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Neuroprotective effects of NU1025, a PARP inhibitor in cerebral ischemia are mediated through reduction in NAD depletion and DNA fragmentation.
Life Sci. 2006 Nov 10; 79(24):2293-302.LS

Abstract

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.

Authors+Show Affiliations

Molecular Neuropharmacology Laboratory, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar (Mohali), Punjab-160062, India.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16935310

Citation

Kaundal, Ravinder K., et al. "Neuroprotective Effects of NU1025, a PARP Inhibitor in Cerebral Ischemia Are Mediated Through Reduction in NAD Depletion and DNA Fragmentation." Life Sciences, vol. 79, no. 24, 2006, pp. 2293-302.
Kaundal RK, Shah KK, Sharma SS. Neuroprotective effects of NU1025, a PARP inhibitor in cerebral ischemia are mediated through reduction in NAD depletion and DNA fragmentation. Life Sci. 2006;79(24):2293-302.
Kaundal, R. K., Shah, K. K., & Sharma, S. S. (2006). Neuroprotective effects of NU1025, a PARP inhibitor in cerebral ischemia are mediated through reduction in NAD depletion and DNA fragmentation. Life Sciences, 79(24), 2293-302.
Kaundal RK, Shah KK, Sharma SS. Neuroprotective Effects of NU1025, a PARP Inhibitor in Cerebral Ischemia Are Mediated Through Reduction in NAD Depletion and DNA Fragmentation. Life Sci. 2006 Nov 10;79(24):2293-302. PubMed PMID: 16935310.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotective effects of NU1025, a PARP inhibitor in cerebral ischemia are mediated through reduction in NAD depletion and DNA fragmentation. AU - Kaundal,Ravinder K, AU - Shah,Kaushik K, AU - Sharma,Shyam S, Y1 - 2006/08/02/ PY - 2006/04/24/received PY - 2006/07/24/revised PY - 2006/07/27/accepted PY - 2006/8/29/pubmed PY - 2006/12/21/medline PY - 2006/8/29/entrez SP - 2293 EP - 302 JF - Life sciences JO - Life Sci VL - 79 IS - 24 N2 - 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. SN - 0024-3205 UR - https://www.unboundmedicine.com/medline/citation/16935310/Neuroprotective_effects_of_NU1025_a_PARP_inhibitor_in_cerebral_ischemia_are_mediated_through_reduction_in_NAD_depletion_and_DNA_fragmentation_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0024-3205(06)00596-0 DB - PRIME DP - Unbound Medicine ER -