Peripheral and central effects of NADPH oxidase inhibitor, mitoapocynin, in a rat model of diisopropylfluorophosphate (DFP) toxicity.
Peripheral and central effects of NADPH oxidase inhibitor, mitoapocynin, in a rat model of diisopropylfluorophosphate (DFP) toxicity.
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DOI：
10.3389/fncel.2023.1195843
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发表时间：
2023
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
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作者：
有机磷酸盐（OP）是一种高毒性的化学神经毒剂，已被用于化学战。目前，还没有有效的医学对策（MCM）来减轻OP暴露的慢性影响。氧化应激是外周和中枢神经系统中OP诱导的细胞死亡和炎症的关键机制，并且不能通过可用的MCM减轻。NADPH氧化酶（NOX）是癫痫持续状态（SE）后活性氧（ROS）的主要产生者之一。在这项研究中，我们在OP毒性的大鼠二异丙基氟磷酸盐（DFP）模型中测试了脑靶向NOX抑制剂mitoapocynin（MPO）（10 mg/kg，口服）的疗效。在DFP暴露的动物中，MPO降低了血清中的氧化应激标志物亚硝酸盐、ROS和GSSG。此外，MPO显著降低DFP暴露后的促炎细胞因子IL-1β、IL-6和TNF-α。有一个显着的增加GP 91 phox，一个NOX 2亚基，在DFP暴露动物的大脑中1周后的挑战。然而，MPO治疗并不影响脑中NOX 2的表达。神经变性（NeuN和FJB）和神经胶质增生[小胶质细胞（IBA 1和CD 68）和星形胶质细胞（GFAP和C3）]定量显示，DFP暴露后神经变性和神经胶质增生显著增加。在DFP + MPO中观察到小胶质细胞和C3与GFAP共定位的边缘减少。本研究中使用的MPO给药方案（10 mg/kg）不影响小胶质细胞CD 68表达、星形胶质细胞计数或神经变性。MPO降低了血清中的DFP诱导的氧化应激和炎症标志物，但仅轻微减轻了脑中的影响。需要进行剂量优化研究，以确定MPO的有效剂量，以减轻DFP诱导的大脑变化。
Organophosphates (OP) are highly toxic chemical nerve agents that have been used in chemical warfare. Currently, there are no effective medical countermeasures (MCMs) that mitigate the chronic effects of OP exposure. Oxidative stress is a key mechanism underlying OP-induced cell death and inflammation in the peripheral and central nervous systems and is not mitigated by the available MCMs. NADPH oxidase (NOX) is one of the leading producers of reactive oxygen species (ROS) following status epilepticus (SE). In this study, we tested the efficacy of the mitochondrial-targeted NOX inhibitor, mitoapocynin (MPO) (10 mg/kg, oral), in a rat diisopropylfluorophosphate (DFP) model of OP toxicity. In DFP-exposed animals, MPO decreased oxidative stress markers nitrite, ROS, and GSSG in the serum. Additionally, MPO significantly reduced proinflammatory cytokines IL-1β, IL-6, and TNF-α post-DFP exposure. There was a significant increase in GP91phox, a NOX2 subunit, in the brains of DFP-exposed animals 1-week post-challenge. However, MPO treatment did not affect NOX2 expression in the brain. Neurodegeneration (NeuN and FJB) and gliosis [microglia (IBA1 and CD68), and astroglia (GFAP and C3)] quantification revealed a significant increase in neurodegeneration and gliosis after DFP-exposure. A marginal reduction in microglial cells and C3 colocalization with GFAP in DFP + MPO was observed. The MPO dosing regimen used in this study at 10 mg/kg did not affect microglial CD68 expression, astroglial count, or neurodegeneration. MPO reduced DFP-induced oxidative stress and inflammation markers in the serum but only marginally mitigated the effects in the brain. Dose optimization studies are required to determine the effective dose of MPO to mitigate DFP-induced changes in the brain.
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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
影响因子：
7.4
作者：
Dikalov, Sergey
通讯作者：
Dikalov, Sergey
DOI：
10.1124/jpet.115.230839
发表时间：
2016-03-01
影响因子：
3.5
作者：
Gao, Jie;Naughton, Sean X.;Terry, Alvin V., Jr.
通讯作者：
Terry, Alvin V., Jr.
影响因子：
6.6
作者：
Langley, Monica;Ghosh, Anamitra;Kanthasamy, Anumantha G.
通讯作者：
Kanthasamy, Anumantha G.
NADPH 氧化酶抑制剂罗布麻素可降低 D-半乳糖诱导的衰老模型大鼠耳蜗腹侧核线粒体功能障碍和细胞凋亡
影响因子：
4.2
作者：
Du, Zheng-De;Yu, Shukui;Gong, Shu-Sheng
通讯作者：
Gong, Shu-Sheng