背景:慢性海湾战争疾病(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。本研究旨在调查Epidiolex®的疗效,美国食品和药物管理局(FDA)批准的大麻二酚(CBD),改善慢性GWI大鼠模型的脑功能。
方法:暴露于低剂量GWI相关化学物质[溴吡啶斯的明,N,N-二乙基间甲苯酰胺(DEET),和氯菊酯(PER)]以及中等压力,患有慢性GWI的大鼠给予媒介物(VEH)或CBD(20mg/kg,口服)16周。在治疗开始后11周进行神经行为测试,以评估大鼠在与联想识别记忆相关的任务中的表现,对象位置内存,模式分离,和蔗糖偏好。还检查了CBD对痛觉过敏的影响。在行为测试之后,处理脑组织用于免疫组织化学和分子研究。
结果:用VEH治疗的GWI大鼠在所有认知任务和快感缺失中表现出损伤,而CBD治疗的GWI大鼠在所有认知任务中均显示出改善,并且没有快感缺失。此外,CBD治疗减轻GWI大鼠的痛觉过敏。对VEH处理的大鼠的海马组织的分析显示星形胶质细胞肥大和呈现NOD-的活化小胶质细胞的百分比增加,含有LRR和pyrin结构域的蛋白3(NLRP3)复合物以及参与NLRP3炎性体激活和Janus激酶/信号转导和转录激活因子(JAK/STAT)信号传导的蛋白质水平升高。此外,促炎和氧化应激标志物浓度升高,神经发生减少.相比之下,CBD处理的GWI大鼠的海马显示介导NLRP3炎性体和JAK/STAT信号激活的蛋白质水平降低,促炎细胞因子和氧化应激标志物的标准化浓度,和改善神经发生。值得注意的是,CBD治疗不会改变海马中内源性大麻素anandamide的浓度。
结论:已证明使用FDA批准的CBD(Epidiolex®)可有效缓解认知和情绪障碍以及与慢性GWI相关的痛觉过敏。重要的是,在这项研究中,在患有慢性GWI的大鼠中观察到的改善归因于CBD显著抑制信号通路的能力,这些信号通路使慢性神经炎症持续存在.
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.