Methamphetamine (METH) administration in mice, results in a chronic
dopamine (DA) depletion associated with nerve terminal damage, with DA oxidation and generation of
reactive oxygen species (ROS) primarily mediating this neurotoxicity. The oxidative stress induced by METH putatively activates nuclear
enzyme poly(ADP-ribose) polymerase (PARP), with excessive PARP activation eventually leading to cell death. In this study, we show that prevention of PARP activation by treatment with
FR261529 [2-(4-chlorophenyl)-5-quinoxalinecarboxamide], the compound that was recently identified as a novel
PARP inhibitor (IC50 for PARP-1 = 33 nM, IC50 for PARP-2 = 7 nM), protects against both ROS-induced cells injury in vitro and METH-induced dopaminergic neuronal damage in an in vivo
Parkinson's disease (PD) model. In PC12 cells, exposure of
hydrogen peroxide or METH markedly induced PARP activation, and treatment with
FR261529 (1 microM) significantly reduced PARP activation and attenuated cell death. In the mouse METH model, METH (15 mg/kg x 2 i.
p., 2 h apart) intoxication accelerated DA metabolism and oxidation in the striatum, with subsequent cell damage in nigrostriatal dopaminergic neurons after 4 days.
Oral administration of
FR261529 (10 or 32 mg/kg) attenuated the damage of dopaminergic neurons via marked reduction of PARP activity and not via changes in
dopamine metabolism or body temperature. These findings indicate that the
neuroprotective effects of a novel
PARP inhibitor,
FR261529, were accompanied by inhibition of METH-induced PARP activation, suggesting that METH induces nigrostriatal dopaminergic neurodegeneration involving PARP activation and also orally active and brain-penetrable
PARP inhibitor FR261529 could be a novel attractive therapeutic candidate for
neurodegenerative disorders such as PD.