Comparative effectiveness of phosphodiesterase 3, 4, and 5 inhibitors in amelioration of high‐fat diet‐induced nonalcoholic fatty liver in rats

• Published in: Fundamental & clinical pharmacology 2020-06, Vol.34 (3), p.353-364
• Main Authors: El‐Deen, Reham M., Heeba, Gehan H., Abdel‐latif, Rania G., Khalifa, Mohamed M.A.
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Antioxidants - metabolism; Bilirubin; Biomarkers - metabolism; Body composition; Cholesterol; Cilostazol - pharmacology; Cytokines; Diet; Diet, High-Fat - adverse effects; Disease; Disease resistance; Fatty liver; Fatty Liver - drug therapy; Fatty Liver - metabolism; Health services; High fat diet; inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inhibitors; Insulin; Insulin - metabolism; Insulin resistance; Insulin Resistance - physiology; Liver; Liver - drug effects; Liver - metabolism; Liver diseases; Male; Markers; Metabolic disorders; Nitric oxide; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; nonalcoholic fatty liver disease; Oxidation resistance; Oxidative stress; Oxidative Stress - drug effects; Pentoxifylline - pharmacology; Pharmacology; Phosphodiesterase; phosphodiesterase inhibitors; Phosphodiesterase Inhibitors - pharmacology; Phosphoric Diester Hydrolases - drug effects; Phosphoric Diester Hydrolases - metabolism; Rats; Rats, Wistar; Rodents; Serum levels; Sildenafil; Sildenafil Citrate - pharmacology; Steatosis; Triglycerides; Triglycerides - metabolism
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/fcp.12530

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease linked to insulin resistance, oxidative stress, and cytokine imbalance. Phosphodiesterase (PDE) inhibitors have shown remarkable antioxidant and anti‐inflammatory potential in different disease sets including liver diseases. This study aimed to compare the ameliorative effect of different PDE inhibitors on a high‐fat diet (HFD)‐induced NAFLD. Male Wistar rats were fed a HFD for 16 weeks to induce NAFLD, and then, oral treatments of a vehicle or different PDE inhibitors (pentoxifylline (50 mg/kg), cilostazol (20 mg/kg), or sildenafil (5 mg/kg)) were started in the last four weeks and given on a daily basis. Rats’ body composition and liver indices were recorded. Serum levels of liver enzymes, glucose, insulin, bilirubin, total cholesterol, triglycerides, and nitric oxide were measured. Liver tissues were used for histopathological examination and detecting oxidative stress and inflammatory markers. Results showed that different PDE inhibitors exhibited different efficacy against liver injury and metabolic disorders associated with HFD‐induced NAFLD in rodents evident by different strength‐ameliorated effects on the aforementioned parameters. Compared to cilostazol and sildenafil, insulin resistance, hepatic oxidative stress, and inflammatory markers were significantly reduced by pentoxifylline treatment. Furthermore, pentoxifylline nearly completely reversed hepatocyte steatosis and exhibited superior rectifying effect on the rats’ liver status compared with other PDE inhibitors. This investigation highlighted the potential role of PDE inhibitors in NAFLD treatment. Pentoxifylline had the most remarkable ameliorative effects against NAFLD, while sildenafil was the least effective.