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

Citation
Mc. Laplaca et al., Pharmacologic inhibition of poly(ADP-ribose) polymerase is neuroprotectivefollowing traumatic brain injury in rats, J NEUROTRAU, 18(4), 2001, pp. 369-376
Citations number
49
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROTRAUMA
ISSN journal
08977151 → ACNP
Volume
18
Issue
4
Year of publication
2001
Pages
369 - 376
Database
ISI
SICI code
0897-7151(200104)18:4<369:PIOPPI>2.0.ZU;2-O
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 inhibito r, 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/k g, i.p.), subjected to lateral fluid percussion (FP) brain injury of modera te 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 f ragmentation 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 in jury, a significant cortical lesion and number of TUNEL-positive/nonapoptot ic cells and TUNEL-positive/apoptotic cells in the injured cortex of vehicl e-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 GP I 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 inh ibition as a means to reduce cellular damage associated with TBI.