PARP inhibition: A novel approach to treat ischaemia/reperfusion and inflammation-related injuries

J. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Poly(ADP-ribose) polymerase (PARP) is one of the most abundant nuclear enzymes. When it is activated by DNA strand breaks, PARP synthesises poly(ADP-ribose) by using nicotinamide adenine dinucleotide (NAD) as substrate. Early PARP research focused primarily on its role in facilitating structural changes of chromosomal DNA, such as during DNA repair, gene expression, DNA replication, DNA rearrangement, sister chromatid exchange, differentiation and mutagenesis. The recent discovery of PARP as a substrate for caspases has led to an intensive search for possible PARP involvement in the apoptosis pathway. Although the exact physiologic functions of PARP still remain to be firmly established, it has long been known that PARP activation can cause a rapid depletion of cellular NAD and ATP. This is mainly due to the high turnover rate of poly(ADP-ribose), which is degraded by poly(ADP-ribose) glycohydrolase. Thus, it has been proposed as a 'suicidal hypothesis' that PARP activation contributes to the energy failure that leads to cell death elicited by massive DNA damage. Indeed, there is accumulating evidence to suggest that activation of PARP by free radical damaged DNA plays a pivotal role in mediating ischaemia/reperfusion injuries. PARP emerges as a novel target to treat such injuries. The strategy of targeting PARP inhibition is validated by the findings that PARP deficient mice are extremely resistant to both cerebral and myocardial ischaemia. PARP inhibitors have demonstrated remarkable efficacy in reducing the infarct volumes of cerebral focal ischaemia and regional heart ischaemia. They also exhibit strong anti-inflammatory activities in rodent models of inflammation related injuries, e.g., septic shock, arthritis and Type I diabetes. Therefore, even at an early stage of drug discovery, PARP inhibitors have shown great potential for treating a broad spectrum of diseases.

Original languageEnglish (US)
Pages (from-to)209-221
Number of pages13
JournalEmerging Drugs
Volume4
StatePublished - 1999
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology

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