Neuroprotective effects of inhibiting poly(ADP-ribose) synthetase on focal cerebral ischemia in rats

Kazushi Takahashi, Joel H. Greenberg, Paul Jackson, Keith Maclin, Jie Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Poly(adenosine 5'-diphosphoribose) synthetase (PARS) has been described as an important candidate for mediation of neurotoxicity by nitric oxide. In the current study, we demonstrate for the first time that in vivo administration of a potent PARS inhibitor, 3,4-dihydro 5-[4-1(1-piperidinyl) butoxy]-1(2H)-isoquinolinone, leads to a significant reduction of infarct volume in a focal cerebral ischemia model in the rat. Focal cerebral ischemia was produced by cauterization of the right distal middle cerebral artery (MCA) with bilateral temporary common carotid artery occlusion for 90 minutes. 3,4-Dihydro 5[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone was dissolved in dimethyl sulfoxide and injected intraperitoneally. Animals were treated 2 hours before MCA occlusion (control, n = 14; 5 mg/kg, n = 7; 10 mg/kg, n = 7; 20 mg/kg, n = 7; 40 mg/kg, n = 7), and 2 hours after MCA occlusion (same doses as before treatment). Twenty-four hours after MCA occlusion, the total infarct volume was measured using 2,3,5- triphenyltetrazolium chloride. Inhibition of PARS leads to a significant decrease in the damaged volume in the 5 mg/kg-treated group (106.7 ± 23.2 mm3; mean ± SD, P <0.002), the 10 mg/kg-treated group (76.4 ± 16.8 mm3, P <0.001), and the 20 mg/kg-treated group (110.2 ± 42.0 mm3, P <0.02) compared with the control group (165.2 ± 34.0 mm3). The substantial reduction in infarct volume indicates that the activation of PARS may play an important role in the pathogenesis of brain damage in cerebral ischemia through intracellular energy depletion.

Original languageEnglish (US)
Pages (from-to)1137-1142
Number of pages6
JournalJournal of Cerebral Blood Flow and Metabolism
Volume17
Issue number11
StatePublished - Nov 1997
Externally publishedYes

Keywords

  • Cerebral ischemia
  • Middle cerebral artery occlusion
  • Neuroprotection
  • Nitric oxide
  • Poly(ADP-ribose) polymerase
  • Rat

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

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