Interactions between pyridostigmine bromide and stress on glutamatergic neurochemistry: Insights from a rat model of Gulf War Illness
Interactions between pyridostigmine bromide and stress on glutamatergic neurochemistry: Insights from a rat model of Gulf War Illness
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DOI：
10.1016/j.ynstr.2019.100210
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发表时间：
2020-05-01
影响因子：
5
通讯作者：
Fadel, J. R.
中科院分区：
文献类型：
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作者：
Macht, V. A.;Woodruff, J. L.;Fadel, J. R.
在第一次海湾战争期间，溴化吡啶斯的明（PB）被用作预防性治疗，以防止在暴露于神经毒剂的情况下发生毒性。虽然最初认为对士兵的风险很小，但流行病学研究已经将PB管理与各种症状的发展相关联，包括认知功能障碍，称为海湾战争疾病（GWI）。我们以前证明在啮齿类动物模型的GWI，中枢胆碱能反应改变了各种刺激。在目前的研究中，我们使用体内微透析来研究PB和重复约束应激（RRS）的组合如何改变细胞外谷氨酸水平，以响应先天免疫挑战（脂多糖; LPS）和固定应激挑战前额叶皮层（PFC）和海马。本研究分为四组：溶媒非强制降解对照组（Veh-NSC）、溶媒强制降解组（Veh-RRS）、PB-NSC和PB-RRS。虽然LPS降低了PB治疗的大鼠相对于溶剂治疗的大鼠在PFC中的谷氨酸水平，PB和应激相互作用以减弱LPS诱导的海马谷氨酸水平的降低。虽然固定应激增加了PFC中的谷氨酸，但相对于溶剂处理的大鼠，PB-NSC大鼠中的谷氨酸水平在应激后阶段未能恢复。在海马中，PB-应激大鼠未能表现出习惯性的谷氨酸盐反应相对于车辆应激大鼠固定应激。总的来说，这些结果表明，PB和压力相互作用，对谷氨酸神经化学产生脑区特异性影响，为深入了解GWI退伍军人免疫系统和持续认知功能障碍之间相互作用的潜在机制提供了依据。
Pyridostigmine bromide (PB) was administered to soldiers during the first Gulf War as a prophylactic treatment to protect against toxicity in the event of exposure to nerve agents. Although originally thought to pose minimal risk to soldiers, epidemiological studies have since correlated PB administration with the development of a variety of symptoms, including cognitive dysfunction, termed Gulf War Illness (GWI). We previously demonstrated in a rodent model of GWI that central cholinergic responses were altered to various stimuli. In the current study we used in vivo microdialysis to examine how combinations of PB and repeated restraint stress (RRS) altered extracellular glutamate levels in response to an innate immune challenge (lipopolysaccharide; LPS) and an immobilization stress challenge in the prefrontal cortex (PFC) and hippocampus. There were four groups in this study: vehicle non-stressed control (Veh-NSC), vehicle-stressed (Veh-RRS), PB-NSC, and PB-RRS. While LPS decreased glutamate levels in PB-treated rats relative to vehicle-treated rats in the PFC, PB and stress interacted to attenuate LPS-induced decreases in hippocampal glutamate levels. Although immobilization stress increased glutamate in the PFC, glutamate levels in PB-NSC rats failed to recover in the post-stress period relative to vehicle-treated rats. In the hippocampus, PB-stressed rats failed to exhibit habituation of the glutamate response to immobilization stress relative to vehicle-stressed rats. Collectively, these results indicate that PB and stress interacted to produce brain-region specific effects on glutamate neurochemistry, providing insight into the potential mechanisms underlying interactions between the immune system and persistent cognitive dysfunction in veterans with GWI.