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: M C LaPlaca, J Zhang, R Raghupathi, J H Li, F Smith, F M Bareyre, S H Snyder, D I Graham, T K McIntosh
• Journal: Journal of neurotrauma (J Neurotrauma) Vol. 18 Issue 4 Pg. 369-76 (Apr 2001) ISSN: 0897-7151 [Print] United States
• PMID: 11336438 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzopyrans
• Enzyme Inhibitors
• GPI 6150
• Isoquinolines
• Neuroprotective Agents
• Poly(ADP-ribose) Polymerase Inhibitors

Topics

• Animals
• Apoptosis (drug effects)
• Benzopyrans (pharmacology)
• Brain Injuries (enzymology, genetics, pathology)
• DNA Fragmentation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Isoquinolines (pharmacology)
• Male
• Neuroprotective Agents (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors
• Rats
• Rats, Sprague-Dawley