Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat.
Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat.
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琥珀酸盐前药作为大鼠氟乙酸中毒期间急性代谢危机的治疗。
DOI：
10.1007/s11010-022-04589-9
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发表时间：
2023-06
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
--
作者：
氟乙酸钠（FA）是一种代谢性毒物，可全身抑制三羧酸（TCA）循环，导致能量不足，最终导致多器官衰竭。由于其高毒性，潜在的化学武器用途以及缺乏有效的解毒剂治疗，它对社会构成了重大威胁。在这项研究中，我们研究了细胞渗透性琥珀酸盐前药作为急性FA中毒的潜在治疗方法。我们假设琥珀酸前药可以绕过FA诱导的线粒体功能障碍，提供代谢支持，并防止急性FA中毒期间的代谢危机。为了验证这一假设，大鼠暴露于FA （0.75 mg/kg）和琥珀酸前药候选NV354。根据心脏和大脑线粒体呼吸、线粒体含量、代谢谱和组织病理学来评估治疗效果。在心脏中，FA增加了TCA代谢物柠檬酸盐浓度（+ 4.2倍，p < 0.01），降低了ATP水平（- 1.9倍，p < 0.001），证实了FA对TCA循环的抑制作用。心脏线粒体的高分辨率呼吸测量进一步揭示了线粒体复合体V （CV）相关代谢的损伤，磷酸化系统控制率降低（- 41%,p < 0.05）。抑制cv相关代谢是FA心脏毒性的一种新机制，这对药物开发具有影响，并且在给定剂量下NV354无法抵消。在脑内，FA诱导β-羟基丁酸的积累（+ 1.4倍，p < 0.05）和线粒体复合体I （CI）连接的氧化磷酸化（OXPHOSCI）的减少（- 20%,p < 0.01）， NV354成功缓解了后者。NV354的这一前景值得进一步研究，以确定其潜在的神经保护作用。
Sodium fluoroacetate (FA) is a metabolic poison that systemically inhibits the tricarboxylic acid (TCA) cycle, causing energy deficiency and ultimately multi-organ failure. It poses a significant threat to society because of its high toxicity, potential use as a chemical weapon and lack of effective antidotal therapy. In this study, we investigated cell-permeable succinate prodrugs as potential treatment for acute FA intoxication. We hypothesized that succinate prodrugs would bypass FA-induced mitochondrial dysfunction, provide metabolic support, and prevent metabolic crisis during acute FA intoxication. To test this hypothesis, rats were exposed to FA (0.75 mg/kg) and treated with the succinate prodrug candidate NV354. Treatment efficacy was evaluated based on cardiac and cerebral mitochondrial respiration, mitochondrial content, metabolic profiles and tissue pathology. In the heart, FA increased concentrations of the TCA metabolite citrate (+ 4.2-fold, p < 0.01) and lowered ATP levels (− 1.9-fold, p < 0.001), confirming the inhibition of the TCA cycle by FA. High-resolution respirometry of cardiac mitochondria further revealed an impairment of mitochondrial complex V (CV)-linked metabolism, as evident by a reduced phosphorylation system control ratio (− 41%, p < 0.05). The inhibition of CV-linked metabolism is a novel mechanism of FA cardiac toxicity, which has implications for drug development and which NV354 was unable to counteract at the given dose. In the brain, FA induced the accumulation of β-hydroxybutyrate (+ 1.4-fold, p < 0.05) and the reduction of mitochondrial complex I (CI)-linked oxidative phosphorylation (OXPHOSCI) (− 20%, p < 0.01), the latter of which was successfully alleviated by NV354. This promising effect of NV354 warrants further investigations to determine its potential neuroprotective effects.
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影响因子：
4.7
作者：
Demarest TG;Schuh RA;Waddell J;McKenna MC;Fiskum G
通讯作者：
Fiskum G
DOI：
10.1071/bi9850139
发表时间：
1985-01-01
期刊：
AUSTRALIAN JOURNAL OF BIOLOGICAL SCIENCES
影响因子：
--
作者：
MEAD, RJ;MOULDEN, DL;TWIGG, LE
通讯作者：
TWIGG, LE
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
影响因子：
5.2
作者：
DeLey Cox VE;Hartog MA;Pueblo E;Racine M;Jennings L;Tressler J;Tuet WY;Stone S;Pierce SA;Thompson L;Dukes A;Hoard-Fruchey H;Wong B;McCranor BJ
通讯作者：
McCranor BJ
影响因子：
7.9
作者：
Comfort N;Re DB
通讯作者：
Re DB