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
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.