Cannabinoid receptor-1 antagonism: a new perspective on treating a murine schistosomal liver fibrosis model

BACKGROUND Formation of schistosomal granulomata surrounding the ova can result in schistosomiasis-associated liver fibrosis (SSLF). The current standard of treatment is praziquantel (PZQ), which cannot effectively reverse SSLF. The role of the cannabinoid (CB) receptor family in liver fibrosis has recently been highlighted. OBJECTIVES This study aimed to assess the therapeutic effect of CB1 receptor antagonism in reversing SSLF in a murine model of Schistosoma mansoni infection. METHODS One hundred male Swiss albino mice were divided equally into five groups: healthy uninfected control (group I), infected control (group II), PZQ treated (group III), rimonabant (RIM) (SR141716, a CB1 receptor antagonist)-treated (group IV) and group V was treated with combined PZQ and RIM. Liver sections were obtained for histopathological examination, alpha-1 smooth muscle actin (α-SMA) immunostaining and assessment of CB1 receptor expression using real-time polymerase chain reaction (RT-PCR). FINDINGS The most effective reduction in fibrotic marker levels and granuloma load was achieved by combined treatment with PZQ+RIM (group V): CB1 receptor expression (H = 26.612, p < 0.001), number of α-SMA-positive cells (F = 57.086, p < 0.001), % hepatic portal fibrosis (F = 42.849, p < 0.001) and number of granulomata (F = 69.088, p < 0.001). MAIN CONCLUSIONS Combining PZQ with CB1 receptor antagonists yielded the best results in reversing SSLF. To our knowledge, this is the first study to test this regimen in S. mansoni infection.

背景 虫卵周围血吸虫肉芽肿的形成可引发血吸虫病相关性肝纤维化（schistosomiasis-associated liver fibrosis, SSLF）。当前临床标准治疗药物为吡喹酮（praziquantel, PZQ），但其无法有效逆转SSLF。近期研究明确了大麻素（cannabinoid, CB）受体家族在肝纤维化进程中的作用。
目的 本研究旨在评估CB1受体拮抗作用在曼氏血吸虫（Schistosoma mansoni）感染小鼠模型中逆转SSLF的治疗效果。
方法 将100只雄性瑞士白化小鼠随机均分为5组：健康未感染对照组（I组）、感染未治疗对照组（II组）、吡喹酮治疗组（III组）、利莫那班（rimonabant, RIM，SR141716，一种CB1受体拮抗剂）治疗组（IV组）以及联合吡喹酮与利莫那班治疗组（V组）。获取肝脏组织切片，用于组织病理学检查、α-平滑肌肌动蛋白（alpha-1 smooth muscle actin, α-SMA）免疫染色，以及通过实时聚合酶链反应（real-time polymerase chain reaction, RT-PCR）检测CB1受体的表达水平。
结果 联合使用吡喹酮与利莫那班的V组在降低纤维化标志物水平及肉芽肿负荷方面效果最为显著：其CB1受体表达（H=26.612，p<0.001）、α-SMA阳性细胞数（F=57.086，p<0.001）、肝门管区纤维化占比（F=42.849，p<0.001）以及肉芽肿数量（F=69.088，p<0.001）均得到有效改善。
主要结论 联合应用吡喹酮与CB1受体拮抗剂在逆转SSLF方面效果最优。据我们所知，本研究是首个在曼氏血吸虫感染模型中验证该治疗方案的实验研究。