Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning.
Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning.
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DOI：
10.1038/s41598-022-24472-3
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发表时间：
2022-11-25
影响因子：
4.6
通讯作者：
Kilbaugh TJ
中科院分区：
文献类型：
--
作者：
Piel S;Janowska JI;Ward JL;McManus MJ;Jose JS;Starr J;Sheldon M;Clayman CL;Elmér E;Hansson MJ;Jang DH;Karlsson M;Ehinger JK;Kilbaugh TJ
农药每年在全世界造成数亿起急性中毒病例，其中有机磷（OP）是所有农药相关死亡的主要原因。OP抑制乙酰胆碱酯酶，导致中枢和外周神经系统受损。当前的护理标准（SOC）可缓解急性神经系统、心血管和呼吸道症状，并降低短期死亡率。然而，幸存者往往表现出显着的神经系统后遗症。这突出了进一步开发具有新靶点的连续疗法的迫切需要。虽然AChE的抑制被认为是损伤的主要机制，但线粒体功能障碍和由此产生的代谢危机可能导致这些药物的总体毒性。我们假设，脑靶向琥珀酸酯前药NV354将支持线粒体功能，并减少OP二异丙基氟磷酸盐（DFP）急性中毒期间的脑损伤。为此，我们开发了急性DFP中毒的大鼠模型，并评估了NV354作为阿托品和解磷定治疗SOC的后续治疗的功效。我们证明，NV354，与阿托品和解磷定治疗相结合，显着改善脑线粒体复合物IV相关的呼吸和减少的迹象，脑损伤的啮齿动物模型中的急性DFP暴露。
Pesticides account for hundreds of millions of cases of acute poisoning worldwide each year, with organophosphates (OPs) being responsible for the majority of all pesticide-related deaths. OPs inhibit the enzyme acetylcholinesterase (AChE), which leads to impairment of the central- and peripheral nervous system. Current standard of care (SOC) alleviates acute neurologic-, cardiovascular- and respiratory symptoms and reduces short term mortality. However, survivors often demonstrate significant neurologic sequelae. This highlights the critical need for further development of adjunctive therapies with novel targets. While the inhibition of AChE is thought to be the main mechanism of injury, mitochondrial dysfunction and resulting metabolic crisis may contribute to the overall toxicity of these agents. We hypothesized that the mitochondrially targeted succinate prodrug NV354 would support mitochondrial function and reduce brain injury during acute intoxication with the OP diisopropylfluorophosphate (DFP). To this end, we developed a rat model of acute DFP intoxication and evaluated the efficacy of NV354 as adjunctive therapy to SOC treatment with atropine and pralidoxime. We demonstrate that NV354, in combination with atropine and pralidoxime therapy, significantly improved cerebral mitochondrial complex IV-linked respiration and reduced signs of brain injury in a rodent model of acute DFP exposure.
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影响因子：
13.3
作者：
Eddleston, M;Szinicz, L;Eyer, P;Buckley, N
通讯作者：
Buckley, N
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：
2.5
作者：
Arun, Peethambaran;Abu-Taleb, Rania;Nambiar, Madhusoodana P.
通讯作者：
Nambiar, Madhusoodana P.
影响因子：
4.6
作者：
Brenet A;Somkhit J;Hassan-Abdi R;Yanicostas C;Romain C;Bar O;Igert A;Saurat D;Taudon N;Dal-Bo G;Nachon F;Dupuis N;Soussi-Yanicostas N
通讯作者：
Soussi-Yanicostas N
影响因子：
16.6
作者：
Ehinger JK;Piel S;Ford R;Karlsson M;Sjövall F;Frostner EÅ;Morota S;Taylor RW;Turnbull DM;Cornell C;Moss SJ;Metzsch C;Hansson MJ;Fliri H;Elmér E
通讯作者：
Elmér E