Oxidative stress induced cell injury is reported to contribute to the pathogenesis of
cerebral ischemia.
Reactive oxygen species such as
hydrogen peroxide (H2O2) and
superoxide radical along with
nitric oxide and
peroxynitrite generated during
ischemia-reperfusion injury, causes the overactivation of
poly (ADP-ribose) polymerase (PARP) leading to neuronal cell death. In the present study we have evaluated the effects of
PARP inhibitor, 8-hydroxy-2 methyl-quinazolin-4-[3H]one (
NU1025) in H2O2 and 3-morphilinosyndonimine (SIN-1) induced cytotoxicity in PC12 cells as well as in
middle cerebral artery occlusion (MCAO) induced focal
cerebral ischemia in rats. Exposure of PC12 cells to H2O2 (0.4 mM) and SIN-1 (0.8 mM) resulted in a significant decrease in cell viability after 6 h. Pretreatment with
NU1025 (0.2 mM) restored cell viability to approximately 73 and 82% in H2O2 and SIN-1 injured cells, respectively. In MCAO studies,
NU1025 was administered at different time points (1 h before reperfusion, immediately before reperfusion, 3 h after reperfusion and 6 h after reperfusion).
NU1025 at 1 and 3 mg/kg reduced total
infarct volume to 25% and 45%, respectively, when administered 1 h before reperfusion.
NU1025 also produced significant improvement in neurological deficits. Neuroprotection with
NU1025 was associated with reduction in PAR accumulation, reversal of brain
NAD depletion and reduction in DNA fragmentation. Results of this study demonstrate the neuroprotective activity of
NU1025 and suggest its potential in
cerebral ischemia.