Squire Erica, Lee Hye-Lim, Jeong Woojin, Lee Sumin, Ravichandiran V, Limoli Charles L, Piomelli Daniele, Parihar Vipan Kumar, Jung Kwang-Mook
Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA.
National Institute of Pharmaceutical Education and Research, Hajipur, Bihar, 844102, India.
Neuropharmacology. 2024 Dec 15;261:110142. doi: 10.1016/j.neuropharm.2024.110142. Epub 2024 Sep 4.
Gulf War Illness (GWI) is a chronic disorder characterized by a heterogeneous set of symptoms that include pain, fatigue, anxiety, and cognitive impairment. These are thought to stem from damage caused by exposure under unpredictable stress to toxic Gulf War (GW) chemicals, which include pesticides, nerve agents, and prophylactic drugs. We hypothesized that GWI pathogenesis might be rooted in long-lasting disruption of the endocannabinoid (ECB) system, a signaling complex that serves important protective functions in the brain. Using a mouse model of GWI, we found that tissue levels of the ECB messenger, anandamide, were significantly reduced in the brain of diseased mice, compared to healthy controls. In addition, transcription of the Faah gene, which encodes for fatty acid amide hydrolase (FAAH), the enzyme that deactivates anandamide, was significant elevated in prefrontal cortex of GWI mice and brain microglia. Behavioral deficits exhibited by these animals, including heightened anxiety-like and depression-like behaviors, and defective extinction of fearful memories, were corrected by administration of the FAAH inhibitor, URB597, which normalized brain anandamide levels. Furthermore, GWI mice displayed unexpected changes in the microglial transcriptome, implying persistent dampening of homeostatic surveillance genes and abnormal expression of pro-inflammatory genes upon immune stimulation. Together, these results suggest that exposure to GW chemicals produce a deficit in brain ECB signaling which is associated with persistent alterations in microglial function. Pharmacological normalization of anandamide-mediated ECB signaling may offer an effective therapeutic strategy for ameliorating GWI symptomology.
海湾战争综合症（GWI）是一种慢性疾病，其特征是一系列异质性症状，包括疼痛、疲劳、焦虑和认知障碍。这些症状被认为源于在不可预测的压力下接触海湾战争（GW）有毒化学物质所造成的损害，这些化学物质包括杀虫剂、神经毒剂和预防性药物。我们推测，GWI的发病机制可能源于内源性大麻素（ECB）系统的长期破坏，该信号复合体在大脑中发挥着重要的保护作用。使用GWI小鼠模型，我们发现，与健康对照组相比，患病小鼠大脑中ECB信使分子花生四烯乙醇胺的组织水平显著降低。此外，编码脂肪酸酰胺水解酶（FAAH）的Faah基因的转录在GWI小鼠的前额叶皮层和脑小胶质细胞中显著升高，FAAH是一种使花生四烯乙醇胺失活的酶。这些动物表现出的行为缺陷，包括焦虑样和抑郁样行为加剧，以及恐惧记忆的消退缺陷，通过给予FAAH抑制剂URB597得到纠正，URB597使大脑花生四烯乙醇胺水平恢复正常。此外，GWI小鼠在小胶质细胞转录组中表现出意想不到的变化，这意味着稳态监测基因持续受到抑制，免疫刺激后促炎基因异常表达。总之，这些结果表明，接触GW化学物质会导致大脑ECB信号传导缺陷，这与小胶质细胞功能的持续改变有关。花生四烯乙醇胺介导的ECB信号传导的药理学正常化可能为改善GWI症状提供一种有效的治疗策略。
