Possible mechanisms mediating the protective effect of cilostazol in L-arginine induced acute pancreatitis in rats: role
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ORIGINAL ARTICLE
Possible mechanisms mediating the protective effect of cilostazol in L-arginine induced acute pancreatitis in rats: role of cGMP, cAMP, and HO-1 Asmaa Mohamed Abdel-Aziz 1 & Rehab Ahmed Rifaai 2 & Seham A. Abdel-Gaber 1 Received: 14 September 2019 / Accepted: 6 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Acute pancreatitis (AP) is an inflammatory disorder with a high mortality rate. Cilostazol is a selective phosphodiesterase-3 inhibitor drug that is commonly used as an antiplatelet, antithrombotic, and vasodilator drug. It exhibits antioxidant, antiinflammatory, and anti-apoptotic activities, but its effect on AP has not been fully elucidated yet. The present study aimed to investigate the effects of cilostazol on L-arginine-induced AP and the possible protective mechanisms. A rat model of AP was established by a single i.p. injection of 3-g/kg L-arginine on day 13 of the experiment. The treated groups received a single daily oral dose of either 100 or 300 mg/kg/day for 14 consecutive days. Rats with AP showed histopathological changes of pancreatic tissue injury together with increased serum amylase enzyme activity and decreased serum insulin, pancreatic adiponectin, and cGMP levels. Moreover, AP rats showed increased pancreatic inflammatory biomarker (TNF-α, VCAM-1, and MPO) levels with decreased anti-inflammatory IL-10 levels. In addition, oxidative stress biomarkers (MDA and NO) were increased in AP with decreased antioxidant SOD activity and GSH level. Moreover, HO-1 immunostaining was increased in the AP group. Cilostazol pretreatment reversed the histopathological change; decreased the amylase activity and the levels of TNF-α, VCAM1, and MPO; and increased the levels of insulin, adiponectin, cGMP, cAMP, and IL-10. Moreover, cilostazol decreased MDA and NO but increased SOD and GSH. Lastly, cilostazol increased the HO-1 immunostaining more than in the AP group. These data suggest that cilostazol protects against L-arginine-induced AP, which may be related to an increase in cGMP, cAMP, and upregulation of HO-1 with subsequent anti-inflammatory and antioxidant properties. Keywords Cilostazol . Pancreatitis . Heme oxygenase . Phosphodiesterase inflammation . Oxidative stress
Introduction Acute pancreatitis (AP) is a potentially lethal inflammatory disorder, ranging from a mild self-limited disease in most cases to a severe necrotizing inflammation in nearly 15–20% of patients with up to 30% mortality rate (Liu et al. 2018). The Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00210-020-01897-z) contains supplementary material, which is available to authorized users. * Seham A. Abdel-Gaber [email protected]; [email protected] 1
Departments of Pharmacology, Faculty of Medicine, Minia University, Minia 61511, Egypt
2
Departments of Histology and cell biology, Faculty of Medicine, Minia University, Minia 61511, Egypt
morbidity and mortality associated with pancreatitis are secondary to spread of s
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