Thapa Dinesh, Patil Mohan, Warne Leon N, Carlessi Rodrigo, Falasca Marco
Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia.
College of Science, Health, Engineering and Education, Murdoch University, Perth, WA 6150, Australia.
Cells. 2024 Dec 5;13(23):2013. doi: 10.3390/cells13232013.
Cannabinoids are emerging as promising treatments for inflammatory diseases such as ulcerative colitis. Specifically, cannabinoid 2 (CB2) receptors, which are upregulated during inflammation, have been distinctively linked to anti-inflammatory and analgesic effects. HU308, a synthetic cannabinoid developed to activate CB2 receptors selectively, aims to minimize unwanted off-target side effects. This study evaluated the effectiveness of both cannabidiol (CBD) and HU308 in mouse models of dextran sodium sulphate (DSS)-induced colitis, which mimic the acute and chronic phases of ulcerative colitis. Mice were treated with DSS in drinking water (four percent for the acute model and one to two percent for the chronic model) to induce colitis, as indicated by increased disease activity index (DAI) scores and inflammatory markers. Treatment with 60 mg/kg of CBD, but not lower doses, significantly reduced colitis symptoms, such as inflammation, cytokine levels, and MPO activity, while also normalizing glucagon-like peptide-1 (GLP-1) levels. HU308 showed comparable efficacy to high-dose CBD (60 mg/kg) but at a much lower dose (2.5 mg/kg), without observable toxicity. HU308 effectively normalized DAI scores, colon inflammation, ammonia levels, and GLP-1 expression in both colitis models. These results suggest that both CBD and HU308 are promising treatments for ulcerative colitis. However, HU308 demonstrates enhanced therapeutic potential by achieving similar outcomes at a fraction of the dose required for CBD, reducing the risk of off-target side effects. The ability of HU308 to modulate GLP-1, a biomarker of gut endocrine function, further underscores its promise as a novel treatment option.
大麻素正逐渐成为治疗溃疡性结肠炎等炎症性疾病的有前景的疗法。具体而言，炎症期间上调的大麻素2（CB2）受体，已被明确地与抗炎和镇痛作用相关联。HU308是一种为选择性激活CB2受体而开发的合成大麻素，旨在将不必要的脱靶副作用降至最低。本研究评估了大麻二酚（CBD）和HU308在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型中的有效性，该模型模拟了溃疡性结肠炎的急性和慢性阶段。如疾病活动指数（DAI）评分和炎症标志物升高所示，给小鼠饮用含DSS的水（急性模型为4%，慢性模型为1%至2%）以诱导结肠炎。用60mg/kg的CBD治疗，但较低剂量无效，可显著减轻结肠炎症状，如炎症、细胞因子水平和髓过氧化物酶（MPO）活性，同时还能使胰高血糖素样肽-1（GLP-1）水平恢复正常。HU308显示出与高剂量CBD（60mg/kg）相当的疗效，但剂量低得多（2.5mg/kg），且无明显毒性。HU308在两种结肠炎模型中均有效地使DAI评分、结肠炎症、氨水平和GLP-1表达恢复正常。这些结果表明，CBD和HU308都是治疗溃疡性结肠炎的有前景的疗法。然而，HU308通过以CBD所需剂量的一小部分实现相似的结果，显示出增强的治疗潜力，降低了脱靶副作用的风险。HU308调节GLP-1（一种肠道内分泌功能的生物标志物）的能力，进一步突出了其作为一种新型治疗选择的前景。
