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.

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: Akinori Iwashita, Nobuteru Tojo, Shigeru Matsuura, Syunji Yamazaki, Kazunori Kamijo, Junya Ishida, Hirofumi Yamamoto, Kouji Hattori, Nobuya Matsuoka, Seitaro Mutoh
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 310 Issue 2 Pg. 425-36 (Aug 2004) ISSN: 0022-3565 [Print] United States
• PMID: 15075382 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 5-chloro-2-(3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl)-4(3H)-quinazolinone
• Enzyme Inhibitors
• Poly(ADP-ribose) Polymerase Inhibitors
• Pyridines
• Quinazolines
• Quinazolinones
• Hydrogen Peroxide
• Parp1 protein, rat
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases

Topics

• Animals
• Brain (drug effects, enzymology)
• Brain Ischemia (enzymology, prevention & control)
• Cell Death (drug effects, physiology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
• Humans
• Hydrogen Peroxide (toxicity)
• Male
• Mice
• Neurons (drug effects, enzymology)
• PC12 Cells
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Pyridines (chemistry, pharmacology, therapeutic use)
• Quinazolines (chemistry, pharmacology, therapeutic use)
• Quinazolinones
• Rats
• Rats, Wistar