Treatment with PARP-1 inhibitors, GPI 15427 or GPI 16539, ameliorates intestinal damage in rat models of colitis and shock

Rosanna Di Paola, Emanuela Mazzon, Weizheng Xu, Tiziana Genovese, Dana Ferrraris, Carmelo Muià, Concetta Crisafulli, Jie Zhang, Salvatore Cuzzocrea

Research output: Contribution to journalArticle

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme activated by DNA strand breaks, plays a detrimental role during inflammation. As inflammation is important in the development of colitis and ischemia/reperfusion (I/R) injury of the intestine, we investigated the effects of 10-(4-methyl-piperazin-1- ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-one (GPI 15427) and 2-(4-methyl-piperazin-1-yl)-5H-benzo[c][1,5]naphthyridin-6-one (GPI 16539), two novel and potent inhibitors of PARP-1, in a rat model of gut injury and inflammation, splanchnic artery occlusion (SAO)shock and dinitrobenzene sulfonic acid (DNBS)-induced colitis. We report here for the first time that post-injury administration of GPI 15427 and GPI 16539 exerts potent anti-inflammatory effects by reducing inflammatory cell infiltration and histological injury, and delaying the development of clinical signs in both in vivo models. Furthermore, GPI 15427 and GPI 16539 treatment diminished the accumulation of poly(ADP-ribose) in the ileum of splanchnic artery occlusion-shocked rats and in the colons of dinitrobenzene sulfonic acid-treated rats. Thus, GPI 15427 and GPI 16539 exhibited anti-inflammation activity against damage caused by intestinal ischemia/reperfusion and colitis. GPI 15427 and GPI 16539 may be useful for treating gut ischemia and inflammation.

Original languageEnglish (US)
Pages (from-to)163-171
Number of pages9
JournalEuropean Journal of Pharmacology
Volume527
Issue number1-3
DOIs
StatePublished - Dec 19 2005
Externally publishedYes

Keywords

  • Colitis
  • GPI 15427
  • GPI 16539
  • Ischemia/Reperfusion
  • Myeloperoxidase
  • PARP-1

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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  • Cite this

    Di Paola, R., Mazzon, E., Xu, W., Genovese, T., Ferrraris, D., Muià, C., Crisafulli, C., Zhang, J., & Cuzzocrea, S. (2005). Treatment with PARP-1 inhibitors, GPI 15427 or GPI 16539, ameliorates intestinal damage in rat models of colitis and shock. European Journal of Pharmacology, 527(1-3), 163-171. https://doi.org/10.1016/j.ejphar.2005.09.055