Anti-inflammatory effects of a novel, potent inhibitor of poly (ADP-ribose) polymerase

Mabley, Jon G.; Jagtap, Prakash G.; Perretti, Mauro; Getting, Stephen J.; Salzman, Andrew L.; Virág, László; Szabó, Éva; Soriano, Francisco Garcia; Liaudet, Lucas; Abdelkarim, Galaleldin E.; Haskó, György; Marton, Anita; Southan, Garry J.; Szabó, Csaba

doi:10.1007/pl00000234

Cited by 127 publications

(109 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…PARP overactivation has been implicated in the pathogenesis of various forms of inflammation including autoimmune diabetes (Mabley et al 2001a,b, Suarez-Pinzon et al 2003. Inosine is also metabolized to uric acid, which has been demonstrated to be a scavenger of free radicals, including peroxynitrite (Ames et al 1981, Becker et al 1989.…”

Section: Discussionmentioning

confidence: 99%

The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes

Mabley

Pacher

Murthy

et al. 2008

Journal of Endocrinology

View full text Add to dashboard Cite

Endogenous purines including inosine have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for protection is very high because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic-resistant purine analogue, INO-2002, exerts antiinflammatory effects in two animal models of type I diabetes.

show abstract

Section: Discussionmentioning

confidence: 99%

The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes

Mabley

Pacher

Murthy

et al. 2008

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…Here, we evaluated the role of PARP-1 in zinc-induced microglial activation by using PARP-1 Ϫ/Ϫ microglia and by using wild-type microglia treated with the PARP inhibitor, PJ-34 (Mabley et al, 2001). Zinc-induced microglial activation was almost completely prevented under both of these conditions (Fig.…”

Section: Zinc Induces Microglia Activationmentioning

confidence: 99%

Zinc Triggers Microglial Activation

Kauppinen

Higashi²,

Suh³

et al. 2008

J. Neurosci.

160

172

View full text Add to dashboard Cite

Microglia are resident immune cells of the CNS. When stimulated by infection, tissue injury, or other signals, microglia assume an activated, "ameboid" morphology and release matrix metalloproteinases, reactive oxygen species, and other proinflammatory factors. This innate immune response augments host defenses, but it can also contribute to neuronal death. Zinc is released by neurons under several conditions in which microglial activation occurs, and zinc chelators can reduce neuronal death in animal models of cerebral ischemia and neurodegenerative disorders. Here, we show that zinc directly triggers microglial activation. Microglia transfected with a nuclear factor-B (NF-B) reporter gene showed a severalfold increase in NF-B activity in response to 30 M zinc. Cultured mouse microglia exposed to 15-30 M zinc increased nitric oxide production, increased F4/80 expression, altered cytokine expression, and assumed the activated morphology. Zinc-induced microglial activation was blocked by inhibiting NADPH oxidase, poly(ADP-ribose) polymerase-1 (PARP-1), or NF-B activation. Zinc injected directly into mouse brain induced microglial activation in wild-type mice, but not in mice genetically lacking PARP-1 or NADPH oxidase activity. Endogenous zinc release, induced by cerebral ischemia-reperfusion, likewise induced a robust microglial reaction, and this reaction was suppressed by the zinc chelator CaEDTA. Together, these results suggest that extracellular zinc triggers microglial activation through the sequential activation of NADPH oxidase, PARP-1, and NF-B. These findings identify a novel trigger for microglial activation and a previously unrecognized mechanism by which zinc may contribute to neurological disorders.

show abstract

“…[13,18] The overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidant stress, including circulatory shock, reperfusion injury, stroke, diabetes, hyperhomocysteinemia, aging, transplant acute tubular necrosis, and ischemic acute renal failure. [19][20][21][22][23] It has been reported that pharmacological inhibition and gene ablation of PARP led to improved histology and renal functions in the setting renal ischemia/reperfusion injury and renal injury associated with hemorrhagic shock. [23][24][25][26] Previous studies suggest that oxidative stress may contribute to the development of endotoxemia-induced ARF.…”

Section: Introductionmentioning

confidence: 99%

Poly (ADP-Ribose) Polymerase as a Potential Target for the Treatment of Acute Renal Injury Caused by Lipopolysaccharide

Taşatargil¹,

Aksoy²,

Dalaklıoğlu³

et al. 2008

Renal Failure

View full text Add to dashboard Cite

Recent studies have clearly reported that there is a relationship between endotoxemia and acute renal injury. The aim of this study was to investigate whether treatment with the new potent PARP inhibitor PJ34 could prevent the acute renal injury induced by lipopolysaccharide (LPS). Endotoxemia was induced by LPS injection (10 mg/kg, i.v.). LPS increased blood urea nitrogen (BUN) levels from 22 ± 0.54 mg/dL to 45.7 ± 5.79 mg/dL (p < 0.05). The plasma creatinine levels were 0.38 ± 0.02 mg/dL and 0.47 ± 0.03 mg/dL for the control and LPS groups, respectively. In addition, urinary excretion of N-acetyl-β-dglucosaminidase (NAG, a marker of renal tubular damage) was increased after LPS injection. By light microscopy, structural renal damage was observed in the LPS-treated group. However, PJ34 treatment (10 mg/kg, i.p.) attenuated LPS-induced renal injury, as indicated by plasma BUN and creatinine levels, urinary NAG excretion, and renal histology. These results indicated that the overactivation of the PARP pathway may have a role in LPSinduced renal impairment. Hence, pharmacological inhibition of this pathway might be an effective intervention to prevent endotoxin-induced acute renal injury.

show abstract

Anti-inflammatory effects of a novel, potent inhibitor of poly (ADP-ribose) polymerase

Cited by 127 publications

References 30 publications

The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes

The novel inosine analogue, INO-2002, protects against diabetes development in multiple low-dose streptozotocin and non-obese diabetic mouse models of type I diabetes

Zinc Triggers Microglial Activation

Poly (ADP-Ribose) Polymerase as a Potential Target for the Treatment of Acute Renal Injury Caused by Lipopolysaccharide

Contact Info

Product

Resources

About