E-Mail karger@karger.com Short Communication Pharmacology 2015;95:22–28 DOI: 10.1159/000369826 Selective Cyclooxygenase-1 Inhibition by P6 and Gastrotoxicity: Preliminary Investigation Maria Grazia Perrone   a Dario Domenico Lofrumento   c Paola Vitale   a Francesco De Nuccio   c Velia La Pesa   c Andrea Panella   a Rosa Calvello   b Antonia Cianciulli   b Maria Antonietta Panaro   b Antonio Scilimati   a a  Dipartimento di Farmacia – Scienze del Farmaco and b  Dipartimento di Bioscienze, Biotecnologie e Biofarmaceutica, Università degli Studi di Bari ‘Aldo Moro’, Bari, and c  Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Sezione di Anatomia Umana, Università del Salento, Lecce, Italy ASA-treated mice showed breaks in the epithelial barrier and a marked alteration of foveolae and gastric glands, whereas stomachs isolated from mice sacrificed after 5 days of chron- ic administration of P6 (at a dose of up to 50 mg/kg/day) showed sporadic transient mucosal hyperemia and did not seem to display any significant gastric damage. Conclu- sions: The selective COX-1 inhibition by P6 does not cause gastric damage in mice but preserves mucosal integrity. © 2015 S. Karger AG, Basel Introduction Gastric mucosal injury is often associated with tradi- tional non-steroidal anti-inflammatory drug (tNSAID) administration, even if the mechanisms responsible for the gastrointestinal (GI) erosion and bleeding remain yet to be clarified. tNSAIDs are responsible for the inhibition of cyclo- oxygenase (COX), of which two isoenzymes exist, COX-1 and COX-2. The former is constitutively expressed in a Key Words COX-1 inhibition · Gastric damage · 3-(5-Chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) Abstract Background/Aims: Gastrointestinal damage (GD) is com- monly associated with the inhibition of cyclooxygenase (COX)-1, one of the two known COXs, by traditional non-ste- roidal anti-inflammatory drugs. More recent evidences have proven that GD is caused by the simultaneous inhibition of the two COXs. This study was designed to evaluate the effect of the selective COX-1 inhibition on gastric integrity. Meth- ods: GD was evaluated in male CD1 mice. Drugs were admin- istered by gastric gavage at a dose of 50 mg/kg (injection volume of 100 μl). Control mice received an equal volume of the vehicle (10% ethanol). Each mouse, in groups of at least 6 mice, received one dose/day for 5 days. Results: In Western blot analysis, COX-1 expression levels were found to be sig- nificantly reduced in mice treated with 3-(5-chlorofuran- 2-yl)-5-methyl-4-phenylisoxazole (P6) in comparison to mice pretreated with aspirin (ASA), which exhibited higher levels of COX-1, thus confirming the high selectivity of P6 towards COX-1 enzyme inhibition. Mucosal sections obtained from Received: July 24, 2014 Accepted after revision: November 11, 2014 Published online: January 9, 2015 Prof. Antonio Scilimati Dipartimento di Farmacia – Scienze del Farmaco Università degli Studi di Bari ‘Aldo Moro’ Via E. Orabona 4, IT–70125 Bari (Italy) E-Mail antonio.scilimati  @  uniba.it © 2015 S. Karger AG, Basel 0031–7012/15/0952–0022$39.50/0 www.karger.com/pha M.G.P., D.D.L., A.S., and M.A.P. contributed equally to this study. Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.214.17.252 - 1/12/2015 4:08:29 PM