Institute for Regenerative Medicine, Department of Cell Biology and Genetics, Texas A&M University Health Science Center School of Medicine, College Station, TX, 77843, USA.
Mil Med Res. 2024 Aug 22;11(1):61. doi: 10.1186/s40779-024-00563-2.
Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex, a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI.
Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N-diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests.
GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus.
The use of an FDA-approved CBD (Epidiolex) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.
慢性海湾战争综合征（GWI）的特征是认知和情绪障碍，以及持续的神经炎症和氧化应激。本研究旨在探讨食品和药物管理局（FDA）批准的大麻二酚（CBD）Epidiolex 对慢性 GWI 大鼠模型脑功能的改善作用。
暴露于低剂量与 GWI 相关的化学物质[溴化吡斯的明、N，N-二乙基间甲苯酰胺（DEET）和氯菊酯（PER）]和中度应激 6 个月后，给予慢性 GWI 大鼠载体（VEH）或 CBD（20mg/kg，口服）治疗 16 周。在治疗开始后 11 周进行神经行为测试，以评估大鼠在联想识别记忆、物体位置记忆、模式分离和蔗糖偏好相关任务中的表现。还检查了 CBD 对痛觉过敏的影响。在行为测试后，对脑组织进行免疫组织化学和分子研究。
用 VEH 治疗的 GWI 大鼠在所有认知任务和快感缺失方面均表现出损伤，而用 CBD 治疗的 GWI 大鼠在所有认知任务中均得到改善且无快感缺失。此外，CBD 治疗减轻了 GWI 大鼠的痛觉过敏。用 VEH 治疗的大鼠海马组织分析显示，星形胶质细胞肥大，激活的小胶质细胞百分比增加，存在 NOD、LRR 和富含吡咯烷的蛋白 3（NLRP3）复合物，参与 NLRP3 炎性小体激活和 Janus 激酶/信号转导和转录激活因子（JAK/STAT）信号的蛋白水平升高。此外，促炎和氧化应激标志物的浓度升高，神经发生减少。相比之下，CBD 治疗的 GWI 大鼠海马体显示出介导 NLRP3 炎性小体和 JAK/STAT 信号激活的蛋白水平降低，促炎细胞因子和氧化应激标志物的浓度正常化，神经发生改善。值得注意的是，CBD 治疗并未改变海马体中内源性大麻素大麻酰胺的浓度。
使用 FDA 批准的 CBD（Epidiolex）可有效缓解与慢性 GWI 相关的认知和情绪障碍以及痛觉过敏。重要的是，在本研究中，慢性 GWI 大鼠的改善归因于 CBD 显著抑制持续慢性神经炎症的信号通路的能力。
