PARS ACTIVATION AFTER TBI

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Poly(ADP-ribose) synthetase (PARS), also termed poly (ADP- ribose)polymerase or PARP, is a ubiquitous nuclear protein that facilitates repair of DNA strand breaks in a process that consumes NAD and ATP. Several in vitro studies in non-neuronal cells support a "suicide theory of PARS activation" where active PARS leads to energy failure and cell death by necrosis. Our preliminary studies provide evidence that PARS is activated after traumatic brain injury (TBI). Mice deficient in PARS showed dramatic from functional deficits typically produced by TBI, suggesting that in toto PARS activation is detrimental after TBI. Our hypothesis is that oxidative DNA damage produced by peroxynitrite activates PARS, disturbs cellular energetics, injures mitochondria, and contributes to necrotic cell death. Specific aims to address this hypothesis include testing the effects of peroxynitrite-induced PARS activation on oxidative DNA damage, cellular energetics, mitochondrial function, and apoptotic necrotic and total cell death in neurons in vitro using pharmacologic PARS inhibitors. The role of PARS after TBI will be established by first characterizing PARS activation in mice, rats, and human samples after TBI; then testing the effects of PARS activation on NAD stores, mitochondrial injury, brain edema and cerebral blood flow, apoptotic necrotic, and total cell death, and neuropathologic outcome after TBI using pharmacologic inhibitors or genetic disruption (PARS knockout mice). Preserving cellular energy stores by inhibiting PARS may represent a key strategy for the treatment of TBI. Importantly, PARS inhibition may target necrotic neuronal death which has been previously felt to be unmanipulable. However, PARS may also play a beneficial role after TBI by participating in the maintenance of genomic integrity. The potential dual-role of PARS after TBI needs to be carefully addressed prior to implementation of clinical treatment strategies targeting PARS after acute brain injury. TBI strikes without warning and is a major cause of morbidity and mortality in adults and children. Cellular energy failure and necrotic neuronal death contribute to morbidity and mortality and currently only few non-specific therapies are available. The proposed experiments address the key question, does oxidative stress produced by peroxynitrite trigger PARS-mediated mitochondrial damage, energy failure, and neuronal death in vitro and after TBI in vivo? The development of novel and clinically-relevant pharmacologic strategies that target energy failure and necrosis after TBI may prove to be powerful and efficacious agents for the treatment of TBI.