The NADPH Oxidase Inhibitor, Mitoapocynin, Mitigates DFP-Induced Reactive Astrogliosis in a Rat Model of Organophosphate Neurotoxicity.
The NADPH Oxidase Inhibitor, Mitoapocynin, Mitigates DFP-Induced Reactive Astrogliosis in a Rat Model of Organophosphate Neurotoxicity.
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DOI：
10.3390/antiox12122061
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发表时间：
2023-11-30
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影响因子：
--
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中科院分区：
文献类型：
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NADPH氧化酶（NOX）是超氧化物的主要介质，在二异丙基氟磷酸盐（DFP）中毒后促进氧化应激、神经变性和神经炎症。尽管口服线粒体靶向NOX抑制剂mitoapocynin （MPO, 10 mg/kg）可降低外周氧化应激和促炎细胞因子，但其对dfp暴露大鼠脑区的作用有限。在这项研究中，我们将MPO封装在基于1,6-双（对羧基苯氧基）己烷（CPH）和癸二酸酐（SA）的聚酸酐纳米颗粒（NPs）中，以增强药物向大脑的传递，并与高剂量的MPO （30 mg/kg）进行比较。在8天的大鼠DFP模型研究中，分析了NOX2 （GP91phox）调控和小胶质细胞（IBA1）形态学，以确定MPO-NP与mpo -口服的疗效。与对照组相比，dfp暴露的动物表现出NOX2的显著上调，小胶质细胞突起的长度和数量减少，表明小胶质细胞反应性。MPO处理均未减弱DFP效应。无论治疗方式如何，dfp暴露组的神经变性（FJB+NeuN）显著增加。有趣的是，DFP+ mpo处理动物的神经元损失与对照组没有显著差异。口服mpo可挽救海马CA1区抑制性神经元损失。值得注意的是，MPO-NP和MPO-oral显著减少星形胶质细胞增生（绝对GFAP计数）和反应性胶质细胞增生（C3+GFAP）。对星形胶质细胞内正向钾通道（Kir4.1）的分析显示，DFP+VEH组脑区显著减少，但MPO没有影响。总的来说，np包封和口服MPO具有相似的效果。我们的研究结果表明，MPO有效地减轻了dfp诱导的几个关键脑区域的反应性星形胶质细胞增生，并保护CA1中的神经元，这可能对自发性癫痫发作和行为合并症有长期有益的影响。需要长期遥测和行为研究以及MPO的不同给药方案来了解其治疗潜力。
NADPH oxidase (NOX) is a primary mediator of superoxides, which promote oxidative stress, neurodegeneration, and neuroinflammation after diisopropylfluorophosphate (DFP) intoxication. Although orally administered mitoapocynin (MPO, 10 mg/kg), a mitochondrial-targeted NOX inhibitor, reduced oxidative stress and proinflammatory cytokines in the periphery, its efficacy in the brain regions of DFP-exposed rats was limited. In this study, we encapsulated MPO in polyanhydride nanoparticles (NPs) based on 1,6-bis(p-carboxyphenoxy) hexane (CPH) and sebacic anhydride (SA) for enhanced drug delivery to the brain and compared with a high oral dose of MPO (30 mg/kg). NOX2 (GP91phox) regulation and microglial (IBA1) morphology were analyzed to determine the efficacy of MPO-NP vs. MPO-oral in an 8-day study in the rat DFP model. Compared to the control, DFP-exposed animals exhibited significant upregulation of NOX2 and a reduced length and number of microglial processes, indicative of reactive microglia. Neither MPO treatment attenuated the DFP effect. Neurodegeneration (FJB+NeuN) was significantly greater in DFP-exposed groups regardless of treatment. Interestingly, neuronal loss in DFP+MPO-treated animals was not significantly different from the control. MPO-oral rescued inhibitory neuronal loss in the CA1 region of the hippocampus. Notably, MPO-NP and MPO-oral significantly reduced astrogliosis (absolute GFAP counts) and reactive gliosis (C3+GFAP). An analysis of inwardly rectifying potassium channels (Kir4.1) in astroglia revealed a significant reduction in the brain regions of the DFP+VEH group, but MPO had no effect. Overall, both NP-encapsulated and orally administered MPO had similar effects. Our findings demonstrate that MPO effectively mitigates DFP-induced reactive astrogliosis in several key brain regions and protects neurons in CA1, which may have long-term beneficial effects on spontaneous seizures and behavioral comorbidities. Long-term telemetry and behavioral studies and a different dosing regimen of MPO are required to understand its therapeutic potential.
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影响因子：
5.3
作者：
Djukic, Biljana;Casper, Kristen B.;McCarthy, Ken D.
通讯作者：
McCarthy, Ken D.
影响因子：
5.3
作者：
Gage M;Putra M;Gomez-Estrada C;Golden M;Wachter L;Gard M;Thippeswamy T
通讯作者：
Thippeswamy T
DOI：
10.1016/j.bbadis.2013.09.007
发表时间：
2014-08
影响因子：
6.2
作者：
Jin, Huajun;Kanthasamy, Arthi;Ghosh, Anamitra;Anantharam, Vellareddy;Kalyanaraman, Balaraman;Kanthasamy, Anumantha G.
通讯作者：
Kanthasamy, Anumantha G.
DOI：
10.1124/jpet.123.001836
发表时间：
2024-01-17
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
通讯作者：
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影响因子：
4.3
作者：
Green, Tabitha R. F.;Murphy, Sean M.;Moreno-Montano, Maria P.;Audinat, Etienne;Rowe, Rachel K.
通讯作者：
Rowe, Rachel K.