Residual effects of the 1990–1991 Gulf War (GW) still plague veterans 30 years later as Gulf War Illness (GWI). Thought to stem mostly from deployment-related chemical overexposures, GWI is a disease with multiple neurological symptoms with likely immunological underpinnings. Currently, GWI remains untreatable, and the long-term neurological disease manifestation is not characterized fully. The present study sought to expand and evaluate the long-term implications of prior GW chemicals exposure on neurological function 6–8 months post GWI-like symptomatology induction. Additionally, the beneficial effects of delayed treatment with the glycan immunotherapeutic lacto-N-fucopentaose III (LNFPIII) were evaluated. Male C57BL/6J mice underwent a 10-day combinational exposure (i.p.) to GW chemicals, the nerve agent prophylactic pyridostigmine bromide (PB) and the insecticide permethrin (PM; 0.7 and 200 mg/kg, respectively). Beginning 4 months after PB/PM exposure, a subset of the mice were treated twice a week until study completion with LNFPIII. Evaluation of cognition/memory, motor function, and mood was performed beginning 1 month after LNFPIII treatment initiation. Prior exposure to PB/PM produced multiple locomotor, neuromuscular, and sensorimotor deficits across several motor tests. Subtle anxiety-like behavior was also present in PB/PM mice in mood tests. Further, PB/PM-exposed mice learned at a slower rate, mostly during early phases of the learning and memory tests employed. LNFPIII treatment restored or improved many of these behaviors, particularly in motor and cognition/memory domains. Electrophysiology data collected from hippocampal slices 8 months post PB/PM exposure revealed modest aberrations in basal synaptic transmission and long-term potentiation in the dorsal or ventral hippocampus that were improved by LNFPIII treatment. Immunohistochemical analysis of tyrosine hydroxylase (TH), a dopaminergic marker, did not detect major PB/PM effects along the nigrostriatal pathway, but LNFPIII increased striatal TH. Additionally, neuroinflammatory cells were increased in PB/PM mice, an effect reduced by LNFPIII. Collectively, long-term neurobehavioral and neurobiological dysfunction associated with prior PB/PM exposure was characterized; delayed LNFPIII treatment provided multiple behavioral and biological beneficial effects in the context of GWI, highlighting its potential as a GWI therapeutic.

30 年后，1990-1991 年海湾战争 (GW) 的残余影响仍然困扰着退伍军人，称为海湾战争病 (GWI)。 GWI 被认为主要源于与部署相关的化学品过度暴露，是一种具有多种神经系统症状的疾病，可能具有免疫学基础。目前，GWI 仍无法治疗，且长期神经系统疾病表现尚未完全表征。本研究旨在扩大和评估先前 GW 化学品暴露对 GWI 样症状诱导后 6-8 个月神经功能的长期影响。此外，还评估了聚糖免疫治疗乳-N-岩藻五糖 III (LNFPIII) 延迟治疗的有益效果。雄性 C57BL/6J 小鼠接受 GW 化学品、神经毒剂预防性溴化吡斯的明 (PB) 和杀虫剂氯菊酯（PM；分别为 0.7 和 200 mg/kg）为期 10 天的组合暴露 (ip)。从 PB/PM 暴露后 4 个月开始，一部分小鼠每周接受两次 LNFPIII 治疗，直至研究完成。 LNFPIII 治疗开始后 1 个月开始评估认知/记忆、运动功能和情绪。之前接触 PB/PM 导致多项运动测试中出现多种运动、神经肌肉和感觉运动缺陷。在情绪测试中，PB/PM 小鼠也出现了微妙的焦虑样行为。此外，暴露于 PB/PM 的小鼠学习速度较慢，主要是在学习和记忆测试的早期阶段。 LNFPIII 治疗恢复或改善了其中许多行为，特别是在运动和认知/记忆领域。 PB/PM 暴露后 8 个月从海马切片收集的电生理学数据显示，背侧或腹侧海马的基础突触传递和长期增强存在适度的畸变，LNFPIII 治疗可改善这些畸变。酪氨酸羟化酶 (TH)（一种多巴胺能标记物）的免疫组织化学分析未检测到 PB/PM 对黑质纹状体途径的主要影响，但 LNFPIII 增加了纹状体 TH。此外，PB/PM 小鼠中的神经炎症细胞增加，而 LNFPIII 则降低了这一效应。总的来说，与先前的 PB/PM 暴露相关的长期神经行为和神经生物学功能障碍得到了表征；延迟的 LNFPIII 治疗在 GWI 背景下提供了多种行为和生物学有益效果，突出了其作为 GWI 治疗的潜力。