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More data on Pirdenidone.

Potent antioxidant role of Pirfenidone in experimental cirrhosis

http://www.ncbi.nlm.nih.gov/pubmed/18652820?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

or

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-4SY6W7S-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=0e8d644a4f630c0c1daa9d49c9bd0adc

Adriana Salazar-Montesa, Luis Ruiz-Corroa, Alberto López-Reyesa, Eugenio Castrejón-Gómeza and Juan Armendáriz-Borunda

Institute for Molecular Biology in Medicine and Gene Therapy, CUCS, University of Guadalajara, Guadalajara, Jalisco, Mexico

OPD Hospital Civil, Guadalajara, Jalisco, Mexico

Received 15 April 2008;
revised 19 June 2008;
accepted 27 June 2008.
Available online 9 July 2008.

Abstract

Three important features must be considered when proposing therapeutic strategies in liver cirrhosis: inflammation, oxidative stress and fibrogenesis. Pirfenidone is a synthetic molecule which oxidative action has not been tested in cirrhosis. Cirrhosis was induced in rats by ligation of the common bile duct or carbon tetrachloride (CCl4) chronic intoxication and treated with Pirfenidone or Diphenyleneiodonium (a potent known antioxidant) for the last two weeks for bile duct ligation model or for the last three weeks for CCl4 chronic intoxication. A 60% reduction in fibrosis index for bile duct ligation model and 42% for CCl4 along with reduced inflammation was observed. Considerable reduction on hepatic enzymes and total and direct bilirubins were detected with Pirfenidone in both models. Pirfenidone antioxidant capacity rendered a 28% and 30% reduction in nitrites and Malonyldealdehide concentration in bile duct ligation and 52% and 38% in CCl4. With respect to gene expression, fibrotic genes like transforming growth factor-β (TGF-β) and Collagen Iα (Col-1α) were down-regulated by Pirfenidone and increased expression of regenerative genes like hepatocyte growth factor (HGF) and c-met . superoxide dismutase (SOD), catalase (CAT) and inducible nitric oxide synthase (iNOS) gene expression were importantly down-regulated where nuclear factor kappa B (NF-κB) binding activity also decreased with Pirfenidone treatment. Also, SOD and CAT functional activity decreased after Pirfenidone action. On the other hand, Diphenyleneiodonium induced a drop in oxidative stress similar in extent to Pirfenidone, but it was not as effective as Pirfenidone in reducing fibrosis.

In this work, we showed antioxidant properties of Pirfenidone beyond its well-known antifibrotic effect. These features make Pirfenidone an attractive drug for trying fibrotic diseases accompanied by oxidative stress processes.

Keywords: Pirfenidone; Experimental liver; Gastrointestinal and urogenital pharmacology

Abbreviations: CCl4, carbon tetrachloride; TGF-β, transforming growth factor; GAPDH, glyceraldehyde-3P-dehydrogenase; SOD, superoxide dismutase; CAT, catalase; iNOS, inducible nitric oxide synthase; HSC, hepatic stellate cells.
Article Outline
1. Introduction
2. Materials and methods

2.1. Materials
2.2. Animals
2.3. Biochemical assays
2.4. Fibrosis index determination
2.5. Griess reaction
2.6. Malonyldealdehide (MDA) determination
2.7. Real time polymerase chain reaction (PCR)
2.8. Superoxide dismutase activity
2.9. Catalase activity
2.10. Obtention of nuclear extracts
2.11. Gel mobility shift assays

3. Results
4. Discussion
Acknowledgements
Further Reading
References