TY - JOUR
T1 - Treatment with PARP-1 inhibitors, GPI 15427 or GPI 16539, ameliorates intestinal damage in rat models of colitis and shock
AU - Di Paola, Rosanna
AU - Mazzon, Emanuela
AU - Xu, Weizheng
AU - Genovese, Tiziana
AU - Ferrraris, Dana
AU - Muià, Carmelo
AU - Crisafulli, Concetta
AU - Zhang, Jie
AU - Cuzzocrea, Salvatore
PY - 2005/12/19
Y1 - 2005/12/19
N2 - 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.
AB - 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.
KW - Colitis
KW - GPI 15427
KW - GPI 16539
KW - Ischemia/Reperfusion
KW - Myeloperoxidase
KW - PARP-1
UR - http://www.scopus.com/inward/record.url?scp=28544450635&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28544450635&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2005.09.055
DO - 10.1016/j.ejphar.2005.09.055
M3 - Article
C2 - 16310767
AN - SCOPUS:28544450635
SN - 0014-2999
VL - 527
SP - 163
EP - 171
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -