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Poly(ADP‐ribose) Polymerase‐1 and Its Clinical Applications in Brain Injury

Barr, Taura L.; Conley, Yvette P.

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Author Information

Questions or comments about this article may be directed to Taura L. Barr, BSN RN, at barrt@mail.nih.gov. She is an intramural research training award fellow at the National Institute of Nursing Research, Bethesda, MD.

Yvette P. Conley, PhD, is an assistant professor in the Department of Health Promotion at the University of Pittsburgh School of Nursing, Pittsburgh, PA.

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Abstract

Traumatic brain injury (TBI) is a devastating occurrence that may result in short‐ and long‐term complications. Oxidative stress (an imbalance between oxidants and antioxidants) plays a critical role in the development of secondary injuries following TBI and, consequently, in patient outcomes. Secondary injuries resulting from oxidative stress produce DNA strand breaks that activate poly(adenosine diphosphate [ADP]‐ribose) polymerase‐1 (PARP‐1) and produce another level of injury. PARP‐1 functions as a DNA‐damage sensor and signaling molecule. In response to the severe DNA damage after brain injury, PARP‐1 becomes overactivated and depletes the cells' energy sources, which leads to cellular and neuronal death. Recently, PARP‐1 inhibition has been studied in various animal models of brain injury with promising results. TBI treatments based on PARP‐1 inhibition in humans are far from the clinical arena, although descriptive studies of PARP‐1 activation in humans are beginning to emerge. Nurses should become involved in this area of collaborative research in human response to brain injury by helping design and implement safe and meaningful clinical trials.

Traumatic brain injury (TBI) is a devastating occurrence that may result in severe short‐ and long‐term complications. Population‐based studies estimate that 1.4 million Americans sustain a TBI each year, and of this number, 50,000 die, 235,000 are hospitalized, and 80,000‐90,000 experience permanent disability from their injury (Langlois, Rutland‐Brown, & Thomas, 2004). While we have little control over the incidence of TBI itself, each case has a window of opportunity in which the outcome can be improved by preventing secondary injuries. To facilitate recovery, nurses need to be aware of the cellular mechanisms involved in secondary injuries following TBI. Knowledge of these mechanisms will enhance the nurses' ability to safely monitor, accurately treat, and correctly predict potential complications in the TBI patient. This article reviews one source of secondary injury—a chain of cellular‐level events precipitated by a state called oxidative stress—and discusses a potential method of treatment that involves inhibition of one of the enzymes in the process, namely, poly(adenosine diphosphate [ADP]‐ribose) polymerase‐1 (PARP‐1).

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Oxidative Stress, Free Radicals, and Secondary Injury

Surviving the initial TBI is only half the battle; secondary injuries in the acute period (days to weeks) following a TBI can be just as destructive, and they have a tremendous impact on patient recovery. These secondary injuries stem from physiologic, vascular, and biochemical events that are an extension of the primary injury and involve changes at the cellular level that contribute significantly to tissue injury. Such sequelae include hypoxia and ischemia, initiation of neuronal cell death cascades, cerebral swelling, increased oxidative stress, and inflammation (Reilly, 2001; Ruppel, Clark, Bayir, Satchell, & Kochanek, 2002). The process by which cellular and neuronal death occurs is extremely complex and continues for hours or days following the primary injury and initiation of these secondary insults.

Research has shown that oxidative stress plays a critical role in the development of further secondary injuries and ultimately tissue necrosis following TBI (Bayir et al., 2005; Cristofori et al., 2005; Kerr, Bender, & Monti, 1996; Tavazzi et al., 2005). Oxidative stress is an imbalance between oxidants and antioxidants that favors tissue destruction via exposure to free radicals (Sies, 1985; Warner, Sheng, & Batinic‐Haberle, 2004). A free radical, also known as a reactive oxygen species (ROS) when oxygen centered, is any atom or molecule with an unpaired electron in its outer orbit (Kerr et al.). In normal metabolism, free radicals are created during electron transport and energy production, and in the presence of adequate oxygen, they are neutralized by enzymes or endogenous antioxidants. Two examples of ROS are superoxide (O2) and nitric oxide (NO). Under normal conditions, these species help regulate blood flow and neurotransmission; however, alterations in their production can have pathologic consequences (Warner et al., 2004).

Free radicals are produced in almost every form of secondary brain injury, and particularly in ischemia and hypoxia. Free radicals primarily target the cell membrane, where they break down the membrane components, damage DNA, and impair cellular enzymes and proteins. The brain is particularly vulnerable to free radical production, even in the absence of brain injury, because it requires large amounts of energy to maintain stability (Cole & Perez‐Polo, 2004). Cerebral ischemia followed by reperfusion results in the production of superoxide and other ROS, as well as reactive nitrogen species. Effects include lipid peroxidation, protein denaturation, inactivation of enzymes, DNA damage, and increased permeability of the blood‐brain barrier (Kerr et al., 1996; Kontos, 2001). Hypoxia produces an abundance of ROS, both immediately and subsequently; ROS accelerates axonal injury and neuronal death in the days following TBI and contributes to further brain damage.

Under normal circumstances, cells have the ability to repair the damage caused by ROS. However, after TBI, ROS are produced at an accelerated rate, overwhelming these repair abilities. Developing a better understanding of how ROS impacts secondary injury and how to prevent such cellular injury could help improve outcomes after a TBI.

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Cellular Mechanisms of Oxidative Stress and Production of Free Radicals

Changes produced at the cellular level following ischemia and reperfusion have been studied extensively (Bayir et al., 2005; Cazevieille, Muller, Meynier, & Bonne, 1993; Flamm, Demopoulos, Seligman, Poser, & Ransohoff, 1978; Islekel, Islekel, Guner, & Ozdamar, 1999; Xiong, Shie, Zhang, Lee, & Ho, 2005). During cerebral ischemia, free fatty acid concentrations are increased as a result of membrane damage. Lipid peroxidation increases (Inci, Ozcan, & Kilinc, 1998) and antioxidant defenses decrease (Islekel et al.). In conjunction with cellular energy depletion, these processes influence the severity of secondary brain injury (Tavazzi et al., 2005).

Significantly, these responses have been effectively mediated in experimental cerebral ischemia by treatment with free‐radical scavengers and antioxidants (Xiong et al., 2005; Yu et al., 2005). However, these protective effects have yet to be established in humans. Only one large clinical study of the effect of tirilazad (a drug that inhibits lipid peroxidation) on patient outcome following head injury has been published, and no significant differences were found at 6‐month outcomes (Roberts, 2000). However, the group receiving tirilazad more frequently had hypotension or hypoxia before treatment, a finding that suggests that the contributing factors may not have been properly analyzed (Rhodes, 2003).

Research shows that following TBI, many cellular events lead to neuronal dysfunction; these events are summarized in Figure 1. Initially, glutamate concentrations increase, because of hypoxia and ischemia. The glutamate acts on N‐methyl‐D‐aspartate (NMDA) receptors, resulting in free Ca+2 entering the intracellular space (Koh, Dawson, & Dawson, 2005). This surge of Ca+2 activates nearby nitric oxide synthase (NOS) isoforms, particularly neuronal NOS (nNOS; Smythies, 2000), which produces nitric oxide (NO). Nitric oxide is widely expressed in neuronal tissues and serves as a local neuronal messenger and neuromodulator to influence the functions of neurons. NO released secondary to NMDA activation reacts with superoxide (endogenous free radical) to form peroxynitrite (a potent oxidant), which destructively interacts with lipids, proteins, and DNA.

Fig 1
Fig 1
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PARP‐1 and Its Role in Cell Death

Thus far, the process of cellular injury after TBI has been outlined from the onset of oxidative stress to the production of free radicals. This section addresses the next level: how oxidative‐stress‐induced DNA damage leads to cell death by energy depletion. The key molecule in this step is PARP‐1. DNA damage initiates a cascade of events mediated by the activation of PARP‐1. This cascade encompasses an energy‐consuming cycle that results in rapid depletion of cellular adenosine triphosphate (ATP). Since the brain does not store ATP, cell death quickly ensues. Thus, PARP‐1 appears to play a significant role in cell survival and thereby influences patient outcomes.

Poly(ADP‐ribose) polymerase‐1 (PARP‐1) appears to play a significant role in cell survival and thereby influences patient outcomes.

PARP‐1 is an abundant nuclear protein and base excision repair enzyme found in most cells, residing within the nucleus and mitochondria, but can be present in the cytoplasm as well. PARP‐1 is the best‐characterized member of a superfamily of about 18 known proteins all encoded by different genes, which can function as a sensor for DNA damage and as a signaling molecule (Diefenbach & Burkle, 2005). The genome is comprised of the totality of DNA in a single cell and is kept stable through various enzymatic processes. There is approximately one PARP‐1 molecule for each 1,000 DNA base pairs, of which there are more than 3 billion in one copy of the human genome.

In general, PARP‐1 is activated by single‐stranded DNA breaks following ROS exposure. Activation of PARP‐1 stimulates poly ADP‐ribosylation, which in turn leads to the formation of poly(ADP‐ribose) (PAR) units that serve as protein modifying agents (Koh et al., 2005). The functioning of PARP‐1 and PAR is summarized in Figure 2; details of the mechanism are discussed in the next section.

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When fully activated, as is the case after ROS exposure following TBI, PARP‐1 activation and ADP‐ribosylation deplete the nicotinamide adenine dinucleotide (NAD+) and ATP cellular energy stores (Berger, Sims, Catino, & Berger, 1983; Chambon, Weill, & Mandel, 1963; Virag & Szabo, 2002). Since these substances are involved in mitochondrial respiration and glycolysis (Fig 2), their depletion results in cell death by energy failure (Koh et al., 2005; Tavazzi et al., 2005).

Evidence from animal TBI models suggests that this overactivation and subsequent energy depletion contributes to cellular and neuronal death following TBI (Besson, Croci, Boulu, Plotkine, & Marchand‐Verrecchia, 2003; Ha & Snyder, 2000; Hortobagyi et al., 2003). In other animal studies, cell necrosis and apoptosis have been prevented by PARP‐1 inhibitors, providing further evidence that PARP‐1 is involved in cell death (Cole & Perez‐Polo, 2002). Inhibition of PARP‐1 also prevents glutamate toxicity, a significant cause of cellular dysfunction and death after TBI: mice genetically bred not to produce PARP‐1 have minimal to no NMDA receptor toxicity and experience improved functional outcome after TBI (Whalen et al., 1999).

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Mechanism of PARP‐1 Activity

After TBI, DNA damage may be produced by ROS, as discussed above, and also by direct mechanical injury or activation of endogenous endonucleases. Single‐stranded DNA breaks, hydroxyl radicals, and peroxynitrite are key activators of PARP‐1 (Koh et al., 2005). In the absence of exposure to DNA fragments, PARP‐1 displays negligible activity. However, binding to DNA breaks initiates a 500‐fold increase in enzyme activity (Diefenbach & Burkle, 2005). PARP‐1 activation is an early event in DNA repair and is elicited by very small amounts of DNA damage.

Upon activation, PARP‐1 binds to damaged DNA at a specific DNA binding motif and catalyzes the transfer of ADP ribose units from NAD+ to various acceptor proteins, including histones (proteins that coiled DNA is wrapped around) and PARP‐1 itself, to form long branched chains of poly(ADP‐ribose) (PAR).

The biological role of PAR is complex and involves many functions, including DNA repair; protein expression via transcriptional regulation; cellular replication and differentiation; cell survival; and cell death (Cole & Perez‐Polo, 2004). PAR alters the DNA binding activity and the catalytic activity (energy required to form a protein product) of proteins it modifies. The inclusion of PAR onto modified acceptor proteins aids in the coordination of cellular processes in response to genotoxic stress (i.e., damage to DNA and the energy required to repair it), thus facilitating DNA repair and cell survival (Cole & Perez‐Polo, 2004; Koh et al., 2005; Lindahl, Satoh, Poirier, & Klungland, 1995). Physiologic PAR has a short half‐life of less than 1 minute, because it is quickly cleaved by poly(ADP‐ribose) glycohydrolase (PARG; Koh et al.). This short half‐life indicates that “clean‐up” of PAR is an important part of the cellular response to DNA damage. However, the half‐life of PAR during pathophysiologic conditions, such as TBI, is unknown.

PAR polymers facilitate the opening of the condensed chromatin within the cell, thus modifying the structure of the acceptor proteins and allowing DNA repair at damaged sites. This opening dramatically alters the function of these acceptor proteins and helps play a role in many physiologic and pathophysiologic phenomena (Koh et al., 2005). The ribosylation of PARP‐1 serves to regulate this process and down‐regulates PARP‐1 activity. The ribosylation of acceptor proteins facilitates DNA repair and increases access to other DNA repair enzymes (Lindahl et al., 1995). Therefore, controlled PARP‐1 activity and PAR formation is essential to genomic stability. Overactivation of PARP‐1 by extensive DNA damage depletes NAD+ and ATP stores, resulting in cell death (Koh et al.; Tavazzi et al., 2005).

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Research on PARP‐1 in Human Disease

PARP‐1 was first implicated in neuronal cell death associated with the production of NO (Zhang, Dawson, Dawson, & Snyder, 1994). Later it was implicated in cell death in focal ischemia associated with stroke (Chiarugi, 2005; Ikeda et al., 2005), as well as in other nonneurologic disease processes, such as diabetes (Szabo, 2005) and cardiac infarct (Xiao, Chen, Zsengeller, & Szabo, 2004). Excessive PARP‐1 activation is the final common pathway in neuronal death following noxious attacks, such as ischemia.

At present, only a few published studies have assessed PARP‐1 expression in human brain injury. Ang and associates (2003) found PARP‐1 to be present in pericontusional brain tissue, with higher amounts early after injury, but there was no correlation between PARP‐1 distribution and clinical parameters, such as the Glasgow Coma Scale score or intracranial pressure. Further human studies are warranted to determine whether an increase in PARP‐1 activity within the cytoplasm may also be associated with an apoptotic process or whether those patients with increased cytoplasmic staining for PARP‐1 had more severe injuries. Love, Barber, and Wilcock (2000) demonstrated that PARP‐1 and PAR were present in infarcted and penumbral brain tissue; however, this work should be interpreted with caution because all brain tissue was collected at autopsy. Fink and colleagues (2005) found that PAR‐modified protein expression is increased in the cerebrospinal fluid of pediatric TBI patients compared to controls.

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Clinical Significance of PARP‐1 Inhibition

Because it is known that overactivation of the PARP‐1 cascade can lead to cell death, PARP‐1 inhibition has recently garnered interest as a possible therapeutic treatment following TBI, in which cellular and neuronal death is the predominant form of injury. Because PARP‐1 plays a role in many physiologic processes aimed at maintaining the stability of cellular genetic material, it would appear that inhibition of this process would have grave consequences. However, PARP‐1 inhibitors have been suggested as treatments for a wide range of disease states. Many preclinical studies and some clinical trials have demonstrated the efficacy of PARP‐1 inhibitors in cancer treatment (Plummer et al., 2005). Others have found that PARP‐1 inhibitors provide protection in certain cardiovascular and neurologic conditions, including ischemia‐ and reperfusion‐related injury, hemorrhagic shock, thoracoabdominal aortic aneurysm surgery, acute renal failure, and stroke (Takahashi et al., 1999; Watts, Grattan, Whitlow, & Kine, 2001). Moreover, one PARP‐1 inhibitor (INO‐1001; Inotek Pharmaceuticals, n.d.) has successfully progressed through phase I safety studies and has entered into phase II clinical studies for myocardial infarction, cardiopulmonary bypass, and thoracoabdominal aortic aneurysm surgery (Graziani & Szabo, 2005; Khan et al., 2003). In a preclinical model, PARP‐1 inhibition provided myocardial protection and improved cardiac function after regional ischemia and cardioplegia‐cardiopulmonary bypass (Khan et al.).

Thus, a growing body of evidence suggests that PARP‐1 inhibition may be a successful treatment strategy following TBI in humans. PARP‐1 inhibition targets a relatively late event in TBI, and, therefore, the therapeutic window is quite wide (Virag & Szabo, 2002).

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Future Directions

The long‐term consequences of PARP‐1 inhibition have yet to be established. Further preclincial studies are warranted to gain a better understanding of both the PARP‐1 activation cascade in itself and the role of PARP‐1 activation and expression following TBI in humans. In addition, further work is needed to verify the safety and efficacy of PARP‐1 inhibitors in a TBI population.

Some researchers believe that inhibiting PARP‐1 is not advisable because PARP‐1 plays such a significant role in genomic stability. These researchers suggest a somewhat different approach, namely targeting PARG, the enzyme that degrades PARP‐1 and ultimately keeps PARP‐1 activation in check. PARG rapidly reverses poly‐ADP‐ribosylation, the rapidity suggesting PARG may be important in signal transduction and gene expression. Like PARP‐1, PARG may be a useful target for therapeutic application.

In terms of clinical practice, routine methods of administration and monitoring will need to be established. One company has developed an orally bioavailable PARP inhibitor that crosses the bloodbrain barrier that will be used as a chemotherapeutic agent (MGI Pharma, n.d.). It is possible that oral formulations may be used in ischemic events, such as stroke and brain injury, as well. The oral route is the preferred method of entry; however, this route is subject to uncertainties regarding the permeability of the blood‐brain barrier and effectiveness of drug distribution. Intranasal administration may also prove to be efficacious (Ying et al., 2007). The activity of PARP‐1 can be measured directly by immunohistochemical analysis of tissue or indirectly by PAR‐modified protein expression. The PAR‐modified proteins resulting from PARP‐1 activation can easily be quantified using an enzyme linked immunosorbent assay (ELISA).

With so few human studies performed to date, it is difficult to speculate on what role PARP‐1 plays following TBI. Before safe and meaningful clinical trials can be performed on a TBI population, an adequate understanding of the process in humans is necessary. Nurses can become involved in this process by collaborating with the healthcare team and scientific researchers to aid in the development of knowledge, theory, and clinical protocols regarding this new strategy for improving outcomes in TBI.

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Nursing Implications

Astute nursing assessment is necessary to verify the safety and adequacy of management of the TBI patient. The neuroscience nurse must be aware of the pathophysiologic concerns following a TBI and must also seek out and follow the evidence‐based standards of practice for minimizing secondary injuries put forth by the Brain Trauma Foundation (Fig 3). While much of the clinical care of the severe TBI patient currently lies in providing physiologic support, new therapies are constantly being explored to improve outcome in this population. As newer therapies become available, the neuroscience nurse must be even more diligent in observing physiologic responses to therapies delivered.

Fig 3
Fig 3
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Although PARP‐1 treatment is not yet available for TBI, evidence‐based standards of practice for this treatment have been developed. In addition, nurses can become involved in the design and implementation of clinical trials to determine the safety and efficacy of PARP‐1 inhibition in the neuroscience population. Clinically relevant data is being collected regarding PARP‐1 inhibition in other human disease states (cancer and cardiovascular disease), and nurses will be involved in the design and implementation of these studies, as well as in assessing risks and benefits to individual patients.

Above all, the nurse is in charge of coordinating care for TBI patients and must be knowledgeable about the physiologic and pathophysiologic responses to TBI. Neuroscience nurses need to be aware of the process of oxidative stress injury and novel approaches to mediate this response. Although PARP‐1 research is in preclinical stages, it will not be long until it reaches the bedside, and nurses will be in charge of mediating the transition to this new mode of treatment. Without vigilant care on their part, any new pharmacologic therapies will be ineffective.

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Summary

Advances in TBI care in the last few decades have focused on prevention and minimization of secondary injuries. However, much of the pathophysiology behind these secondary injuries is still not understood. As our knowledge of the process of secondary injury, oxidative stress, and PARP‐1 activation following TBI increases, so will our ability to develop therapeutic applications to mediate these responses. Neuroscience nurses need to understand what is known regarding these responses and ways in which they can be appropriately managed.

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© 2007 American Association of Neuroscience Nurses

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