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This study was designed to investigate the possible protective effects of metformin alone and in combination with different phosphodiesterase inhibitors (PDEIs). Rats were fed a high-fat diet (HFD) for 16 weeks to induce NAFLD. Starting from week 12, rats received metformin alone or in combination with pentoxifylline, cilostazol, or sildenafil. HFD administration resulted in hepatic steatosis and inflammation in rats. In addition, liver index, body composition index, activities of liver enzymes, and serum lipids deviated from normal. Further, significant elevations were recorded compared to control in terms of serum glucose, insulin, and HOMA-IR (homeostasis model assessment index for insulin resistance), oxidative stress parameters, hepatic TNF-\u03b1 and NF-\u03baB gene expression, and iNOS protein expression. Rats treated with metformin showed a significant improvement in the aforementioned parameters. However, the addition of pentoxifylline to metformin treatment synergized its action and produced a fortified effect against HFD-induced NAFLD better than other PDEIs. Data from this study indicated that combined treatment of metformin and pentoxifylline had the most remarkable ameliorated effects against HFD-induced NAFLD; further clinical investigations are needed to approve PDEIs for NAFLD treatment. <\/jats:p>","DOI":"10.1139\/cjpp-2019-0487","type":"journal-article","created":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T21:37:26Z","timestamp":1582321046000},"page":"498-505","update-policy":"https:\/\/doi.org\/10.1139\/csp-crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Combined treatments with metformin and phosphodiesterase inhibitors alleviate nonalcoholic fatty liver disease in high-fat diet fed rats: a comparative study"],"prefix":"10.1139","volume":"98","author":[{"given":"Gehan H.","family":"Heeba","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reham M.","family":"El-Deen","sequence":"additional","affiliation":[{"name":"Ministry of Health and Population, Undersecretary preventive sector, General administration viral hepatitis, Cairo, Egypt."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rania G.","family":"Abdel-latif","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed M.A.","family":"Khalifa","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia 61111, Egypt."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"155","reference":[{"key":"refg1\/ref1","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v7.i11.1450"},{"key":"refg2\/ref2","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-1318"},{"key":"refg3\/ref3","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5922"},{"key":"refg4\/ref4","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.12.3458"},{"key":"refg5\/ref5","doi-asserted-by":"publisher","DOI":"10.1385\/ENDO:23:2-3:177"},{"key":"refg6\/ref6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2005.41583.x"},{"key":"refg7\/ref7","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2015.12.012"},{"key":"refg8\/ref8","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.2.1013"},{"key":"refg9\/ref9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.2007.05001.x"},{"key":"refg10\/ref10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1872-034X.2007.00215.x"},{"key":"refg11\/ref11","doi-asserted-by":"publisher","DOI":"10.4172\/2167-0889.1000177"},{"issue":"4","key":"refg12\/ref12","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S1665-2681(19)31902-7","volume":"6","author":"Duseja A.","year":"2007","journal-title":"Ann. 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