The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.
The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.
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DOI：
10.1371/journal.pone.0242427
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Simard JM
中科院分区：
文献类型：
--
作者：
Keledjian K;Tsymbalyuk O;Semick S;Moyer M;Negoita S;Kim K;Ivanova S;Gerzanich V;Simard JM
海湾战争（GW）疾病（GWI）是一种使人衰弱的疾病，具有复杂的免疫，内分泌和神经症状，包括认知障碍，焦虑和抑郁。我们研究了一种新的GWI模型，该模型基于3种已知的常见GW暴露（GWE）：（i）鼻内脂多糖，人员在沙漠沙尘暴期间暴露于此;（ii）溴化吡啶斯的明，用于预防化学战;（iii）慢性不可预测的压力，战争中不可避免的因素。我们使用该模型来评价用PPARγ激动剂罗格列酮（ROSI）的预防性治疗。大鼠接受三种GWE 33天。在系列1和2中，将雄性和雌性GWE大鼠与未处理大鼠进行比较。在系列3中，将患有GWE的雄性大鼠随机分配至ROSI（GWE-ROSI）或溶媒预防性治疗组。暴露33天后，评估三个神经功能领域：认知（新物体识别）、焦虑样行为（高架十字迷宫、旷场）和抑郁样行为（被毛状态、蔗糖偏好、飞溅试验、悬尾和强迫游泳）。分析大脑的星形胶质细胞和小胶质细胞活化和神经炎症（GFAP，Iba 1，肿瘤坏死因子和转运蛋白）。将具有相似暴露的大鼠的神经功能数据合并到3个组中：未处理组、GWE组和GWE-ROSI组。与未处理的大鼠相比，GWE-大鼠在三个神经功能域中显示出显著的异常，沿着杏仁核和海马中的显著神经炎症。男性和女性之间的GWE没有差异。GWE-ROSI大鼠表现出神经炎症和一些神经功能异常的显着衰减。这种新的GWI模型概括了退伍军人GWI报告的关键神经功能异常。在该模型中，同时预防性治疗ROSI是有益的。
Gulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment, anxiety and depression. We studied a novel model of GWI based on 3 known common GW exposures (GWE): (i) intranasal lipopolysaccharide, to which personnel were exposed during desert sand storms; (ii) pyridostigmine bromide, used as prophylaxis against chemical warfare; and (iii) chronic unpredictable stress, an inescapable element of war. We used this model to evaluate prophylactic treatment with the PPARγ agonist, rosiglitazone (ROSI). Rats were subjected to the three GWE for 33 days. In series 1 and 2, male and female GWE-rats were compared to naïve rats. In series 3, male rats with GWE were randomly assigned to prophylactic treatment with ROSI (GWE-ROSI) or vehicle. After the 33-day exposures, three neurofunctional domains were evaluated: cognition (novel object recognition), anxiety-like behaviors (elevated plus maze, open field) and depression-like behaviors (coat state, sucrose preference, splash test, tail suspension and forced swim). Brains were analyzed for astrocytic and microglial activation and neuroinflammation (GFAP, Iba1, tumor necrosis factor and translocator protein). Neurofunctional data from rats with similar exposures were pooled into 3 groups: naïve, GWE and GWE-ROSI. Compared to naïve rats, GWE-rats showed significant abnormalities in the three neurofunctional domains, along with significant neuroinflammation in amygdala and hippocampus. There were no differences between males and females with GWE. GWE-ROSI rats showed significant attenuation of neuroinflammation and of some of the neurofunctional abnormalities. This novel GWI model recapitulates critical neurofunctional abnormalities reported by Veterans with GWI. Concurrent prophylactic treatment with ROSI was beneficial in this model.
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