U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010, USA.
Toxicol Sci. 2012 Apr;126(2):497-505. doi: 10.1093/toxsci/kfr353. Epub 2012 Jan 12.
The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.
高毒性有机磷化合物 VX（O-乙基 S-[2-（二异丙基氨基）乙基]甲基膦酸酯）是乙酰胆碱酯酶（AChE）的不可逆抑制剂。AChE 的持续抑制会增加内源性乙酰胆碱水平，并在神经突触和运动终板处产生毒性。我们假设，反复接触亚致死剂量的 VX 会影响与细胞存活、神经元可塑性和神经元重塑相关的基因，包括脑源性神经营养因子（BDNF）。我们研究了重复接触（每天 1 次×每周 5 天×2 周）亚致死剂量 VX（0.2 LD（50）和 0.4 LD（50））后 C57BL/6 小鼠大脑中 BDNF 表达的时间进程。BDNF 信使 RNA 表达在多个脑区显著升高（p<0.05），包括海马结构中的齿状回、CA3 和 CA1 区，以及梨状皮层、下丘脑、杏仁核和丘脑，在最后一次 0.4 LD（50）VX 暴露后 72 小时。然而，BDNF 蛋白表达仅在海马 CA3 区增加。对亚致死剂量 VX 暴露的反应中 BDNF 的增加是防止细胞损伤的适应性反应，还是即将发生脑损伤的前兆，还有待确定。如果升高的 BDNF 是对亚致死剂量 VX 暴露的适应性反应，那么外源性 BDNF 可能是减少神经毒剂暴露毒性作用的潜在治疗靶点。
