Novel phenanthridinone inhibitors of poly(adenosine 5′-diphosphate-ribose) synthetase: Potent cytoprotective and antishock agents*

Abstract

The novel series of phenanthridinone PARS inhibitors have potent cytoprotective effects in vitro and significant protective effects in shock and reperfusion injury in rodent models in vivo.

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

“…We further tested the effect of blocking PARP-1 signaling with the pharmacological inhibitor PJ-34 (10 mg/kg intraperitonealy at MCAO onset, Jagtap et al, 2002;Abdelkarim et al, 2001) in ovary-intact WT female mice and obtained results consistent with those from female PARP-1-knockouts (Figure 9). Increased damage was observed in both cortex and striatum of PJ-34-treated mice with corresponding Physiological levels of E2 were restored to ovariectomized (OVX) PARPÀ/À and wild-type (WT) female mice.…”

The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity

“…Poly(ADP-ribose) polymerase (PARP) is an abundant nuclear enzyme with complex regulatory functions (Hiromatsu et al 1992, De Murcia et al 1994, Menissier-de Murcia et al 1997, Szabó et al 1997b, 1998a, 2000, Le Rhun et al 1998, Rudat et al 1998, De Murcia &Shall 2000, Davidovic et al 2001, Virág & Szabó 2002. Poly(ADPribose) polymerase-1 (PARP-1, EC 2.4.2.30) [also known as poly(ADP-ribose) synthetase (PARS)], the major PARP isoform, is a member of the PARP enzyme family consisting of PARP-1 and many additional, recently identified poly(ADP-ribosylating) enzymes (minor PARP isoforms).…”

“…Numerous overviews and monographs appeared in recent years about the structure and functions of PARP (Szabó et al 1998a, 2000, Virág & Szabó 2002, Zhang 2002. PARP is a DNA damage sensor and signaling molecule and binds to both single-and double stranded DNA breaks, becomes activated, forms homodimers and initiates an energy-consuming cycle by transferring ADP ribose units from NAD + onto nuclear acceptor proteins such as histones, transcriptional factors, DNA replication factors and signaling molecules (AP-1, DNA-PK, NFkB, Oct-1, p53) with PARP itself being the major acceptor.…”

“…In case of the histones, this process leads to electrostatic repulsion between DNA and loosening up the chromatin structure thereby making genes more accessible for gene transcription (Oikawa et al 1980, Poirier et al 1982, Park et al 1983, Satoh & Lindahl 1992, Lautier et al 1993, Herceg et al 2001. The effect of PARP on the function of these proteins is carried out by non-covalent protein-protein interactions and by covalent poly(ADP-ribosylation) (for review see Virág & Szabó 2002). Poly(ADP-ribosylation) is a dynamic process as the polymer is rapidly degraded by two enzymes: poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosyl protein lyase.…”

“…When activated by DNA breaks, PARP initiates an energy-consuming cycle resulting in the depletion of NAD + and ATP, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and necrotic cell death. Necrosis is the least desirable form of cell death as the cellular content is released into the tissue exposing neighboring cells to proteases and various pro-inflammatory factors, thereby triggering positive feedback pathways of inflammatory tissue injury (Virág & Szabó 2002). PARP-overactivation induced necrosis is also related to intracellular acidification (Herceg et al 2001, Affar et al 2002.…”