Phillips Kristin F, Deshpande Laxmikant S
Department of Neurology, Virginia Commonwealth University, PO Box 980599, 1217 East Marshall Street, Richmond, VA 23284.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 1217 East Marshall Street, Richmond, VA 23284.
Mil Med. 2018 Mar 1;183(suppl_1):552-555. doi: 10.1093/milmed/usx148.
Over 20 yr have elapsed since the end of the First Gulf War, yet approximately one-third of the veterans exhibit Gulf War Illness (GWI) symptoms, particularly depression and memory impairments. Exposure to organophosphate (OP) compounds is implicated for GWI development. The role of calcium (Ca2+) signaling in learning, memory, and mood is well established and disruptions in Ca2+ homeostasis are observed in many neurological disorders. However, the status of Ca2+ homeostasis in the development of GWI behavioral impairments is not known. Male Sprague-Dawley rats were exposed to OP agent diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c. 5 days), and at 6 mo post-DFP exposure, rats were subjected to behavioral assays for the determination of GWI neurological morbidities. Fura-2AM loaded acutely isolated hippocampal neurons were used for [Ca2+]i estimations. We observed chronic depressive symptoms and cognitive deficits in rats exposed to repeated low-dose DFP. The GWI rats also manifested elevations in hippocampal [Ca2+]i along with a significant increase in the number of neurons displaying these elevations. As Ca2+ is a major second-messenger molecule, such sustained increases in its levels could activate multiple signaling cascades and alter gene expression of proteins involved in synaptic plasticity and possibly underlie the neuronal injury and chronic morbidities in GWI.
自第一次海湾战争结束以来，已经过去了20多年，但仍有大约三分之一的退伍军人表现出海湾战争综合征（GWI）症状，尤其是抑郁和记忆障碍。有机磷酸酯（OP）化合物的暴露被认为与GWI的发展有关。钙（Ca2+）信号在学习、记忆和情绪中的作用已得到充分证实，并且在许多神经疾病中都观察到Ca2+稳态的破坏。然而，GWI行为损伤发展过程中Ca2+稳态的状况尚不清楚。将雄性Sprague-Dawley大鼠暴露于OP剂二异丙基氟磷酸酯（DFP；0.5 mg/kg，皮下注射，共5天），在DFP暴露后6个月，对大鼠进行行为测定以确定GWI神经病变。使用Fura-2AM加载的急性分离海马神经元来估计[Ca2+]i。我们观察到暴露于重复低剂量DFP的大鼠出现慢性抑郁症状和认知缺陷。GWI大鼠的海马[Ca2+]i也升高，同时显示这些升高的神经元数量显著增加。由于Ca2+是一种主要的第二信使分子，其水平的持续升高可能会激活多个信号级联反应，并改变参与突触可塑性的蛋白质的基因表达，这可能是GWI中神经元损伤和慢性病变的基础。
