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A novel and potent poly(ADP-ribose) polymerase-1 inhibitor, FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), attenuates neuronal damage in in vitro and in vivo models of cerebral ischemia.
J Pharmacol Exp Ther. 2004 Aug; 310(2):425-36.JP

Abstract

The activation of poly(ADP-ribose) polymerase-1 (PARP-1) after exposure to nitric oxide or oxygen-free radicals can lead to cell injury via severe, irreversible depletion of NAD. Genetic deletion or pharmacological inhibition of PARP-1 attenuates brain injury after focal ischemia and neurotoxicity in several neurodegenerative models in animals. FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone) is a novel PARP-1 inhibitor that has recently been identified through structure-based drug design. In an enzyme kinetic analysis, FR247304 exhibits potent and competitive inhibition of PARP-1 activity, with a K(i) value of 35 nM. Here, we show that prevention of PARP activation by FR247304 treatment protects against both reactive oxygen species-induced PC12 cell injury in vitro and ischemic brain injury in vivo. In cell death model, treatment with FR247304 (10(-8)-10(-5) M) significantly reduced NAD depletion by PARP-1 inhibition and attenuated cell death after hydrogen peroxide (100 microM) exposure. After 90 min of middle cerebral artery occlusion in rats, poly(ADP-ribosy)lation and NAD depletion were markedly increased in the cortex and striatum from 1 h after reperfusion. The increased poly(ADP-ribose) immunoreactivity and NAD depletion were attenuated by FR247304 (32 mg/kg i.p.) treatment, and FR247304 significantly decreased ischemic brain damage measured at 24 h after reperfusion. Whereas other PARP inhibitors such as 3-aminobenzamide and PJ34 [N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylactamide] showed similar neuroprotective actions, they were less potent in in vitro assays and less efficacious in an in vivo model compared with FR247304. These results indicate that the novel PARP-1 inhibitor FR247304 exerts its neuroprotective efficacy in in vitro and in vivo experimental models of cerebral ischemia via potent PARP-1 inhibition and also suggest that FR247304 or its derivatives could be attractive therapeutic candidates for stroke and neurodegenerative disease.

Authors+Show Affiliations

Iwashita A
Department of Neuroscience, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6 Kashima, Yodogawa-ku, Osaka 532-8514, Japan. aki_iwashita@po.fujisawa.co.jp
Tojo N
No affiliation info available
Matsuura S
No affiliation info available
Yamazaki S
No affiliation info available
Kamijo K
No affiliation info available
Ishida J
No affiliation info available
Yamamoto H
No affiliation info available
Hattori K
No affiliation info available
Matsuoka N
No affiliation info available
Mutoh S
No affiliation info available

MeSH

AnimalsBrainBrain IschemiaCell DeathDose-Response Relationship, DrugEnzyme InhibitorsHumansHydrogen PeroxideMaleMiceNeuronsPC12 CellsPoly (ADP-Ribose) Polymerase-1Poly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesPyridinesQuinazolinesQuinazolinonesRatsRats, Wistar

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

15075382

Citation

Iwashita, Akinori, et al. "A Novel and Potent poly(ADP-ribose) Polymerase-1 Inhibitor, FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), Attenuates Neuronal Damage in in Vitro and in Vivo Models of Cerebral Ischemia." The Journal of Pharmacology and Experimental Therapeutics, vol. 310, no. 2, 2004, pp. 425-36.
Iwashita A, Tojo N, Matsuura S, et al. A novel and potent poly(ADP-ribose) polymerase-1 inhibitor, FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), attenuates neuronal damage in in vitro and in vivo models of cerebral ischemia. J Pharmacol Exp Ther. 2004;310(2):425-36.
Iwashita, A., Tojo, N., Matsuura, S., Yamazaki, S., Kamijo, K., Ishida, J., Yamamoto, H., Hattori, K., Matsuoka, N., & Mutoh, S. (2004). A novel and potent poly(ADP-ribose) polymerase-1 inhibitor, FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), attenuates neuronal damage in in vitro and in vivo models of cerebral ischemia. The Journal of Pharmacology and Experimental Therapeutics, 310(2), 425-36.
Iwashita A, et al. A Novel and Potent poly(ADP-ribose) Polymerase-1 Inhibitor, FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), Attenuates Neuronal Damage in in Vitro and in Vivo Models of Cerebral Ischemia. J Pharmacol Exp Ther. 2004;310(2):425-36. PubMed PMID: 15075382.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel and potent poly(ADP-ribose) polymerase-1 inhibitor, FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), attenuates neuronal damage in in vitro and in vivo models of cerebral ischemia. AU - Iwashita,Akinori, AU - Tojo,Nobuteru, AU - Matsuura,Shigeru, AU - Yamazaki,Syunji, AU - Kamijo,Kazunori, AU - Ishida,Junya, AU - Yamamoto,Hirofumi, AU - Hattori,Kouji, AU - Matsuoka,Nobuya, AU - Mutoh,Seitaro, Y1 - 2004/04/09/ PY - 2004/4/13/pubmed PY - 2005/3/29/medline PY - 2004/4/13/entrez SP - 425 EP - 36 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 310 IS - 2 N2 - The activation of poly(ADP-ribose) polymerase-1 (PARP-1) after exposure to nitric oxide or oxygen-free radicals can lead to cell injury via severe, irreversible depletion of NAD. Genetic deletion or pharmacological inhibition of PARP-1 attenuates brain injury after focal ischemia and neurotoxicity in several neurodegenerative models in animals. FR247304 (5-chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone) is a novel PARP-1 inhibitor that has recently been identified through structure-based drug design. In an enzyme kinetic analysis, FR247304 exhibits potent and competitive inhibition of PARP-1 activity, with a K(i) value of 35 nM. Here, we show that prevention of PARP activation by FR247304 treatment protects against both reactive oxygen species-induced PC12 cell injury in vitro and ischemic brain injury in vivo. In cell death model, treatment with FR247304 (10(-8)-10(-5) M) significantly reduced NAD depletion by PARP-1 inhibition and attenuated cell death after hydrogen peroxide (100 microM) exposure. After 90 min of middle cerebral artery occlusion in rats, poly(ADP-ribosy)lation and NAD depletion were markedly increased in the cortex and striatum from 1 h after reperfusion. The increased poly(ADP-ribose) immunoreactivity and NAD depletion were attenuated by FR247304 (32 mg/kg i.p.) treatment, and FR247304 significantly decreased ischemic brain damage measured at 24 h after reperfusion. Whereas other PARP inhibitors such as 3-aminobenzamide and PJ34 [N-(6-oxo-5,6-dihydro-phenanthridin-2-yl)-N,N-dimethylactamide] showed similar neuroprotective actions, they were less potent in in vitro assays and less efficacious in an in vivo model compared with FR247304. These results indicate that the novel PARP-1 inhibitor FR247304 exerts its neuroprotective efficacy in in vitro and in vivo experimental models of cerebral ischemia via potent PARP-1 inhibition and also suggest that FR247304 or its derivatives could be attractive therapeutic candidates for stroke and neurodegenerative disease. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15075382/A_novel_and_potent_poly_ADP_ribose__polymerase_1_inhibitor_FR247304__5_chloro_2_[3__4_phenyl_36_dihydro_1_2H__pyridinyl_propyl]_4_3H__quinazolinone__attenuates_neuronal_damage_in_in_vitro_and_in_vivo_models_of_cerebral_ischemia_ DB - PRIME DP - Unbound Medicine ER -
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