摘要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.