Department of Physiology and Pharmacology, University of Georgia, Athens, GA, United States; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, United States.
Department of Physiology and Pharmacology, University of Georgia, Athens, GA, United States; Neuroscience PhD Program, University of Georgia, Athens, GA, United States.
Brain Res. 2021 Sep 1;1766:147513. doi: 10.1016/j.brainres.2021.147513. Epub 2021 May 5.
Approximately one-third of Persian Gulf War veterans are afflicted by Gulf War Illness (GWI), a chronic multisymptom condition that fundamentally presents with cognitive deficits (i.e., learning and memory impairments) and neuroimmune dysfunction (i.e., inflammation). Factors associated with GWI include overexposures to neurotoxic pesticides and nerve agent prophylactics such as permethrin (PM) and pyridostigmine bromide (PB), respectively. GWI-related neurological impairments associated with PB-PM overexposures have been recapitulated in animal models; however, there is a paucity of studies assessing PB-PM-related aberrations in hippocampal synaptic plasticity and transmission that may underlie behavioral impairments. Importantly, FDA-approved neuroactive treatments are currently unavailable for GWI. In the present study, we assessed the efficacy of an immunomodulatory therapeutic, lacto-N-fucopentaose-III (LNFPIII), on ameliorating acute effects of in vivo PB-PM exposure on synaptic plasticity and transmission as well as trophic factor/cytokine expression along the hippocampal dorsoventral axis. PB-PM exposure resulted in hippocampal synaptic transmission deficits 48 h post-exposure, a response that was ameliorated by LNFPIII coadministration, particularly in the dorsal hippocampus (dH). LNFPIII coadministration also enhanced synaptic transmission in the dH and the ventral hippocampus (vH). Notably, LNFPIII coadministration elevated long-term potentiation in the dH. Further, PB-PM exposure and LNFPIII coadministration uniquely altered key inflammatory cytokine and trophic factor production in the dH and the vH. Collectively, these findings demonstrate that PB-PM exposure impaired hippocampal synaptic responses 48 h post-exposure, impairments that differentially manifested along the dorsoventral axis. Importantly, LNFPIII ameliorated GWI-related electrophysiological deficits, a beneficial effect indicating the potential efficacy of LNFPIII for treating GWI.
大约三分之一的海湾战争老兵患有海湾战争病（GWI），这是一种慢性多症状疾病，主要表现为认知缺陷（即学习和记忆障碍）和神经免疫功能障碍（即炎症）。与 GWI 相关的因素包括过度暴露于神经毒性杀虫剂和神经毒剂预防剂，如氯菊酯（PM）和溴化吡啶斯的明（PB）。在动物模型中重现了与 PB-PM 过度暴露相关的 GWI 相关神经损伤；然而，评估 PB-PM 相关海马突触可塑性和传递异常的研究很少，这些异常可能是行为损伤的基础。重要的是，目前尚无 FDA 批准的神经活性治疗方法可用于 GWI。在本研究中，我们评估了免疫调节治疗剂乳-N-岩藻戊糖-III（LNFPIII）的疗效，以改善体内 PB-PM 暴露对海马沿背腹轴突可塑性和传递以及营养因子/细胞因子表达的急性影响。PB-PM 暴露后 48 小时会导致海马突触传递缺陷，LNFPIII 共同给药可改善这种反应，特别是在背侧海马（dH）。LNFPIII 共同给药还增强了 dH 和腹侧海马（vH）中的突触传递。值得注意的是，LNFPIII 共同给药可增强 dH 中的长时程增强。此外，PB-PM 暴露和 LNFPIII 共同给药独特地改变了 dH 和 vH 中关键炎症细胞因子和营养因子的产生。总之，这些发现表明，PB-PM 暴露会损害海马突触反应，48 小时后暴露，损伤沿背腹轴表现出差异。重要的是，LNFPIII 改善了 GWI 相关的电生理缺陷，这一有益效应表明 LNFPIII 治疗 GWI 的潜在疗效。
