Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat

Lu, Xi‐Chun M.; Massuda, Edmond; Lin, Qian; Li, Weixing; Li, Jiahe; Zhang, Jie

doi:10.1016/s0006-8993(03)02774-4

Cited by 65 publications

(56 citation statements)

References 16 publications

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“…It has been reported that PARG inhibitors protect neural cells from oxidative stress, excitotoxicity and brain ischemia (Ying et al, 2001;Lu et al, 2003). Possibly, acute drug actions have a different outcome than congenital PARG suppression.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) Accumulation and Enhancement of Postischemic Brain Damage in 110-kDa Poly(ADP-ribose) Glycohydrolase Null Mice

Cozzi

Cipriani

Fossati

et al. 2005

J Cereb Blood Flow Metab

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Poly(ADP-ribose) (PAR) is a polymer synthesized by poly(ADP-ribose) polymerases (PARPs) and metabolized into free adenosine diphosphate (ADP)-ribose units by poly(ADP-ribose) glycohydrolase (PARG). Perturbations in PAR synthesis have been shown to play a key role in brain disorders including postischemic brain damage. A single parg gene but two PARG isoforms (110 and 60 kDa) have been detected in mouse cells. Complete suppression of parg gene causes early embryonic lethality, whereas mice selectively lacking the 110 kDa PARG isoform (PARG 110 À/À ) develop normally. We used PARG 110 À/À mice to evaluate the importance of PAR catabolism to postischemic brain damage. Poly(ADP-ribose) contents were higher in the brain tissue of PARG 110 À/À than PARG 110 + / + mice, both under basal conditions and after PARP activation. Distal middle cerebral artery occlusion caused higher increase of brain PAR levels and larger infarct volumes in PARG 110 À/À mice than in wildtype counterparts. Of note, the brain of PARG 110 À/À mice showed reduced heat-shock protein (HSP)-70 and increased cyclooxygenase-2 expression under both control and ischemic conditions. No differences were detected in brain expression/activation of procaspase-3, PARP-1, Akt, HSP-25 and interleukin-1b. Our findings show that PAR accumulation worsens ischemic brain injury, and highlight the therapeutic potential of strategies capable of maintaining PAR homeostasis.

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Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribose) Accumulation and Enhancement of Postischemic Brain Damage in 110-kDa Poly(ADP-ribose) Glycohydrolase Null Mice

Cozzi

Cipriani

Fossati

et al. 2005

J Cereb Blood Flow Metab

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“…In fact, gallotannin enhanced the damage in astrocytes associated with the nonoxidative DNA-damaging agent N-methyl-NЈ-nitro-N-nitrosoguanidine. In the same study, the authors looked at the synthetic PARG inhibitor GPI 16552, which was shown recently to be protective in a model of brain I/R (20). It was found that GPI 16552 had no effect on astrocyte death models, and the maximal inhibition of PARG achieved with GPI 16552 was only 40% (43).…”

Section: Discussionmentioning

confidence: 99%

Mice Lacking the 110-kD Isoform of Poly(ADP-Ribose) Glycohydrolase Are Protected against Renal Ischemia/Reperfusion Injury

Patel

Cortes

Poala

et al. 2005

Journal of the American Society of Nephrology

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“…Thus, PARG appears to be an enzyme essential in development, especially of the central nervous system, through its effects on PAR degradation. However, PARG inhibitors and siRNA depletion of PARG had protective effects in animal models of stroke and hydrogen peroxide (H 2 O 2 )-induced cell death (24)(25)(26)(27). Viable and fertile mice deficient in nuclear 110-kDa PARG were generated by targeted deletion of exons 2 and 3 of the parg gene (28).…”

mentioning

confidence: 99%

ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress

Mashimo

Katō

Moss

2013

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

139

156

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Poly (ADP ribose) (PAR) formation catalyzed by PAR polymerase 1 in response to genotoxic stress mediates cell death due to necrosis and apoptosis. PAR glycohydrolase (PARG) has been thought to be the only enzyme responsible for hydrolysis of PAR in vivo. However, we show an alternative PAR-degradation pathway, resulting from action of ADP ribosyl-acceptor hydrolase (ARH) 3. PARG and ARH3, acting in tandem, regulate nuclear and cytoplasmic PAR degradation following hydrogen peroxide (H 2 O 2 ) exposure. PAR is responsible for induction of parthanatos, a mechanism for caspaseindependent cell death, triggered by apoptosis-inducing factor (AIF) release from mitochondria and its translocation to the nucleus, where it initiates DNA cleavage. PARG, by generating protein-free PAR from poly-ADP ribosylated protein, makes PAR translocation possible. A protective effect of ARH3 results from its lowering of PAR levels in the nucleus and the cytoplasm, thereby preventing release of AIF from mitochondria and its accumulation in the nucleus. Thus, PARG release of PAR attached to nuclear proteins, followed by ARH3 cleavage of PAR, is essential in regulating PAR-dependent AIF release from mitochondria and parthanatos.posttranslational modification | cytotoxicity P oly-ADP ribosylation is a reversible posttranslational modification of proteins, which results from the covalent attachment of branched polymers of ADP ribose moieties to amino acid residues of target proteins, in a reaction catalyzed by poly (ADP ribose) polymerases (PARP) (1-3). PARP1, a well-characterized member of the PARP family, is a nuclear protein that acts as a molecular sensor of DNA-strand breaks. Upon binding to sites of single-strand DNA breaks, PARP1 catalyzes the formation of a branched, long poly (ADP ribose) (PAR) chain attached to glutamate or aspartate residues of acceptor proteins including histones, DNA polymerases, topoisomerases, DNA ligase-2, transcription factors, and PARP1 itself (4-7). Poly-ADP ribosylation of these acceptor proteins alters their physical and biological properties, leading to DNA repair and the maintenance of genomic stability. In contrast, PARP1 overactivation, resulting from widespread DNA damage, accelerates

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Post-treatment with a novel PARG inhibitor reduces infarct in cerebral ischemia in the rat

Cited by 65 publications

References 16 publications

Poly(ADP-ribose) Accumulation and Enhancement of Postischemic Brain Damage in 110-kDa Poly(ADP-ribose) Glycohydrolase Null Mice

Poly(ADP-ribose) Accumulation and Enhancement of Postischemic Brain Damage in 110-kDa Poly(ADP-ribose) Glycohydrolase Null Mice

Mice Lacking the 110-kD Isoform of Poly(ADP-Ribose) Glycohydrolase Are Protected against Renal Ischemia/Reperfusion Injury

ADP-ribosyl-acceptor hydrolase 3 regulates poly (ADP-ribose) degradation and cell death during oxidative stress

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