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Dapagliflozin, an SGLT2 inhibitor, ameliorates acetic acid-induced colitis in rats by targeting NFκB/AMPK/NLRP3 axis
Inflammopharmacology ( IF 4.6 ) Pub Date : 2021-05-17 , DOI: 10.1007/s10787-021-00818-7
Magdy Abou El-Rous 1 , Sameh Saber 2 , Eman M Raafat 1 , Amany A E Ahmed 1
Affiliation  

The development of effective treatment strategies has been hindered by the complex pathogenesis of ulcerative colitis (UC). UC patients treated with current therapeutic approaches experienced either treatment failure or suffered excessive adverse reactions. Overactivity of NLRP3 inflammasome enhances inflammation, resulting in aggravation of colonic damage. We were interested in exploring, for the first time, the potential coloprotective effect of dapagliflozin (DPZ) on acetic acid-induced UC in rats in comparison with 5-ASA. DPZ improved histologic and macroscopic features of colon tissues and prolonged survival of UC rats. DPZ also prevented colon shortening and declined disease activity. Additionally, DPZ lessened colon tissue neutrophil content and improved antioxidant defense machinery. Further, DPZ specifically declined the colonic inflammatory marker IL-6 and upregulated the anti-inflammatory cytokine IL-10. The pyroptosis process is constrained in consequence of the repressed caspase-1 activity and caspase-1-dependent release of the bioactive cytokines IL-1β and IL-18. These protective effects might be attributed to that DPZ on the one hand, prevented the priming step (signal 1) of NLRP3 inflammasome activation as revealed by modulating NFκB/AMPK interplay and on the other hand, inhibited the activation step (signal 2) as indicated by interrupting NLRP3/caspase-1 signaling. Since DPZ was found to be safe and well tolerated by healthy volunteers with no evidence of hypoglycemia, it might show promise in the future management of UC. However, further investigations are warranted to confirm the reversal of injury and that the coloprotective effect is substantial.



中文翻译:

Dapagliflozin 是一种 SGLT2 抑制剂,通过靶向 NFκB/AMPK/NLRP3 轴改善醋酸诱导的大鼠结肠炎

溃疡性结肠炎 (UC) 的复杂发病机制阻碍了有效治疗策略的发展。用目前的治疗方法治疗的 UC 患者要么治疗失败,要么遭受过度的不良反应。NLRP3 炎性体的过度活跃会增强炎症,导致结肠损伤加重。我们有兴趣首次探索达格列净 (DPZ) 与 5-ASA 相比对大鼠醋酸诱导的 UC 的潜在协同保护作用。DPZ 改善了结肠组织的组织学和宏观特征,延长了 UC 大鼠的生存期。DPZ 还可以防止结肠缩短并降低疾病活动度。此外,DPZ 减少了结肠组织中性粒细胞的含量并改善了抗氧化防御机制。更远,DPZ 特异性降低结肠炎症标志物 IL-6 并上调抗炎细胞因子 IL-10。由于抑制的 caspase-1 活性和生物活性细胞因子 IL-1β 和 IL-18 的 caspase-1 依赖性释放,细胞焦亡过程受到限制。这些保护作用可能是由于 DPZ 一方面阻止了 NLRP3 炎性体激活的启动步骤(信号 1),如通过调节 NFκB/AMPK 相互作用所揭示的那样,另一方面,如图所示抑制了激活步骤(信号 2)通过中断 NLRP3/caspase-1 信号。由于 DPZ 被发现是安全的并且健康志愿者耐受性良好且没有低血糖的证据,因此它可能在 UC 的未来管理中显示出希望。然而,

更新日期:2021-05-18
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