Abstract

Spinal cord trauma initiates a series of sequential events that lead to neuronal cell death. While the precise mechanisms responsible for this secondary damage remain undefined, several studies have suggested that free radicals contribute to the neurodestructive processes of spinal cord injury [1]. Moreover, peroxynitrite, a highly reactive molecule generated when nitric oxide and superoxide combine, has recently been proposed to induce secondary neuronal damage resulting from spinal cord injury [2–5]. Peroxynitrite can mediate several destructive interactions, including activation of poly(ADP-ribose) polymerase (PARP). In the present study we have examined whether peroxynitrite exerts toxic effects on primary cultures of spinal cord neurons via activation of PARP. Peroxynitrite dose-dependently reduced the viability of spinal cord neurons in culture and induced cell death. Furthermore, exposure to peroxynitrite markedly increased DNA strand breaks in spinal cord neurons resulting in activation of PARP. To determine whether PARP activation plays a role in peroxynitrite-induced neurotoxicity we assessed the effects of various PARP inhibitors on cell viability and death in spinal cord neurons exposed to peroxynitrite. The presence of PARP inhibitors in the cultures protected spinal cord neurons from the deleterious actions of peroxynitrite. Therefore, our results demonstrate that peroxynitrite exerts cytotoxic effects on spinal cord neurons in vitro through a PARP-dependent pathway. References: 1.Anderson DK, Hall ED: Pathophysiology of spinal cord trauma. Ann Emerg Med, 1993; 22: 987-992 2.Scott GS, Jakeman LB, Stokes BT, Szabó C: Peroxynitrite production and activation of poly(adenosine diphosphate-ribose) synthetase in spinal cord injury. Ann Neurol, 1999; 45: 120-124 3.Liu D, Ling X, Wen J, Liu J: The role of reactive nitrogen species in secondary spinal cord injury: Formation of nitric oxide, peroxynitrite and nitrated protein. J Neurochem, 2000; 75: 2144-2154 4.Xu J, Kim G-M, Chen S, Yan P et al: iNOS and nitrotyrosine expression after spinal cord injury. J Neurotrauma, 2001; 18: 523-532 5.Bao F, Liu D: Peroxynitrite generated in the rat spinal cord induces neuron death and neurological deficits. Neuroscience, 2002; 115: 839-849

Keywords: spinal cord injury, peroxynitrite, PARP