Department of Molecular Biosciences, Davis School of Veterinary Medicine, University of California, 1089 Veterinary Medicine Drive, Davis, CA, 95616, USA.
Department of Pharmacology, School of Medicine, University of California, Davis, CA, 95616, USA.
Arch Toxicol. 2023 May;97(5):1355-1365. doi: 10.1007/s00204-023-03475-7. Epub 2023 Mar 13.
Hexahydro-1,3,5-trinitro-1,3,5-triazine, or Royal Demolition Explosive (RDX), is a major component of plastic explosives such as C-4. Acute exposures from intentional or accidental ingestion are a documented clinical concern, especially among young male U.S. service members in the armed forces. When ingested in large enough quantity, RDX causes tonic-clonic seizures. Previous in silico and in vitro experiments predict that RDX causes seizures by inhibiting α1β2γ2 γ-aminobutyric acid type A (GABA) receptor-mediated chloride currents. To determine whether this mechanism translates in vivo, we established a larval zebrafish model of RDX-induced seizures. After a 3 h of exposure to 300 µM RDX, larval zebrafish exhibited a significant increase in motility in comparison to vehicle controls. Researchers blinded to experimental group manually scored a 20-min segment of video starting at 3.5 h post-exposure and found significant seizure behavior that correlated with automated seizure scores. Midazolam (MDZ), an nonselective GABAR positive allosteric modulator (PAM), and a combination of Zolpidem (α1 selective PAM) and compound 2-261 (β2/3-selective PAM) were effective in mitigating RDX-triggered behavioral and electrographic seizures. These findings confirm that RDX induces seizure activity via inhibition of the α1β2γ2 GABAR and support the use of GABAR-targeted anti-seizure drugs for the treatment of RDX-induced seizures.
六氢-1,3,5-三硝基-1,3,5-三嗪，或简称旋风炸药（RDX），是 C-4 等塑料炸药的主要成分。有意或意外摄入引起的急性暴露是一个有记录的临床问题，尤其是在美国军队中的年轻男性军人中。当摄入的量足够大时，RDX 会引起强直阵挛性癫痫发作。先前的计算机模拟和体外实验预测，RDX 通过抑制α1β2γ2γ-氨基丁酸 A 型（GABA）受体介导的氯离子电流引起癫痫发作。为了确定这种机制是否在体内转化，我们建立了 RDX 诱导的癫痫发作的幼虫斑马鱼模型。在 300μM RDX 暴露 3 小时后，与载体对照相比，幼虫斑马鱼的运动性显著增加。对实验分组不知情的研究人员手动对暴露后 3.5 小时开始的 20 分钟视频片段进行评分，发现与自动癫痫评分相关的显著癫痫行为。咪达唑仑（MDZ），一种非选择性 GABAAR 正变构调节剂（PAM），以及唑吡坦（α1 选择性 PAM）和化合物 2-261（β2/3 选择性 PAM）的组合，在减轻 RDX 引发的行为和脑电图癫痫发作方面均有效。这些发现证实 RDX 通过抑制α1β2γ2GABAAR 引起癫痫活动，并支持使用 GABAAR 靶向抗癫痫药物治疗 RDX 引起的癫痫发作。
