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

• Published in: Journal of neurotrauma Vol. 18; no. 4; pp. 369 - 376
• Main Authors: LAPLACA, Michelle C, JIE ZHANG, RAGHUPATHI, Ramesh, LI, Jia-He, SMITH, Fraser, BAREYRE, Florence M, SNYDER, Solomon H, GRAHAM, David I, MCINTOSH, Tracy K
• Format: Journal Article
• Language: English
• Published: Larchmont, NY Liebert 01.04.2001; Mary Ann Liebert, Inc
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Benzopyrans - pharmacology; Biological and medical sciences; Brain Injuries - enzymology; Brain Injuries - genetics; Brain Injuries - pathology; Cell death; DNA damage; DNA Fragmentation - drug effects; DNA repair; Enzyme Inhibitors - pharmacology; Gene amplification; Immunohistochemistry; In Situ Nick-End Labeling; Ischemia; Isoquinolines - pharmacology; Male; Medical sciences; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - pharmacology; Pharmacology. Drug treatments; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley; Trauma; Traumatic brain injury; United States > US; Maryland; Baltimore Maryland; Nervous system diseases; Rat; Enzyme; Transferases; Craniocerebral; Glycosyltransferases; Rodentia; Diseases of the osteoarticular system; Enzyme inhibitor; Neuroprotective agent; Trauma; Cerebral disorder; NAD; Pathology; Vertebrata; Chemotherapy; Mammalia; Treatment; Animal; Central nervous system disease; Skull disease; ADP-ribosyltransferase; Pentosyltransferases; Apoptosis
• ISSN: 0897-7151; 1557-9042
• DOI: 10.1089/089771501750170912

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.