title: Aggravating effect of atorvastatin on indomethacin-induced gastric injury: Focus on PGE2, TNF-α, neutrophils and iNOS.
abstract: Statins are suggested to possess healing properties due to their antioxidant and antiinflammatory effects in animal ulcer models. In contrary, a clinical report indicated the formation of gastric ulcer by the use of atorvastatin. In this study, we aimed to investigate the effects of atorvastatin (0.5, 5 and 50mg/kg, p.o.) after single (acute) and multiple (subchronic, 5 days) applications on indomethacin-induced gastric ulcer in rats. In both acute and subchronic models high dose atorvastatin (50mg/kg), unlike to lower doses (0,5 and 5mg/kg), significantly aggravated ulcer lesions induced by indomethacin (30 mg/kg) although, a direct ulcerogenic influence was lacking. Proulcerogenic effect of atorvastatin are likely to be associated with decreased mucosal defense mechanisms (GSH and PGE2), and increased neutrophil infiltration and proinflammatory factors (TNF-a and iNOS) possibly via independently from mevalonate pathway. Thus, atorvastatin therapy should be monitorized in patients for an increased risk of gastric ulcer particularly when used concomitantly with NSAIDs.
authors.affiliation: Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey.
authors.forename: F Ilkay Alp
authors.initials: FI
authors.lastname: Yildirim
authors.affiliation: Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey.
authors.forename: Özge
authors.initials: Ö
authors.lastname: Uyanik
authors.affiliation: Istanbul University, Faculty of Veterinary Medicine, Department of Pathology, Istanbul, Turkey.
authors.forename: Hande
authors.initials: H
authors.lastname: Özyoğurtçu
authors.affiliation: Istanbul University, Faculty of Veterinary Medicine, Department of Pathology, Istanbul, Turkey.
authors.forename: Aydın
authors.initials: A
authors.lastname: Gürel
authors.affiliation: Istanbul University, Cerrahpasa Medical Faculty, Department of Biochemistry, Istanbul, Turkey.
authors.forename: Pınar
authors.initials: P
authors.lastname: Atukeren
authors.affiliation: Istanbul University, Cerrahpasa Medical Faculty, Department of Biochemistry, Istanbul, Turkey.
authors.forename: Koray
authors.initials: K
authors.lastname: Gümüştaş
authors.affiliation: Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey; Cyprus International University, Faculty of Health Sciences, Department of Pharmacology, Lefkoşa, North Cyprus, Cyprus.
authors.forename: Osman
authors.initials: O
authors.lastname: Özdemir
authors.affiliation: Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey. Electronic address: sonmezuydesdogan@gmail.com.
authors.forename: Sönmez
authors.initials: S
authors.lastname: Uydeş-Doğan
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D000069059:Atorvastatin / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism*; D004357:Drug Synergism; D005260:Female; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D051381:Rats; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000578:Amidines; D001596:Benzylamines; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D014409:Tumor Necrosis Factor-alpha; D000069059:Atorvastatin; D052247:Nitric Oxide Synthase Type II; D015232:Dinoprostone; D008798:Mevalonic Acid; D007213:Indomethacin
keywords: Atorvastatin; Indomethacin-induced gastric ulcer; Neutrophil infiltration; PGE(2); TNF-a; iNOS