Lipidomic Profiling of Phosphocholine Containing Brain Lipids in Mice with Sensorimotor Deficits and Anxiety-Like Features After Exposure to Gulf War Agents
Lipidomic Profiling of Phosphocholine Containing Brain Lipids in Mice with Sensorimotor Deficits and Anxiety-Like Features After Exposure to Gulf War Agents
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DOI：
10.1007/s12017-012-8192-z
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发表时间：
2012-12-01
影响因子：
3.5
通讯作者：
Crawford, Fiona C.
中科院分区：
文献类型：
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作者：
Abdullah, Laila;Evans, James E.;Crawford, Fiona C.
海湾战争病 (GWI) 的中枢神经系统 (CNS) 症状包括运动功能障碍、焦虑和认知障碍。海湾战争 (GW) 制剂，如溴化吡斯的明 (PB)、氯菊酯 (PER)、N,N-二乙基间甲苯酰胺 (DEET) 和应激，是 GWI 病理学的促成因素。本研究描述了与 GW 制剂暴露相关的神经行为和神经病理学特征所伴随的含磷酸胆碱脂质的紊乱。暴露的小鼠连续 28 天每天接受 PB 口服、皮肤涂抹 PER 和 DEET 以及约束应激，而对照组在此期间接受媒介物。神经行为研究包括旋转棒测试、开放场地测试和莫里斯水迷宫测试。组织病理学评估包括神经胶质原纤维酸性蛋白、CD45 和尼氏染色。采用负电离和正电离扫描模式下源碰撞诱导解离的液相色谱/质谱法来表征脑磷脂酰胆碱 (PC) 和鞘磷脂 (SM)。与对照组相比，暴露小鼠体内含有乙醚的 PC（ePC34:0、ePC36:2 和 ePC36:1）或含有长链脂肪酸的 PC（38:1、40:4、40:2）显着增加。在差异表达的 PC 中，单不饱和脂肪酸的水平比饱和和多不饱和脂肪酸的水平受到的影响更大。与对照组相比，暴露小鼠中观察到感觉运动缺陷和焦虑，以及星形细胞增多症的增加。这些脂质变化表明，过氧化物酶体途径和硬脂酰辅酶A去饱和酶活性的改变伴随着GW制剂暴露后的神经行为和神经病理学变化，并且代表了GWI中枢神经系统症状的可能治疗目标。
The central nervous system (CNS)-based symptoms of Gulf War Illness (GWI) include motor dysfunction, anxiety, and cognitive impairment. Gulf War (GW) agents, such as pyridostigmine bromide (PB), permethrin (PER), N,N-diethyl-meta-toluamide (DEET), and stress, are among the contributory factors to the pathobiology of GWI. This study characterizes disturbances in phosphocholine-containing lipids that accompany neurobehavioral and neuropathological features associated with GW agent exposure. Exposed mice received PB orally, dermal application of PER and DEET and restraint stress daily for 28 days, while controls received vehicle during this period. Neurobehavioral studies included the rotarod, open field, and Morris water maze tests. Histopathological assessments included glial fibrillary acid protein, CD45, and Nissl staining. Liquid chromatography/mass spectrometry with source collision-induced dissociation in negative and positive ionization scanning modes was performed to characterize brain phosphatidylcholine (PC) and sphingomyelin (SM). A significant increase in ether containing PC (ePC34:0, ePC36:2, and ePC36:1) or long-chain fatty acid-containing PC (38:1, 40:4, 40:2) was observed in exposed mice compared with controls. Among differentially expressed PCs, levels of those with monounsaturated fatty acids were more affected than those with saturated and polyunsaturated fatty acids. Sensorimotor deficits and anxiety, together with an increase in astrocytosis, were observed in exposed mice compared with controls. These lipid changes suggest that alterations in peroxisomal pathways and stearoyl-CoA desaturase activity accompany neurobehavioral and neuropathological changes after GW agent exposure and represent possible treatment targets for the CNS symptoms of GWI.