Effects of 5‐aminoisoquinolinone, a water‐soluble, potent inhibitor of the activity of poly (ADP‐ribose) polymerase on the organ injury and dysfunction caused by haemorrhagic shock

McDonald, Michelle C.; Mota-Filipe, Hélder; Wright, James A.; Abdelrahman, Maha; Threadgill, Michael D.; Thompson, Andrew S.; Thiemermann, Christoph

doi:10.1038/sj.bjp.0703391

Cited by 90 publications

(84 citation statements)

References 34 publications

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“…However, this damaging sequence of events was not seen in PARP-deficient mice with hemorrhagic shock (24). In addition, other studies of rats undergoing hemorrhagic shock and resuscitation have shown that the prevention of PARP activation decreases hepatic damage and dysfunction (28,45). In our study, PARP fragmentation was significantly prevented by pyruvate administration compared with the 0.9% and 10% NaCl groups of swine.…”

Section: Discussionsupporting

confidence: 57%

Pyruvate improves redox status and decreases indicators of hepatic apoptosis during hemorrhagic shock in swine

Mongan

Capacchione

West

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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. Pyruvate improves redox status and decreases indicators of hepatic apoptosis during hemorrhagic shock in swine. Am J Physiol Heart Circ Physiol 283: H1634-H1644, 2002. First published June 20, 2002 10.1152/ ajpheart.01073.2001.-Previous studies have shown that the liver is the first organ to display signs of injury during hemorrhagic shock. We examined the mechanism by which pyruvate can prevent liver damage during hemorrhagic shock in swine anesthetized with halothane. Thirty minutes after the induction of a 240-min controlled arterial hemorrhage targeted at 40 mmHg, hypertonic sodium pyruvate (0.5 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ) was infused to achieve an arterial concentration of 5 mM. The volume and osmolality effects of pyruvate were matched with 10% saline (HTS) and 0.9% saline (NS). Although the peak hemorrhage volume increased significantly in both the pyruvate and HTS group, only the pyruvate treatment was effective in delaying cardiovascular decompensation. In addition, pyruvate effectively maintained the NADH/NAD redox state, as evidenced by increased microdialysate pyruvate levels and a significantly lower lactateto-pyruvate ratio. Pyruvate also prevented the loss of intracellular antioxidants (GSH) and a reduction in the GSH-to-GSSG ratio. These beneficial effects on the redox environment decreased hepatic cellular death by apoptosis. Pyruvate significantly increased the ratio of Bcl-Xl (antiapoptotic molecule)/Bax (proapoptotic molecule), prevented the release of cytochrome c from mitochondria, and decreased the fragmentation of caspase 3 and poly(ADP ribose) polymerase (DNA repair enzyme). These beneficial findings indicate that pyruvate infused 30 min after the onset of severe hemorrhagic shock is effective in maintaining the redox environment, preventing the loss of the key antioxidant GSH, and decreasing early apoptosis indicators. glutathione; redox state; caspases DESPITE ADVANCES IN THE EARLY CARE of trauma victims over the past two decades, multiple organ failure (MOF) continues to be a major factor in the morbidity and mortality that occurs after resuscitation from hemorrhagic shock (16). While there are numerous factors that influence the development of MOF, there is increasing evidence that hepatic dysfunction plays a central role (21,24,42,43). Experimental studies have shown that despite acute aggressive resuscitation, there is a consistent depression in microvascular blood flow that results in hypoperfusion and progressive hepatic dysfunction (32,42,43). This suggests that despite the restoration of global oxygen delivery, additional pharmacological therapies are needed to prevent or reverse ongoing hepatotoxicity. However, the precise mechanisms of hepatocellular dysfunction after severe hemorrhagic shock are not well defined. Some investigators have shown that the reduction in immunological mediators, such as tumor necrosis factor-␣, improves outcome indicators (23,41). Others have shown that there is severe hepatic energy depletion during hemorrhagic shock and that improvement in the hepatoce...

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Section: Discussionsupporting

confidence: 57%

Pyruvate improves redox status and decreases indicators of hepatic apoptosis during hemorrhagic shock in swine

Mongan

Capacchione

West

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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“…To investigate whether the effect of oxChol on EAE we observed was mediated by PARP we used the PARP inhibitor, 5-Aminoisoquinolinone (AIQ) (20). We found that AIQ abrogated the worsening of EAE caused by oxChol both clinically (P Ͻ 0.0001, 2-way ANOVA) and histopathologically (P Ͻ 0.001, 1-way ANOVA) (Fig.…”

Section: Cholesterol Derivatives Worsen Experimental Autoimmune Encepmentioning

confidence: 99%

“…by preincubation of the serum with excess, unbound PLP 261-277 , but not with a control peptide, HSP60 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] (Fig. S1B).…”

Section: Conditions To Detect Specific Microarray Autoantibodies In Msmentioning

confidence: 99%

Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis

Quintana

Farez

Viglietta

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

229

213

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Multiple sclerosis (MS) is a chronic relapsing disease of the central nervous system (CNS) in which immune processes are believed to play a major role. To date, there is no reliable method by which to characterize the immune processes and their changes associated with different forms of MS and disease progression. We performed antigen microarray analysis to characterize patterns of antibody reactivity in MS serum against a panel of CNS protein and lipid autoantigens and heat shock proteins. Informatic analysis consisted of a training set that was validated on a blinded test set. The results were further validated on an independent cohort of relapsing-remitting (RRMS) samples. We found unique autoantibody patterns that distinguished RRMS, secondary progressive (SPMS), and primary progressive (PPMS) MS from both healthy controls and other neurologic or autoimmune driven diseases including Alzheimer's disease, adrenoleukodystropy, and lupus erythematosus. RRMS was characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. In addition, RRMS, SPMS, and PPMS were characterized by unique patterns of reactivity to CNS antigens. Furthermore, we examined sera from patients with different immunopathologic patterns of MS as determined by brain biopsy, and we identified unique antibody patterns to lipids and CNS-derived peptides that were linked to each type of pathology. The demonstration of unique serum immune signatures linked to different stages and pathologic processes in MS provides an avenue to monitor MS and to characterize immunopathogenic mechanisms and therapeutic targets in the disease.antibodies ͉ autoimmunity ͉ biomarker

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“…[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. [27,28] Besides, a role for PARP in inflammation, which is a possible causative factor for renal damage during sepsis, has been reported.…”

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

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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.

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Effects of 5‐aminoisoquinolinone, a water‐soluble, potent inhibitor of the activity of poly (ADP‐ribose) polymerase on the organ injury and dysfunction caused by haemorrhagic shock

Cited by 90 publications

References 34 publications

Pyruvate improves redox status and decreases indicators of hepatic apoptosis during hemorrhagic shock in swine

Pyruvate improves redox status and decreases indicators of hepatic apoptosis during hemorrhagic shock in swine

Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis

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

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