-
Salvatore Cuzzocrea,
Emanuela Mazzon,
Tiziana Genovese,
Concetta Crisafulli,
Woo-Kee Min,
Rosanna Di Paola,
Carmelo Muià, Jia-He Li,
Giuseppe Malleo,
Weizhen Xu,
Edmond Massuda,
Emanuela Esposito,
Jie Zhang,
Zhao-Qi Wang
[show abstract]
[hide abstract]
ABSTRACT: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD) by poly(ADP-ribose) polymerase 1 (PARP-1) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The aim of the present study was to examine the role of PARG in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Mice lacking the functional 110-kDa isoform of PARG (PARG(110)KO mice) were resistant to colon injury induced by DNBS. The mucosa of colon tissues showed reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Moreover, overproduction of proinflammatory factors TNF-alpha and IL-1beta and activation of cell death signaling pathway, i.e., the FAS ligand, were inhibited in these mutant mice. Finally pharmacological treatment of WT mice with GPI 16552 and 18214, two novel PARG inhibitors, showed a significant protective effect in DNBS-induced colitis. These genetic and pharmacological studies demonstrate that PARG modulates the inflammatory response and tissue injury events associated with colitis and PARG may be considered as a novel target for pharmacological intervention for the pathogenesis.
Free Radical Biology and Medicine 02/2007; 42(1):90-105. · 5.42 Impact Factor
-
Salvatore Cuzzocrea,
Tiziana Genovese,
Emanuela Mazzon,
Concetta Crisafulli,
Wookee Min,
Rosanna Di Paola,
Carmelo Muià, Jia-He Li,
Emanuela Esposito,
Placido Bramanti,
Weizheng Xu,
Edmond Massuda,
Jie Zhang,
Zhao-Qi Wang
[show abstract]
[hide abstract]
ABSTRACT: The aim of the present study was to examine the role of poly-(ADP-ribose) glycohydrolase (PARG) on the modulation of the inflammatory response and tissue injury associated with neurotrauma. Spinal cord trauma was induced in wild-type (WT) mice by the application of vascular clips (force of 24 g) to the dura via a two-level T(6) to T(7) laminectomy. Spinal cord injury in WT mice resulted in severe trauma characterized by edema, neutrophil infiltration, and cytokine production followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, apoptosis, and disease. The genetic disruption of the PARG gene in mice or the pharmacological inhibition of PARG with GPI 16552 [N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide] (40 mg/kg i.p. bolus), a novel and potent PARG inhibitor, significantly reduced the degree of spinal cord inflammation and tissue injury (histological score), neutrophil infiltration, cytokine production (tumor necrosis factor-alpha and interleukin-1beta), and apoptosis. In a separate experiment, we have clearly demonstrated that PARG inhibition significantly ameliorated the recovery of limb function. Taken together, our results indicate that PARG activity modulates the inflammatory response and tissue injury events associated with spinal cord trauma and participate in target organ damage under these conditions.
Journal of Pharmacology and Experimental Therapeutics 11/2006; 319(1):127-38. · 3.83 Impact Factor
-
Salvatore Cuzzocrea,
Rosanna Di Paola,
Emanuela Mazzon,
Ulrich Cortes,
Tiziana Genovese,
Carmelo Muià,
Weixing Li,
Weizheng Xu, Jia-He Li,
Jie Zhang,
Zhao-Qi Wang
[show abstract]
[hide abstract]
ABSTRACT: Poly (ADP-ribosyl)ation, an early post-translational modification in response to DNA damage, is catalyzed by poly (ADP-ribose) polymerase (PARP-1) and catabolized by poly(ADP-ribose) glycohydrolase (PARG). The aim of this study was to investigate the role of PARG on the modulation of the inflammatory response caused by splanchnic ischemia and reperfusion. SAO shock in rats and wild-type (WT) mice was associated with a significant neutrophil infiltration in the ileum and production of tumor necrosis factor-alpha (TNF-alpha). Reperfused ileum tissue sections from SAO-shocked WT mice and rats showed positive staining for P-selectin and ICAM-1 localized mainly in the vascular endothelial cells. Genetic disruption of the PARG gene in mice or pharmacological inhibition of PARG by PARG inhibitors significantly improved the histological status of the reperfused tissues associated with reduced expression of P-selectin and ICAM-1, neutrophil infiltration into the reperfused intestine, and TNF-alpha production. These results suggest that PARG activity modulates the inflammatory response in ischemia/reperfusion and participates in end (target) organ damage under these conditions.
The FASEB Journal 05/2005; 19(6):558-66. · 5.71 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The activation of the PARP/PARG pathway has been found in a variety of animal models of diseases, including septic shock-like syndrome. We have previously demonstrated that PARP inhibition by 3-ami-nobenzamide or GPI 6150 ameliorates multiple organ dysfunctions induced by zymosan. In the present study, we investigated whether similar effect could be achieved through PARG inhibition to break the cycle of poly(ADP-ribose) turnaround.
Experimental study.
University laboratory.
Male CD mice (20-22 g).
We tested the effects of GPI 18214 (40 mg/kg intraperitoneally bolus), a novel and potent PARG inhibitor, at 1 and 6 hr after zymosan (500 mg/kg, administered intraperitoneally as a suspension in saline) on the development of septic shock-like syndrome in mice. Organ failure and systemic inflammation in mice were assessed 18 hrs after administration of zymosan and/or GPI 18214 and monitored for 12 days (for loss of body weight and mortality).
At 18 hrs after zymosan administration, we found a significant increase of peritoneal exudates, leukocyte infiltration in peritoneal cavity as well as an infiltration of neutrophils in lung and ileum tissues and subsequent lipid peroxidation, and increased production of plasma tumor necrosis factor-alpha and interleukin-1 beta. Furthermore, zymosan administration induced significant liver, lung, pancreas, intestine, and kidney dysfunction as well as a systemic toxicity and significant loss of body weight. At the end of observation period (12 days), 90% of zymosan-treated mice were dead. GPI 18214 (40 mg/kg intraperitoneally, 1 and 6 hrs after zymosan) treatment significantly reduced peritoneal exudates, inflammatory cell infiltration, and organ injury and mortality rate in zymosan-treated mice.
This study supports early studies that show efficacy from blocking the poly(ADP-ribose) pathway in septic shock-like syndrome model. It provides evidence that GPI 18214, a PARG inhibitor, attenuates the degree of zymosan-induced nonseptic shock in mice, suggesting that PARG may be an alternative therapeutic target for shock treatment.
Critical Care Medicine 07/2004; 32(6):1365-74. · 6.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing chiral bicyclic proline analogues. Details of the synthetic routes, together with preliminary biological activity, will be presented.
Bioorganic & Medicinal Chemistry Letters 12/2003; 13(21):3867-70. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD(+)) by poly(ADP-ribose) polymerase (PARP) and degraded by poly(ADP-ribose) glycohydrolase (PARG). Overactivation of the poly(ADP-ribose) pathway increases nicotinamide and decreases cellular NAD(+)/ATP, which leads to cell death. Blocking poly(ADP-ribose) metabolism by inactivating PARP has been shown to reduce ischemia injury. We investigated whether disrupting the poly(ADP-ribose) cycle by PARG inhibition could achieve similar protection. We demonstrate that either pre- or post-ischemia treatment with 40 mg/kg of N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide, a novel PARG inhibitor, significantly reduces brain infarct volumes by 40-53% in a rat model of focal cerebral ischemia. Our result provides the first evidence that PARG inhibitors can ameliorate ischemic brain damage in vivo, in support of PARG as a new therapeutic target for treating ischemia injury.
Brain Research 08/2003; 978(1-2):99-103. · 2.73 Impact Factor
-
Gregory S Hamilton,
Yong-Qian Wu,
David C Limburg,
Douglas E Wilkinson,
Mark J Vaal, Jia-He Li,
Christine Thomas,
Wei Huang,
Hansjorg Sauer,
Douglas T Ross,
Raj Soni,
Yi Chen,
Hongshi Guo,
Pamela Howorth,
Heather Valentine,
Shi Liang,
Dawn Spicer,
Mike Fuller,
Joseph P Steiner
[show abstract]
[hide abstract]
ABSTRACT: The recent discovery that small molecule ligands for the peptidyl-prolyl isomerase (PPIase) FKBP12 possess powerful neuroprotective and neuroregenerative properties in vitro and in vivo suggests therapeutic utility for such compounds in neurodegenerative disease. The neurotrophic effects of these compounds are independent of the immunosuppressive pathways by which drugs such as FK506 and rapamycin operate. Previous work by ourselves and other groups exploring the structure-activity relationships (SAR) of small molecules that mimic only the FKBP binding domain portion of FK506 has focused on esters of proline and pipecolic acid. We have explored amide and thioester analogues of these earlier structures and found that they too are extremely potent in promoting recovery of lesioned dopaminergic pathways in a mouse model of Parkinson's disease. Several compounds were shown to be highly effective upon oral administration after lesioning of the dopaminergic pathway, providing further evidence of the potential clinical utility of a variety of structural classes of FKBP12 ligands.
Journal of Medicinal Chemistry 09/2002; 45(16):3549-57. · 5.25 Impact Factor
-
Yong-Qian Wu,
Douglas E Wilkinson,
David Limburg, Jia-He Li,
Hansjorg Sauer,
Doug Ross,
Shi Liang,
Dawn Spicer,
Heather Valentine,
Mike Fuller,
Hong Guo,
Pam Howorth,
Raj Soni,
Yi Chen,
Joseph P Steiner,
Gregory S Hamilton
[show abstract]
[hide abstract]
ABSTRACT: The recently discovered small-molecule ligands for the peptidyl and prolyl isomerases (PPIase) of FKBP12 have been shown to possess powerful neuroprotective and neuroregenerative effects. Ketone analogues of the prolyl and pipecolyl esters, which mimic only the FKBP binding domain portion of FK506, are proposed and an efficient synthetic strategy is presented in this report, along with the preliminary results of in vitro and in vivo biological studies.
Journal of Medicinal Chemistry 09/2002; 45(16):3558-68. · 5.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Poly (ADP-ribose) polymerase, a nuclear enzyme activated by DNA strand breaks, has been shown to play an important role in the pathogenesis of inflammatory bowel disease. Here we investigate the effects of 1,11b-dihydro-[2H]benzopyrano [4,3,2-de]isoquinolin-3-one (GPI 6150), a new poly (ADP-ribose) polymerase inhibitor, in animal models of experimental colitis. Colitis was induced in rats by intra-colonic instillation of dinitrobenzene sulfonic acid. Rats experienced hemorrhagic diarrhea and weight loss. At 4 days after administration of dinitrobenzensulfonic acid, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology and an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1. Immunohistochemistry for poly (ADP-ribose) showed an intense staining in the inflamed colon. GPI 6150 (20 or 40 mg/kg daily, i.p.) significantly reduced the degree of hemorrhagic diarrhea and weight loss caused by administration of dinitrobenzensulfonic acid. GPI 6150 also caused a substantial reduction of (i) the degree of colon injury, (ii) the rise in myeloperoxidase activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde, (iv) the increase in staining (immunohistochemistry) for poly (ADP-ribose), as well as (v) the upregulation of ICAM-1 and P-selectin caused by dinitrobenzensulfonic acid in the colon. Thus, GPI 6150 reduces the degree of colitis caused by dinitrobenzensulfonic acid. We propose that GPI 6150 may be useful in the treatment of inflammatory bowel disease.
Biochemical Pharmacology 08/2002; 64(2):327-37. · 4.70 Impact Factor
-
Chi Choi, Jia-He Li,
Mark Vaal,
Christine Thomas,
David Limburg,
Yong-Qian Wu,
Yi Chen,
Raj Soni,
Chad Scott,
Douglas T Ross,
Hong Guo,
Pamela Howorth,
Heather Valentine,
Shi Liang,
Dawn Spicer,
Mike Fuller,
Joseph Steiner,
Gregory S Hamilton
[show abstract]
[hide abstract]
ABSTRACT: Using simple, inexpensive equipment, we have used solution-phase parallel synthesis to rapidly prepare hundreds of sulfonamide- and urea-containing FKBP inhibitors, resulting in rapid identification of extremely potent compounds in these series.
Bioorganic & Medicinal Chemistry Letters 06/2002; 12(10):1421-8. · 2.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of the present study was to investigate the effects of GPI 6150, a new poly(ADP-ribose) polymerase (PARP) inhibitor, in the pathogenesis of splanchnic artery occlusion (SAO) shock. SAO shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed by reperfusion. At 60 min after reperfusion, SAO-shocked rats developed a significant fall in mean arterial blood pressure, significant increase of tissue myeloperoxidase activity (111 +/- 4.3 U/100 mg wet tissue vs. 28 +/- 3.2 U/100 mg wet tissue of sham-operated rats), and marked histological injury to the distal ileum and a significant mortality (0% survival at 2 h after reperfusion). Immuno-histochemical examination demonstrated a marked increase in the immunoreactivity to PARP, P-selectin, and intercellular adhesion molecule (ICAM-1) in the necrotic ileum. GPI 6150 treatment significantly improved mean arterial blood pressure, prevented the infiltration of neutrophils (72 +/- 3.6 U/100 mg wet tissue) into the reperfused intestine, improved the histological status of the reperfused tissues, markedly reduced the intensity of P-selectin and ICAM-1 in tissue section from SAO-shocked rats, and improved survival. In conclusion, our study demonstrates that GPI 6150 exerts multiple protective effects in splanchnic artery occlusion/reperfusion shock.
Shock 04/2002; 17(3):222-7. · 2.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Poly (ADP-ribose) polymerase, a nuclear enzyme activated by DNA strand breaks, has been show to play an important role in the pathogenesis of inflammation. Here, we investigate the effects of GPI 6150 (1,11b-dihydro-[2H]benzopyrano [4,3,2-de]isoquinolin-3-one), a new poly (ADP-ribose) polymerase inhibitor, in animal models of acute and chronic inflammation (carrageenan-induced paw edema, adjuvant-induced arthritis and zymosan-induced multiple organ failure) where oxygen radicals, nitric oxide and peroxynitrite are known to play a crucial role in the inflammatory process. The results show that the poly (ADP-ribose) polymerase inhibitor GPI 6150 inhibits the inflammatory response (paw swelling, and organ injury). The present results demonstrate that inhibition of poly (ADP-ribose) polymerase by GPI 6150 exerts potent anti-inflammatory effects. Part of these anti-inflammatory effects may be related to a reduction of neutrophil recruitment into the inflammatory site.
European Journal of Pharmacology 04/2001; · 2.52 Impact Factor
