title: Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats.
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.
authors.affiliation: Department of Neurosurgery, University of Pennsylvania, Philadelphia, USA. michelle.laplaca@bme.gatech.edu
authors.forename: M C
authors.initials: MC
authors.lastname: LaPlaca
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: R
authors.initials: R
authors.lastname: Raghupathi
authors.forename: J H
authors.initials: JH
authors.lastname: Li
authors.forename: F
authors.initials: F
authors.lastname: Smith
authors.forename: F M
authors.initials: FM
authors.lastname: Bareyre
authors.forename: S H
authors.initials: SH
authors.lastname: Snyder
authors.forename: D I
authors.initials: DI
authors.lastname: Graham
authors.forename: T K
authors.initials: TK
authors.lastname: McIntosh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D001930:Brain Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001578:Benzopyrans; D004791:Enzyme Inhibitors; C417259:GPI 6150; D007546:Isoquinolines; D018696:Neuroprotective Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors