Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats

M. C. LaPlaca, J. Zhang, R. Raghupathi, J. H. Li, F. Smith, F. M. Bareyre, S. H. Snyder, D. I. Graham, T. K. McIntosh

Research output: Contribution to journalArticlepeer-review

Abstract

The nuclear enzyme poly(ADP-ribose) polymerase (PARP), which has been shown to be activated following experimental traumatic brain injury (TBI), binds to DNA strand breaks and utilizes nicotinamide adenine dinucleotide (NAD) as a substrate. Since consumption of NAD may be deleterious to recovery in the setting of CNS injury, we examined the effect of a potent PARP inhibitor, GPI 6150, on histological outcome following TBI in the rat. Rats (n = 16) were anesthetized, received a preinjury dose of GPI 6150 (30 min; 15 mg/kg, i.p.), subjected to lateral fluid percussion (FP) brain injury of moderate severity (2.5-2.8 atm), and then received a second dose 3 h postinjury (15 mg/kg, i.p.). Lesion area was examined using Nissl staining, while DNA fragmentation and apoptosis-associated cell death was assessed with terminal deoxynucleotidyl-transferase-mediated biotin-dUTP nick end labeling (TUNEL) with stringent morphological evaluation. Twenty-four hours after brain injury, a significant cortical lesion and number of TUNEL-positive/nonapoptotic cells and TUNEL-positive/apoptotic cells in the injured cortex of vehicle-treated animals were observed as compared to uninjured rats. The size of the trauma-induced lesion area was significantly attenuated in the GPI 6150-treated animals versus vehicle-treated animals (p < 0.05). Treatment of GPI 6150 did not significantly affect the number of TUNEL-positive apoptotic cells in the injured cortex. The observed neuroprotective effects on lesion size, however, offer a promising option for further evaluation of PARP inhibition as a means to reduce cellular damage associated with TBI.

Original languageEnglish (US)
Pages (from-to)369-376
Number of pages8
JournalJournal of neurotrauma
Volume18
Issue number4
DOIs
StatePublished - 2001

Keywords

  • Apoptosis
  • DNA damage
  • DNA repair
  • Experimental brain injury
  • NAD
  • PARP

ASJC Scopus subject areas

  • Clinical Neurology

Fingerprint

Dive into the research topics of 'Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats'. Together they form a unique fingerprint.

Cite this