Abstract：
Irinotecan use is linked to the development of gastrointestinal toxicity and inflammation, or gastrointestinal mucositis. Selected phytocannabinoids have been ascribed anti-inflammatory effects in models of gastrointestinal inflammation, associated with maintaining epithelial barrier function. We characterised the mucoprotective capacity of the phytocannabinoids: cannabidiol, cannabigerol, cannabichromene and cannabidivarin in a cell-based model of intestinal epithelial stress occurring in mucositis. Transepithelial electrical resistance (TEER) was measured to determine changes in epithelial permeability in the presence of SN-38 (5 μM) or the pro-inflammatory cytokines TNFα and IL-1β (each at 100 ng/mL), alone or with concomitant treatment with each of the phytocannabinoids (1 μM). The DCFDA assay was used to determine the ROS-scavenging ability of each phytocannabinoid following treatment with the lipid peroxidant tbhp (200 μM). Each phytocannabinoid provided significant protection against cytokine-evoked increases in epithelial permeability. Cannabidiol, cannabidivarin and cannabigerol were also able to significantly inhibit SN-38-evoked increases in permeability. None of the tested phytocannabinoids inhibited tbhp-induced ROS generation. These results highlight a novel role for cannabidiol, cannabidivarin and cannabigerol as inhibitors of SN-38-evoked increases in epithelial permeability and support the rationale for the further development of novel phytocannabinoids as supportive therapeutics in the management of irinotecan-associated mucositis.
摘要：
伊立替康的使用与胃肠道毒性和炎症的发展有关，或胃肠道粘膜炎。选定的植物大麻素已归因于在胃肠道炎症模型的抗炎作用，与维持上皮屏障功能有关。我们表征了植物大麻素的粘膜保护能力：大麻二酚，大麻酚,在粘膜炎中发生的肠上皮应激的基于细胞的模型中的大麻色素和大麻素。测量上皮电阻（TEER）以确定在存在SN-38（5μM）或促炎细胞因子TNFα和IL-1β（各100ng/mL）的情况下上皮通透性的变化，单独或伴随用每种植物大麻素(1μM)处理。DCFDA测定用于确定在用脂质过氧化剂tbhp(200μM)处理后每种植物大麻素的ROS清除能力。每种植物大麻素对细胞因子引起的上皮通透性增加提供了显着保护。大麻二酚,大麻二酚和大麻二酚也能够显着抑制SN-38引起的通透性增加。测试的植物大麻素均不抑制tbhp诱导的ROS产生。这些结果突出了大麻二酚的新作用，大麻二酚和大麻二酚作为SN-38引起的上皮通透性增加的抑制剂，并支持进一步开发新型植物大麻素作为伊立替康相关粘膜炎的支持性疗法的理由。
