Abstract

Background:Nitric oxide and free radicals contribute to injury elicited by traumatic brain injury (TBI) [1,2]. Peroxynitrite, resulting from the combination of nitric oxide and superoxide anion triggers DNA strand breakage, leading to the activation of poly(ADP-ribose)polymerase-1 (PARP-1) [3]. As excessive activation of this enzyme induces cell death, we examine the implication of peroxynitrite-PARP-1 pathway in the post-traumatic outcomes of focal TBI caused by fluid percussion on rats [4]. Material/Methods:In a first experiment, animals were killed 30 min, 2, 4, 6, 24, 48 and 72h after TBI for immunohistochemistry of a) 3-nitrotyrosine as a footprint of peroxynitrite production and b) poly(ADP-ribose) as a marker of PARP-1 activation. In a second experiment, the effect of 3-aminobenzamide (3-AB), a widely used PARP inhibitor, was investigated on the neurological deficit, the cerebral lesion and the activation of PARP-1. Rats were given 3-AB (10 and 30 mg/kg, i.p.) or its vehicle 30 min before, and 24, 48 and 72h after TBI. Results: Immunohistochemistry showed that 3-nitrotyrosine and poly(ADP-ribose) were present as early as 30 min post-injury, and persisted for 72h. Treatment with 3-AB significantly decreased the neurological deficit, the cerebral lesion and the poly(ADP-ribose) staining induced by TBI. Conclusions: The present study indicates that TBI induces peroxynitrite production associated with PARP-1 activation. Treatment with 3-AB, a PARP inhibitor, decreases the neurological deficit, the cerebral lesion and the PARP-1 activation caused by TBI. Thus, PARP-1 is involved in the pathogenesis of TBI and may be a promising therapeutic target for the treatment of brain trauma.References: 1.Mésenge C et al: J Neurotrauma, 1996; 13: 209-214 2.Mésenge C et al: J Pineal Res, 1998; 25: 41-46 3.Virág L, Szabó C: Pharmacol Rev, 2002; 54: 375-429 4.Toulmond S et al: Brain Res, 1993; 620: 24-31

Keywords: 3-nitrotyrosine, 3-aminobenzamide, neuroprotection, poly(ADP-ribose)polymerase-1, peroxynitrite, traumatic brain injury