Nguyen Huy, Sahbaie Peyman, Goba Lihle, Sul Julian, Suzaki Aoi, Clark J David, Huang Ting-Ting
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, United States of America; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, United States of America; Geriatric Research, Education, and Clinical Center, VA Palo Alto Health Care System, United States of America.
Department of Anesthesiology, Stanford University School of Medicine, United States of America; Palo Alto Veterans Institute for Research, VA Palo Alto Health Care System, United States of America; Anesthesiology Service, VA Palo Alto Health Care System, United States of America.
Life Sci. 2021 Oct 15;283:119867. doi: 10.1016/j.lfs.2021.119867. Epub 2021 Aug 3.
A substantial contingent of veterans from the first Gulf War continues to suffer from a number of Gulf War-related illnesses (GWI) affecting the neurological and musculoskeletal systems; the most common symptoms include chronic pain and fatigue. Although animal models have recapitulated several aspects of cognitive impairments in GWI, the pain and fatigue symptoms have not been well documented to allow examination of potential pathogenic mechanisms.
We used a mouse model of GWI by exposing mice repeatedly to a combination of Gulf War chemicals (pyridostigmine bromide, permethrin, DEET, and chlorpyrifos) and mild immobilization stress, followed by investigating their pain susceptibilities and fatigue symptoms. To assess whether enhanced antioxidant capacity can counter the effects of GW agents, transgenic mice overexpressing extracellular superoxide dismutase (SOD3OE) were also examined.
The mouse model recapitulated several aspects of the human illness, including hyperalgesia, impaired descending inhibition of pain, and increased tonic pain. There is a close association between chronic pain and fatigue in GWI patients. Consistent with this observation, the mouse model showed a significant reduction in physical endurance on the treadmill. Examination of skeletal muscles suggested reduction in mitochondrial functions may have contributed to the fatigue symptoms. Furthermore, the negative impacts of GW agents in pain susceptibilities were largely diminished in SOD3OE mice, suggesting that increased oxidative stress was associated with the emergence of these Gulf War symptoms.
the mouse model will be suitable for delineating specific defects in the pain pathways and mechanisms of fatigue in GWI.
大量参加过第一次海湾战争的退伍军人仍患有多种与海湾战争相关的疾病（GWI），这些疾病影响神经和肌肉骨骼系统；最常见的症状包括慢性疼痛和疲劳。尽管动物模型已经再现了GWI认知障碍的几个方面，但疼痛和疲劳症状尚未得到充分记录，无法用于研究潜在的致病机制。
我们通过让小鼠反复接触海湾战争化学物质（溴化吡啶斯的明、氯菊酯、避蚊胺和毒死蜱）和轻度固定应激的组合，建立了GWI小鼠模型，随后研究它们的疼痛易感性和疲劳症状。为了评估增强的抗氧化能力是否可以对抗海湾战争化学物质的影响，还对过表达细胞外超氧化物歧化酶（SOD3OE）的转基因小鼠进行了检查。
该小鼠模型再现了人类疾病的几个方面，包括痛觉过敏、下行性疼痛抑制受损和紧张性疼痛增加。GWI患者的慢性疼痛和疲劳之间存在密切关联。与这一观察结果一致，该小鼠模型在跑步机上的身体耐力显著下降。对骨骼肌的检查表明，线粒体功能的降低可能导致了疲劳症状。此外，在SOD3OE小鼠中，海湾战争化学物质对疼痛易感性的负面影响大大减轻，这表明氧化应激增加与这些海湾战争症状的出现有关。
该小鼠模型将适用于描绘GWI疼痛通路和疲劳机制中的特定缺陷。
