Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke.

G. E. Abdelkarim, K. Gertz, C. Harms, J. Katchanov, U. Dirnagl, Csaba Szabo, M. Endres

Research output: Contribution to journalArticle

200 Citations (Scopus)

Abstract

Focal cerebral ischemia activates the nuclear protein poly(ADP-ribose) polymerase (PARP) by single DNA strand breaks which leads to energy depletion and cell necrosis. Deletion or inhibition of PARP protects against ischemic brain injury. Here we examined the neuroprotective effect of PJ34, a novel potent inhibitor of PARP in vitro and in vivo. Serum-free primary neuronal cultures derived from rat cortex (E15-17) and kept in culture for 10 days were exposed to oxygen glucose deprivation (OGD) in vitro. Neuronal injury was quantified by LDH release after 24 h. Pretreatment with 30-1000 nM PJ34 significantly protected from OGD-induced cell injury in a dose-dependent manner. For in vivo experiments SV/129 mice were treated with PJ34 (50 microg) by intraperitoneal injection 2 h before 1 h middle cerebral artery occlusion (MCAo) and again 6 h later. Twenty-three h after reperfusion ischemic injury was significantly decreased compared to vehicle-treated controls (infarct volume reduction of 40%, p<0.05). Similarly, in a rat model of MCAo (2 h occlusion followed by up to 22 h reperfusion), PJ34 administration (10 mg/kg i.v.) significantly reduced infarct size, and the effect of the drug was maintained even if it was given as late as 10 min prior to reperfusion time. PJ34 significantly protected in a 4 h, but not in a 24 h permanent occlusion model. In conclusion, PJ34, a novel, potent inhibitor of PARP exerts massive neuroprotective agents, with a significant therapeutic window of opportunity. The present work strengthens the concept that pharmacological PARP inhibition may be a suitable approach for the treatment of acute stroke in man.

Original languageEnglish (US)
Pages (from-to)255-260
Number of pages6
JournalInternational Journal of Molecular Medicine
Volume7
Issue number3
StatePublished - Mar 2001
Externally publishedYes

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Stroke
Poly(ADP-ribose) Polymerases
Middle Cerebral Artery Infarction
Neuroprotective Agents
Reperfusion
129 Strain Mouse
Oxygen
Single-Stranded DNA Breaks
Glucose
Wounds and Injuries
Nuclear Proteins
Intraperitoneal Injections
Reperfusion Injury
Brain Ischemia
Brain Injuries
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
In Vitro Techniques
Poly(ADP-ribose) Polymerase Inhibitors
Necrosis
Therapeutics

ASJC Scopus subject areas

  • Genetics

Cite this

Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. / Abdelkarim, G. E.; Gertz, K.; Harms, C.; Katchanov, J.; Dirnagl, U.; Szabo, Csaba; Endres, M.

In: International Journal of Molecular Medicine, Vol. 7, No. 3, 03.2001, p. 255-260.

Research output: Contribution to journalArticle

Abdelkarim, G. E. ; Gertz, K. ; Harms, C. ; Katchanov, J. ; Dirnagl, U. ; Szabo, Csaba ; Endres, M. / Protective effects of PJ34, a novel, potent inhibitor of poly(ADP-ribose) polymerase (PARP) in in vitro and in vivo models of stroke. In: International Journal of Molecular Medicine. 2001 ; Vol. 7, No. 3. pp. 255-260.
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