Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, 4115, Egypt.
Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA.
Eur J Pharmacol. 2020 Aug 15;881:173234. doi: 10.1016/j.ejphar.2020.173234. Epub 2020 Jun 1.
The phosphodiesterase-3 inhibitor, cilostazol has been recently shown to protect against chemically induced colitis in animal models. However, whether cyclic adenosine monophosphate (cAMP) contributes to the anti-inflammatory activity of cilostazol in colitis is still unknown. In the current study, we investigated the role of cAMP/silent information regulator-1 (SIRT-1) pathway in the protective effect of cilostazol using rat model of acetic acid-induced colitis. Upregulation of SIRT1 activity and expression has been recently shown to protect against chemically induced colitis. Our results demonstrated that cilostazol alleviated the histopathological changes associated with acetic acid-induced colitis. Interestingly, pre-administration of cilostazol increased cAMP concentration and SIRT1 expression in colonic mucosa to levels similar to that observed in control animals without induction of colitis. In addition, cilostazol inhibited the SIRT1 targets; NF-κB, Akt and MAPK inflammatory pathways as demonstrated by suppression of acetic acid-induced upregulation of NF-κB activity, p-AKT levels and the expression of p38 MAPK. NF-κB activity and the levels of p-AKT, tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) were similar in rats pretreated with cilostazol prior to induction of colitis and the control rats without colitis. Furthermore, cilostazol reduced acetic acid-induced oxidative stress and apoptosis. In conclusion, the protective effect of cilostazol against acetic acid-induced colitis may be attributed to activation of SIRT1 expression by cAMP. SIRT1 is suggested to contribute to cilostazol-induced suppression of NF-κB, Akt and MAPK inflammatory pathways, oxidative stress and apoptosis.
磷酸二酯酶-3 抑制剂西洛他唑最近已被证明可在动物模型中预防化学诱导的结肠炎。然而，环磷酸腺苷 (cAMP) 是否有助于西洛他唑在结肠炎中的抗炎活性仍不清楚。在本研究中，我们使用乙酸诱导的结肠炎大鼠模型研究了 cAMP/沉默信息调节因子-1 (SIRT-1) 通路在西洛他唑保护作用中的作用。最近的研究表明，SIRT1 活性和表达的上调可预防化学诱导的结肠炎。我们的结果表明，西洛他唑减轻了与乙酸诱导的结肠炎相关的组织病理学变化。有趣的是，西洛他唑的预先给药增加了结肠黏膜中的 cAMP 浓度和 SIRT1 表达，使其达到与未诱导结肠炎的对照动物相似的水平。此外，西洛他唑抑制了 SIRT1 的靶标；NF-κB、Akt 和 MAPK 炎症途径，如 NF-κB 活性、p-AKT 水平和 p38 MAPK 表达的抑制所证明的那样。在诱导结肠炎之前用西洛他唑预处理的大鼠和没有结肠炎的对照大鼠中，NF-κB 活性和 p-AKT、肿瘤坏死因子-α (TNF-α)、白细胞介素-1β (IL-1β) 的水平相似。此外，西洛他唑减少了乙酸诱导的氧化应激和细胞凋亡。总之，西洛他唑对乙酸诱导的结肠炎的保护作用可能归因于 cAMP 对 SIRT1 表达的激活。SIRT1 可能有助于西洛他唑诱导的 NF-κB、Akt 和 MAPK 炎症途径、氧化应激和细胞凋亡的抑制。
