Gulf War Illness (GWI), a chronic multisymptom health problem, afflicts ~30% of veterans served in the first GW. Impaired brain function is among the most significant symptoms of GWI, which is typified by persistent cognitive and mood impairments, concentration problems, headaches, chronic fatigue, and musculoskeletal pain. This review aims to discuss findings from animal prototypes and veterans with GWI on mechanisms underlying its pathophysiology and emerging therapeutic strategies for alleviating brain dysfunction in GWI. Animal model studies have linked brain impairments to incessantly elevated oxidative stress, chronic inflammation, inhibitory interneuron loss, altered lipid metabolism and peroxisomes, mitochondrial dysfunction, modified expression of genes relevant to cognitive function, and waned hippocampal neurogenesis. Furthermore, the involvement of systemic alterations such as the increased intensity of reactive oxygen species and proinflammatory cytokines in the blood, transformed gut microbiome, and activation of the adaptive immune response have received consideration. Investigations in veterans have suggested that brain dysfunction in GWI is linked to chronic activation of the executive control network, impaired functional connectivity, altered blood flow, persistent inflammation, and changes in miRNA levels. Lack of protective alleles from Class II HLA genes, the altered concentration of phospholipid species and proinflammatory factors in the circulating blood have also been suggested as other aiding factors. While some drugs or combination therapies have shown promise for alleviating symptoms in clinical trials, larger double-blind, placebo-controlled trials are needed to validate such findings. Based on improvements seen in animal models of GWI, several antioxidants and anti-inflammatory compounds are currently being tested in clinical trials. However, reliable blood biomarkers that facilitate an appropriate screening of veterans for brain pathology need to be discovered. A liquid biopsy approach involving analysis of brain-derived extracellular vesicles in the blood appears efficient for discerning the extent of neuropathology both before and during clinical trials.

海湾战争疾病 (GWI) 是一种慢性多症状健康问题，困扰着在第一个 GW 服役的约 30% 的退伍军人。脑功能受损是 GWI 最显着的症状之一，其典型特征是持续的认知和情绪障碍、注意力不集中、头痛、慢性疲劳和肌肉骨骼疼痛。本综述旨在讨论动物原型和 GWI 退伍军人关于其病理生理学机制的研究结果，以及缓解 GWI 脑功能障碍的新兴治疗策略。动物模型研究已将脑损伤与不断升高的氧化应激、慢性炎症、抑制性中间神经元丢失、脂质代谢和过氧化物酶体改变、线粒体功能障碍、与认知功能相关的基因表达改变以及海马神经发生减弱联系起来。此外，全身性改变的参与，例如血液中活性氧和促炎细胞因子的强度增加、肠道微生物群的转化以及适应性免疫反应的激活，已经得到了考虑。对退伍军人的调查表明，GWI 的脑功能障碍与执行控制网络的慢性激活、功能连接受损、血流改变、持续性炎症和 miRNA 水平的变化有关。缺乏来自 II 类 HLA 基因的保护性等位基因、循环血液中磷脂种类和促炎因子的浓度改变也被认为是其他辅助因素。虽然一些药物或联合疗法在临床试验中显示出缓解症状的希望，但更大的双盲、需要进行安慰剂对照试验来验证这些发现。基于在 GWI 动物模型中观察到的改进，目前正在临床试验中测试几种抗氧化剂和抗炎化合物。然而，需要发现有助于对退伍军人进行适当脑部病理筛查的可靠血液生物标志物。一种涉及分析血液中脑源性细胞外囊泡的液体活检方法似乎可以有效地识别临床试验之前和期间的神经病理学程度。