O'Callaghan James P, Kelly Kimberly A, Locker Alicia R, Miller Diane B, Lasley Steve M
Health Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia, USA.
J Neurochem. 2015 Jun;133(5):708-21. doi: 10.1111/jnc.13088. Epub 2015 Mar 24.
Gulf War Illness (GWI) is a multi-symptom disorder with features characteristic of persistent sickness behavior. Among conditions encountered in the Gulf War (GW) theater were physiological stressors (e.g., heat/cold/physical activity/sleep deprivation), prophylactic treatment with the reversible AChE inhibitor, pyridostigmine bromide (PB), the insect repellent, N,N-diethyl-meta-toluamide (DEET), and potentially the nerve agent, sarin. Prior exposure to the anti-inflammatory glucocorticoid, corticosterone (CORT), at levels associated with high physiological stress, can paradoxically prime the CNS to produce a robust proinflammatory response to neurotoxicants and systemic inflammation; such neuroinflammatory effects can be associated with sickness behavior. Here, we examined whether CORT primed the CNS to mount neuroinflammatory responses to GW exposures as a potential model of GWI. Male C57BL/6 mice were treated with chronic (14 days) PB/ DEET, subchronic (7-14 days) CORT, and acute exposure (day 15) to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor. DFP alone caused marked brain-wide neuroinflammation assessed by qPCR of tumor necrosis factor-α, IL6, chemokine (C-C motif) ligand 2, IL-1β, leukemia inhibitory factor, and oncostatin M. Pre-treatment with high physiological levels of CORT greatly augmented (up to 300-fold) the neuroinflammatory responses to DFP. Anti-inflammatory pre-treatment with minocycline suppressed many proinflammatory responses to CORT+DFP. Our findings are suggestive of a possible critical, yet unrecognized interaction between the stressor/environment of the GW theater and agent exposure(s) unique to this war. Such exposures may in fact prime the CNS to amplify future neuroinflammatory responses to pathogens, injury, or toxicity. Such occurrences could potentially result in the prolonged episodes of sickness behavior observed in GWI. Gulf War (GW) veterans were exposed to stressors, prophylactic medicines and, potentially, nerve agents in theater. Subsequent development of GW Illness, a persistent multi-symptom disorder with features characteristic of sickness behavior, may be caused by priming of the CNS resulting in exaggerated neuroinflammatory responses to pathogens/insults. Nerve agent, diisopropyl fluorophosphate (DFP), produced a neuroinflammatory response that was exacerbated by pre-treatment with levels of corticosterone simulating heightened stressor conditions. While prophylactic treatments reduced DFP-induced neuroinflammation, this effect was negated when those treatments were combined with corticosterone.
海湾战争综合征（GWI）是一种具有持续性疾病行为特征的多症状疾病。在海湾战争（GW）战区遇到的情况包括生理应激源（如热/冷/体力活动/睡眠剥夺）、用可逆性乙酰胆碱酯酶抑制剂溴吡斯的明（PB）进行预防性治疗、使用驱虫剂N,N-二乙基间甲苯酰胺（DEET），以及可能接触神经毒剂沙林。先前在与高生理应激相关水平下接触抗炎糖皮质激素皮质酮（CORT），可能会反常地使中枢神经系统对神经毒剂和全身炎症产生强烈的促炎反应；这种神经炎症效应可能与疾病行为有关。在此，我们研究了CORT是否使中枢神经系统对GW暴露产生神经炎症反应，以此作为GWI的潜在模型。雄性C57BL/6小鼠接受慢性（14天）PB/DEET治疗、亚慢性（7 - 14天）CORT治疗，并在第15天急性暴露于氟磷酸二异丙酯（DFP），DFP是沙林的替代物和不可逆性乙酰胆碱酯酶抑制剂。单独使用DFP会导致通过肿瘤坏死因子-α、白细胞介素6、趋化因子（C - C基序）配体2、白细胞介素-1β、白血病抑制因子和制瘤素M的定量聚合酶链反应评估的全脑明显神经炎症。用高生理水平的CORT进行预处理会极大增强（高达300倍）对DFP的神经炎症反应。用米诺环素进行抗炎预处理可抑制对CORT + DFP的许多促炎反应。我们的研究结果表明，GW战区的应激源/环境与这场战争特有的制剂暴露之间可能存在一种关键但未被认识到的相互作用。这种暴露实际上可能使中枢神经系统对未来病原体、损伤或毒性产生的神经炎症反应放大。这种情况可能会导致在GWI中观察到的疾病行为长期发作。海湾战争（GW）退伍军人在战区接触了应激源、预防性药物以及可能的神经毒剂。随后出现的海湾战争综合征是一种具有疾病行为特征的持续性多症状疾病，可能是由于中枢神经系统的致敏导致对病原体/损伤的神经炎症反应过度。神经毒剂氟磷酸二异丙酯（DFP）产生的神经炎症反应在用模拟高应激源条件水平的皮质酮预处理后会加剧。虽然预防性治疗可减少DFP诱导的神经炎症，但当这些治疗与皮质酮联合使用时，这种效果会被抵消。
