Te Jerez A, Spradling-Reeves Kimberly D, Dillman James F, Wallqvist Anders
Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Materiel Command, ATTN: MCMR-TT, 504 Scott Street, Fort Detrick, MD 21702-5012, United States.
Cell and Molecular Biology Branch, U.S. Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010, United States.
Brain Res. 2015 Aug 27;1618:136-48. doi: 10.1016/j.brainres.2015.05.034. Epub 2015 Jun 4.
Exposure to organophosphate (OP) nerve agents, such as sarin, may lead to uncontrolled seizures and irreversible brain injury and neuropathology. In rat studies, a median lethal dose of sarin leads to approximately half of the animals developing seizures. Whereas previous studies analyzed transcriptomic effects associated with seizing sarin-exposed rats, our study focused on the cohort of sarin-exposed rats that did not develop seizures. We analyzed the genomic changes occurring in sarin-exposed, non-seizing rats and compared differentially expressed genes and pathway activation to those of seizing rats. At the earliest time point (0.25 h) and in multiple sarin-sensitive brain regions, defense response genes were commonly expressed in both groups of animals as compared to the control groups. All sarin-exposed animals activated the MAPK signaling pathway, but only the seizing rats activated the apoptotic-associated JNK and p38 MAPK signaling sub-pathway. A unique phenotype of the non-seizing rats was the altered expression levels of genes that generally suppress inflammation or apoptosis. Importantly, the early transcriptional response for inflammation- and apoptosis-related genes in the thalamus showed opposite trends, with significantly down-regulated genes being up-regulated, and vice versa, between the seizing and non-seizing rats. These observations lend support to the hypothesis that regulation of anti-inflammatory genes might be part of an active and sufficient response in the non-seizing group to protect against the onset of seizures. As such, stimulating or activating these responses via pretreatment strategies could boost resilience against nerve agent exposures.
接触有机磷酸酯（OP）神经毒剂，如沙林，可能会导致不受控制的癫痫发作以及不可逆转的脑损伤和神经病理学变化。在大鼠研究中，沙林的半数致死剂量会导致约一半的动物出现癫痫发作。以往的研究分析了与癫痫发作的沙林暴露大鼠相关的转录组效应，而我们的研究聚焦于未出现癫痫发作的沙林暴露大鼠群体。我们分析了沙林暴露但未癫痫发作的大鼠中发生的基因组变化，并将差异表达基因和通路激活情况与癫痫发作的大鼠进行了比较。在最早的时间点（0.25小时）以及多个对沙林敏感的脑区，与对照组相比，两组动物中均普遍表达了防御反应基因。所有沙林暴露的动物都激活了丝裂原活化蛋白激酶（MAPK）信号通路，但只有癫痫发作的大鼠激活了与凋亡相关的JNK和p38 MAPK信号子通路。未癫痫发作大鼠的一个独特表型是通常抑制炎症或凋亡的基因表达水平发生了改变。重要的是，丘脑炎症和凋亡相关基因的早期转录反应在癫痫发作和未癫痫发作的大鼠之间呈现相反趋势，癫痫发作大鼠中显著下调的基因在未癫痫发作大鼠中上调，反之亦然。这些观察结果支持了这样一种假设，即抗炎基因的调节可能是未癫痫发作组中积极且充分的反应的一部分，以防止癫痫发作的发生。因此，通过预处理策略刺激或激活这些反应可以增强对神经毒剂暴露的抵抗力。
