Treatment with PARP-1 inhibitors, GPI 15427 or GPI 16539, ameliorates intestinal damage in rat models of colitis and shock.
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.
Di Paola
Rosanna
R
Department of Clinical and Experimental Medicine and Pharmacology, Torre Biologica, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi, 98100 Messina, Italy.
Mazzon
Emanuela
E
Xu
Weizheng
W
Genovese
Tiziana
T
Ferrraris
Dana
D
Muià
Carmelo
C
Crisafulli
Concetta
C
Zhang
Jie
J
Cuzzocrea
Salvatore
S
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D003092:Colitis / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007422:Intestines / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology / Q000627:therapeutic use*; D009930:Organic Chemicals / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012769:Shock / Q000188:drug therapy*; D013152:Splanchnic Circulation / Q000187:drug effects
C476143:2-(4-methylpiperazin-1-yl)-5H-benzo(c)(1,5)naphthyridin-6-one; D000893:Anti-Inflammatory Agents; D009287:Naphthyridines; D009930:Organic Chemicals; D010879:Piperazines; D010880:Piperidines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C502278:GPI 15427; D011065:Poly(ADP-ribose) Polymerases