phenotypic screening, and drug repurposing strategy for the evaluations of potential novel OP-treatments using a primary neuronal culture model and time-lapse live imaging microscopy. Two multi-target compounds, lithium chloride (LiCl) and methylene blue (MB), which are FDA-approved for other indications, were evaluated for their ability to prevent the negative effects of the OP, diisopropylfluorophosphate (DFP) on axonal transport. The results indicated that both LiCl and MB prevented DFP-induced impairments in anterograde and retrograde axonal transport velocities in a concentration dependent manner. While in vivo studies will be required to confirm our in vitro findings, these experiments support the potential of LiCl and MB as repurposed drugs for the treatment of the long-term neurological deficits associated with OP exposure (currently an unmet medical need).

中文翻译：

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多功能化合物氯化锂和亚甲基蓝可减轻二异丙基氟磷酸盐对大鼠皮层神经元轴突运输的负面影响。

有机磷酸酯（OPs）在农业中作为农药和控制致命的媒介传播疾病具有重要价值。然而，它们具有剧毒，并与包括长期神经功能缺损在内的许多有害健康的危害有关。可以使用解毒剂治疗方案来对抗由不可逆地抑制乙酰胆碱酯酶（AChE）引起的急性OP毒性症状。但是，尚无针对OP暴露的长期神经系统后果的既定治疗方法。除AChE外，OP还可能对多种蛋白质靶标以及诸如轴突运输等生物过程产生负面影响。考虑到轴突运输到神经元健康的基本性质，我们合理地认为该过程可能是针对OP毒性的新型治疗策略的总体重点领域。在这里描述的研究中，我们采用了多目标，表型筛选和药物重用策略，以使用主要的神经元培养模型和延时实时成像显微镜对潜在的新型OP治疗进行评估。已评估了FDA批准用于其他适应症的两种多目标化合物氯化锂（LiCl）和亚甲基蓝（MB）防止OP轴突运输的负面影响的能力，即二异丙基氟磷酸盐（DFP）。结果表明，LiCl和MB均以浓度依赖的方式阻止了DFP诱导的顺行和逆行轴突运输速度受损。虽然需要进行体内研究来确认我们的体外发现，