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 high-throughput 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 pre- and post-treatment with
FR255595 (10(-9)-10(-5) 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.