Neuroprotective Effects of a Novel Poly(ADP-Ribose) Polymerase-1 Inhibitor, 2-{3-[4-(4-Chlorophenyl)-1-piperazinyl] propyl}-4(3H)-quinazolinone (FR255595), in an in Vitro Model of Cell Death and in Mouse 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Model of Parkinson's Disease

Abstract

The massive activation of poly(ADP-ribose) polymerase-1 (PARP-1) by DNA-damaging stimuli, such as exposure to reactive oxygen species (ROS), can lead to cell injury via severe, irreversible depletion of the NAD and ATP pool, and PARP-1 inhibitors have been expected to rescue neurons from degeneration in a number of disease models. We have recently identified 2-{3-[4-(4-chlorophenyl)-1-piperazinyl] propyl}-4(3H)-quinazolinone (FR255595) as a novel and potent PARP-1 inhibitor through structure-based drug design and highthroughput screening. This compound potently inhibited PARP activity with an IC 50 value of 11 nM and was orally active and highly brain penetrable. Here, we show that prevention of PARP activation by FR255595 protects against both ROS-induced cells injury in vitro and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal dopaminergic damage in an in vivo Parkinson's disease (PD) model. In cell death models in vitro, exposure of hydrogen peroxide induced cell death with PARP overactivation in PC12 cells and SH-SY5Y cells, and preand post-treatment with FR255595 (10 Ϫ9 -10 Ϫ5 M) significantly reduced PARP activation and cell death. In mouse MPTP model, MPTP (20 mg/kg i.p.) intoxication lead to PARP activation and cell damage in the nigrostriatal dopaminergic pathway, which was significantly ameliorated by oral administration of FR255595 (10 -32 mg/kg), both in the substantia nigra and in the striatum via marked reduction of PARP activation, even with delayed treatment. These findings clearly indicate that the novel PARP-1 inhibitor FR255595 exerts neuroprotective effect through its potent PARP-1 inhibitory actions in PD model, suggesting that the drug could be an attractive candidate for several neurodegenerative disorders, including PD.Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme and normally functions in DNA repair, but extensive PARP activation can promote cell death through processes involving energy depletion. It has been reported that reactive oxygen species (ROS)-mediated damage of DNA can activate PARP (Berger, 1985;Szabo and Dawson, 1998) and consumes NAD and consequently ATP, culminating in cell dysfunction or necrosis (Ha and Snyder, 1999). On the other hand, PARP plays a central role in a caspase-independent apoptosis pathway mediated by apoptosis-inducing factor (Yu et al., 2002). Translocation of apoptosis-inducing factor from the mitochondria to the nucleus is dependent on PARP activation in neurons treated with various DNA-damaging stimuli such as N-methly- NЈ-nitro-N-nitrosoguanidine, N-methyl-D-aspartate, or hydrogen peroxide (Yu et al., 2002). This cellular suicide mechanism of both necrosis and apoptosis by PARP activation has been implicated in the pathogenesis of brain injury and neurodegenerative disorders such as Parkinson's disease (PD), a chronic progressive neurologic Article, publication date, and citation information can be found at

Neuroprotective Effect of Protein Kinase Cδ Inhibitor Rottlerin in Cell Culture and Animal Models of Parkinson's Disease

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