Table of Contents Author Guidelines Submit a Manuscript
Oxidative Medicine and Cellular Longevity
Volume 2015 (2015), Article ID 370312, 10 pages
http://dx.doi.org/10.1155/2015/370312
Review Article

Traumatic Brain Injury and NADPH Oxidase: A Deep Relationship

1Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, C.so Augusto 237, 47921 Rimini, Italy
2Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Irnerio 48, 40126 Bologna, Italy
3Neurorehabilitation Unit, Emergency Department, AUSL of Bologna, Via B. Nigrisoli 2, 40133 Bologna, Italy

Received 15 January 2015; Accepted 18 March 2015

Academic Editor: Javier Egea

Copyright © 2015 Cristina Angeloni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Traumatic brain injury (TBI) represents one of the major causes of mortality and disability in the world. TBI is characterized by primary damage resulting from the mechanical forces applied to the head as a direct result of the trauma and by the subsequent secondary injury due to a complex cascade of biochemical events that eventually lead to neuronal cell death. Oxidative stress plays a pivotal role in the genesis of the delayed harmful effects contributing to permanent damage. NADPH oxidases (Nox), ubiquitary membrane multisubunit enzymes whose unique function is the production of reactive oxygen species (ROS), have been shown to be a major source of ROS in the brain and to be involved in several neurological diseases. Emerging evidence demonstrates that Nox is upregulated after TBI, suggesting Nox critical role in the onset and development of this pathology. In this review, we summarize the current evidence about the role of Nox enzymes in the pathophysiology of TBI.

1. Introduction

Traumatic brain injury (TBI) has become the leading cause of disability among young individuals and working age adults [1]. World Health Organization (WHO) has predicted that TBI will be the third leading cause of global mortality and disability by 2020 [2]. In the European Union over a million hospital admissions per year are due to TBI [3], making it one of the major causes of trauma-related mortality in this area [4].

TBI is characterized by primary damage to the brain resulting from mechanical forces applied to the head at the time of trauma as well as delayed damage triggered by different mechanisms that evolve over time [57]. TBI secondary injury includes a complex cascade of biochemical events involving oxidative stress, glutamate excitotoxicity, and neuroinflammation, leading to neuronal cell death [8]. Mitochondrial dysfunction at the neuronal/astrocytic level has been reported to be a key participant in neuroinflammation [9] and also in TBI pathophysiology [10, 11], leading to a marked reactive oxygen species (ROS) accumulation.

Oxidative stress, the imbalance between the level of ROS/reactive nitrogen species (RNS) and antioxidants, has been extensively investigated as one of the major contributors to the pathophysiology of secondary TBI damage. The most commonly occurring cellular free radical is superoxide (), which promotes the formation of other ROS/RNS leading to lipid peroxidation [12]. Mitochondria has been generally considered the main source of following brain injury [13]; however in the last years NADPH oxidase (Nox) family members have emerged as major contributor to generation. Several studies have demonstrated that Nox is upregulated after TBI [1418] and pharmacological and genetic Nox inhibition has been shown to markedly attenuate TBI secondary injury [18, 19], suggesting Nox critical role in the onset and development of this pathology.

The following review summarizes current research on the damaging role of oxidative stress in TBI, focusing on NADPH oxidase as ROS generator enzymes.

2. Pathophysiology of Traumatic Brain Injury

Traumatic brain injury (TBI) is a damage to the brain due to an external physical insult that can lead to loss of consciousness, impairment of cognitive and motor abilities, and disruption of behavioral and/or emotional functioning. These neurological deficits can be temporary or permanent and may lead to physical and psychosocial disability [20]. The outcome may vary from death to surviving with disabilities or even to complete recovery. The most common causes of TBI in adults are road traffic accidents, falls, violence, and armed conflicts [7].

The head trauma can be penetrating or closed according to the mechanism while the clinical severity is usually classified according to the Glasgow Coma Score (GCS) [21]. TBI patients are categorized into mild, moderate, and severe. A GCS score of 13–15 is conventionally associated with mild TBI, a score of 9–12 with moderate TBI, and a score of 8 or less with severe TBI [22].

TBI is characterized by primary and secondary damage. The primary damage is the direct expression of the mechanical forces applied to the head (impact, blast, and penetrating trauma) that cause localized and/or diffuse macroscopic brain lesions [23]. In particular in the case of severe TBI, focal and diffuse damage coexist: the localized damage includes focal contusions and hematomas, whereas diffuse damage includes brain swelling, microvascular damage and diffuse axonal injury (DAI). DAI is characterized by widespread damage to axons in the white matter [24, 25] that can be found up to 72% of moderate to severe TBI [26].

The severity of DAI can be classified in grade 1 or mild (changes diffusely distributed in the white matter but not in the corpus callosum or in the brainstem), grade 2 or moderate (with evidence of involvement of the corpus callosum), and grade 3 or severe (with additional aspects of lesion in the dorsolateral segments of the rostral brainstem) [27].

DAI might be considered a progressive process evolving from axonal damage to ultimate disconnection [28] and therefore, even if scarcely visible with conventional computed tomography (CT), can cause white matter disconnection that sustains cognitive, behavioral, and motor impairments and can heavily affect the short- and long-term outcome [29].

Moderate to severe TBI, as repeated mild TBI, can lead to long-term cognitive impairments and might be associated with increased risk of neurodegenerative diseases [3032].

TBI also initiates a cascade of damage with variable extent and duration and with molecular mechanisms not yet completely understood. These processes take place for hours and days (or even weeks and months) after the brain trauma and may include hypotension, hypoxia, ischemia, excitotoxicity, and inflammation among others.

The secondary damage is non-mechanical, evolves over time [33], and comprises cytoskeletal damage and alteration of cell signaling pathways [34, 35]. A complex series of cellular and molecular changes play a fundamental role in these cascades and include blood-brain barrier (BBB) impairment [3638], ionic imbalance [39], excitotoxicity [40], brain edema [41], neuroinflammation [9, 42, 43], and oxidative stress [44, 45].

In particular, the ischemic pattern observed in TBI impairs the capacity of neurons and glial cells to maintain membrane ionic equilibrium. As a consequence, depolarization occurs in neurons, resulting in activation of presynaptic voltage-dependent channels and in massive release of excitatory neurotransmitters like glutamate and aspartate into the extracellular space [46, 47]. The toxic level of excitatory amino acids activates postsynaptic NMDA (N-methyl-D-aspartate) and metabotropic receptors, which induce calcium overload of the postsynaptic neurons [48]. The final event in ischemic damage is always a massive intracellular accumulation [22] which leads to mitochondrial dysfunction and oxidative stress [49, 50]. Furthermore, excessive cytosolic calcium activates proteolytic enzymes and phospholipases that induce degradation of cytoskeleton and extracellular matrix proteins and enhances ROS production. [47]. Large lines of evidences demonstrate that ROS generation and oxidative stress contribute significantly to the pathophysiology of secondary injury after TBI [48, 51, 52].

3. Reactive Oxygen Species and Oxidative Stress

ROS, historically considered as purely harmful byproduct of metabolism causing cell damage, are now considered as important modulators of intracellular signaling pathways, since they can be intentionally generated in particular by the Nox family [53]. Accumulating evidence suggests that ROS are involved in several pathophysiological responses ranging from cell proliferation to cell death and that deregulated ROS signaling contributed to a multitude of human diseases, such as brain injury and neurodegenerative disease [5459].

When cells, including neurons, are in a homeostatic balance, the availability of antioxidant enzymes (e.g., catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase) and of scavenging molecules (e.g., glutathione, ascorbic acid, and tocopherols) approximately matches ROS level, allowing redox signaling [60].

Oxidative stress, on the contrary, represents the imbalance between ROS level and antioxidant defense and may arise from increased ROS formation or from deficiencies in antioxidant levels [61].

A variety of pathologies have been reported to be related to oxidative stress that causes irreversible oxidative modifications of proteins, lipids, and/or DNA, generating oxidative stress markers (e.g., carbonylated proteins, lipid peroxidation) and leading to cellular necrosis or apoptosis and consequently to tissue injury [53, 62]. Superoxide can directly or indirectly damage DNA through oxidation [63], directly inactivate cellular antioxidants enzymes [64], and activate proinflammatory nuclear factors [65]; therefore, it has been implicated in numerous pathological processes including acute and chronic diseases [66].

Other ROS/RNS that possess different redox characteristics and, thus, different physiological and pathophysiological effects can derive from superoxide. For example, colocalization of superoxide at sites of nitric oxide (NO) production can lead to the formation of peroxynitrite (ONOO) and to oxidative damage due to peroxynitrite decomposition products that possess potent free radical features [62]. Moreover, superoxide is rapidly reduced, both spontaneously and enzymatically, to H2O2. Unlike superoxide, H2O2 is able to cross cellular membranes, through specific aquaporin channels [67], acting at sites distant from its source and modifying DNA and proteins [68]. Moreover, H2O2, in the presence of transition metals, can generate hydroxyl radical () which is highly reactive and indiscriminately oxidizes nucleotides causing breaks and lesions of DNA and lipid peroxidation. The brain is highly susceptible to lipid peroxidation because of its elevated oxygen consumption and richness in polyunsaturated fatty acids [69] and iron [70]. Lipid peroxidation causes alterations in cell membrane fluidity, increases permeability of membranes, and decreases membrane activity, leading to cell injury.

The understanding of oxidative stress mechanisms and the development of antioxidant strategies are of primary interest to optimize brain injury treatment and may provide useful therapeutic strategies for brain injury inflammation and neurodegenerative diseases [56, 7173].

4. Oxidative Stress in Traumatic Brain Injury

ROS generation has a profound impact on the onset of TBI secondary injury. The impaired blood flow following TBI triggers cerebral hypoxia or ischemia with the consequent reduction of oxygen and glucose supply to the brain. The transition from aerobic to anaerobic metabolism generates a state of acidosis which activates pH-dependent calcium channels [74]. The increased levels into neuronal cytoplasm lead to an increase in ROS/RNS production mainly due to the impairment of the mitochondrial electron transport chain and the activation of the calcium dependent proteases and phospholipases [7476]. During blood flow restoration or reperfusion, enzymes involved in ROS production find enough oxygen to generate large quantities of ROS/RNS strongly contributing to oxidative stress in TBI [75]. The most common free radical generated almost immediately following TBI is superoxide [77, 78]. Within the injured nervous system, different possible sources contribute to the production of superoxide radical. induces activation of phospholipases and the downstream arachidonic acid cascade, xanthine oxidase activity, mitochondrial leak, enzymatic or autoxidation of biogenic amine neurotransmitters, oxidation of hemoglobin, and Nox family member activation.

At later time, TBI triggers a series of inflammatory processes that contribute to neuronal damage and failure of functional recovery. These processes are mediated by infiltrating inflammatory cells like activated microglia, neutrophils, and macrophages that produce multiple proinflammatory mediators, such as cytokines, chemokines, inducible NOS and cyclooxygenase-2 (COX-2), and can be additional sources of [11, 79, 80].

In aqueous environments, like the cytoplasm, exists in equilibrium with the hydroperoxyl radical () which is more lipid soluble and a more powerful oxidizing agent [81]. However, under the acidic condition characteristic of TBI, there is a shift of the equilibrium in favor of increasing lipid peroxidation. Lipid peroxidation can induce brain tissue damage by different mechanisms: impairing mitochondrial membrane lipid structure leading to mitochondrial dysfunction [82, 83]; enhancing the accumulation of 4-HNE that inhibits astrocytic glutamate transporters [84, 85], potentially increasing the neurotoxicity mediated by glutamate; compromising homeostasis by damaging the -ATPase in the cell membrane [86]; and mobilizing from intracellular stores like the endoplasmic reticulum [87].

Another important player in post-TBI pathophysiology scenario is peroxynitrite, produced by coupling NO with superoxide. The damaging role of ONOO in TBI has been indirectly demonstrated by the neuroprotective effect of acute treatment of injured mice and rats with NOS inhibitors [88, 89] and by the use of the peroxynitrite derived free radicals scavenger, tempol, that ameliorated the accumulation of nitrotyrosine in injured brains and concomitantly improved neurological recovery in mice [90]. It has also been reported a significant upregulation of all the three NOS isoforms (endothelial, neuronal, and inducible) after TBI [9193] with a consequent increase of NO level.

Red blood cell lysis, due to mechanical trauma, is another important source of oxidative stress in TBI. The main consequence of red blood cells lysis is the release of free hemoglobin [94] whose oxidation to oxyhemoglobin and methemoglobin contributes to ROS generation [9598]. Moreover, hemoglobin degradation by either H2O2 or lipid hydroperoxides (LOOH) gives rise to the release of iron anions which further contributes to the formation of ROS/RNS [75]. Iron is tightly regulated in the brain under physiological conditions but after traumatic injury iron homeostasis is disrupted by acidosis that increases iron solubility and mediates its delocalization from an inactive to an active redox state [99, 100]. In conclusion, in TBI the many different ROS sources synergistically contribute to the onset of an extensive and profound condition of oxidative stress.

5. NADPH Oxidase Enzymes

ROS have been long thought to be only a harmful by-product of the electron transport chain in mitochondria or in enzymatic processes such as nitric oxide synthase (NOS), cytochrome p450, cyclooxygenase, xanthine oxidase, and lipoxygenase. Whereas the enzymatic processes listed above produce ROS as a side-reaction of normal enzymatic function, the accidental production of ROS is not the only modality of ROS generation. In fact, there are a family of membrane enzymes that reduce molecular oxygen to form ROS as their unique enzymatic function: these enzymes are called NADPH oxidases (Nox) since they use NADPH as a source of electrons to reduce molecular oxygen.

The first enzyme to be discovered that “intentionally” generates ROS in mammalian cells is the Nox expressed in the phagocytes. The phagocytic NADPH oxidase (now known as Nox2) is a membrane enzyme that produces large amounts of ROS in a “respiratory burst” characterized by consumption of O2 and production of superoxide and hydrogen peroxide that, in turn, can lead to the production of more reactive species such as peroxynitrite and hypochlorous acid (HOCl) [101].

Nox2 is a membrane enzymatic complex; the catalytic subunit (known as gp91phox) is an integral protein containing both flavin adenine nucleotide (FAD) and a heme group. Other components of the functional complex are the membrane protein p22phox which functions as a docking site for the cytosolic regulator proteins p40phox, p47phox, and p67phox and the small GTPase Rac. When assembled and activated, Nox2 is able to transport electrons from cytosolic NADPH to reduce molecular oxygen to form superoxide to the other side of the membrane.

Nox2 is expressed in neutrophils and other phagocytic cells mediating host defence against microorganisms; in these white cells Nox2 produces high levels of ROS in order to kill phagocytised microbes. The importance of Nox2 in the host defence is highlighted by the fact that mutations in the NADPH oxidase subunit genes can lead to chronic granulomatous diseases (CGD) [102].

Several homologs of gp91phox (Nox2 catalytic subunit) have been identified in non-phagocytic cells; now, the human Nox family consists of seven different isoforms (Nox1, Nox2, Nox3, Nox4, Nox5, Duox1, and Duox2) [101]. In addition, new regulatory proteins have been discovered, NOXO1 (NOX organizer 1) is homolog of p47phox, and NOXA1 (NOX activator 1) is homolog of p67phox. Owing to their structure and regulation Nox enzymes are categorized into two groups: isoforms that require p22phox (Nox1, Nox2, Nox3, and Nox4) and enzymes regulated by calcium through a calcium-binding domain (Nox5, Duox1, and Duox2) [103].

Nox isoforms are distributed in a variety of tissues and cells but, often, high expression of a certain isoform is only found in specific organs or cells. For instance, Nox1 is highly expressed in colon, Nox4 in the kidney, Nox3 in the inner ear, and Duox2 in the thyroid [104]. Nox-derived ROS levels in nonphagocytic cells are typically much lower than in neutrophils since they are not generated to host defense, but as second messengers molecules in response to physiological stimuli such as endothelial growth factor, platelet-derived growth factor, angiotensin II, and insulin.

The most abundant isoforms expressed in the brain are Nox1, Nox2, Nox3, and Nox4. Several studies have investigated the expression of Nox isoforms in specific CNS regions, most of them are focused on Nox2 but data exist also for Nox1, Nox3, and Nox4 [105]. Although available studies do not provide a complete description of the CNS distribution of Nox enzymes, it appears that Nox isoforms are often coexpressed in various CNS regions and that Nox expression in a certain CNS regions appears to be inducible rather than constitutive. Expressions of NOX isoforms in specific CNS cell types have been investigated in vitro on primary cultures. Nox1, Nox2, and Nox4 are present in neurons, astrocytes, and microglia but, unfortunately, the relative amount of different Nox enzymes and their peculiar function in different brain cells are not sufficiently understood [105].

6. NADPH Oxidase in Traumatic Brain Injury

It has been widely demonstrated that NADPH oxidase plays a key role in central nervous system pathophysiology [17, 106, 107] and increasing lines of evidence suggest that NADPH oxidase is major producer of and has a crucial role in the development of secondary injury after TBI [18, 19, 108, 109].

Dohi et al. [110] were the first to evidence a direct involvement of NADPH oxidase in TBI injury. They demonstrated that gp91phox (also known as Nox2) is increased in the ipsilateral hemisphere after TBI and specifically in amoeboid-shaped microglial cells. Moreover, gp91phox−/− mice exhibit reduced primary cortical damage and a lower ROS level after TBI. Several studies have indirectly investigated Nox involvement in TBI by the use of Nox inhibitors like apocynin [111113] that acts through the inhibition of p47phox subunit translocation to catalytic subunit. Choi et al. [19] observed that intraperitoneal delivery of apocynin to rats before TBI decreased ROS production, BBB disruption, microglia activation, and exerted pronounced neuroprotection. The protective effect of Nox inhibition by apocynin was further investigated by Ferreira et al. [108] that evidenced that early treatment with apocynin reduced inflammatory and oxidative damage caused by moderate fluid percussion injury in mice (mLFPI). They also observed that apocynin did not show any protective effect on brain water content, suggesting that NADPH oxidase activity is not involved in the development of brain edema induced by TBI. On the contrary, other authors showed that NADPH oxidase inhibition reduces brain edema induced by cold brain injury and controlled cortical impact [18, 114]. One possible reason for these discrepancies could be found in the different apocynin doses used in the studies.

Recent studies have shown a time-dependent change in Nox function following TBI (Figure 1). Zhang et al. [18] evidenced that Nox activity in the cerebral cortex and hippocampus rapidly increases following TBI with an early peak at 1 h, followed by a secondary peak at 24–96 h. In particular, they suggested that the first peak is of neuronal origin as demonstrated by a strong colocalization of Nox2 and in neurons at 1 h after TBI; whereas the cellular source for the Nox and elevation at 24–96 h appears to be activated microglia. These data were confirmed by a recent study by Lu et al. [15] that evaluated the temporal pattern of Nox2 activation in adult male mouse cerebral cortex following TBI. They observed a rapid and robust elevation of Nox2 expression in the cerebral cortex at 1 h, followed by a decrease to lower, but still elevated levels at 3–12 h after TBI. A second significant elevation was observed at 24 h after TBI with no significant difference in Nox2 expression at 72 h. These data have been challenged by Ansari et al. [14] that reported that both the Nox activity and increased in a time-dependent fashion, with the maximum values at 24 h. The authors postulated that these discrepancies could be ascribed to the different animal model used and to the lack of inhibitors for other sources of during the detection procedure used by Zhang et al. [18] and suggested that such an early peak is most probably associated with mitochondrial dysfunction that is known to occur within 30 min after TBI [16]. Song et al. demonstrated a significant Nox activation between 48 and 72 h after a diffuse brain injury [17] but they did not measure Nox activity before 48 h. Dohi et al. [110] showed that Nox is highly expressed in chronically activated microglia up to 4 months after TBI, and recently Loane et al. [115] extended this time period observing that Nox is upregulated in highly activated microglia surrounding the lesion site up to 1 y. Microglial Nox might cause neurotoxicity through two related mechanisms: activation of Nox leads to the production of extracellular ROS that are cytotoxic to neighboring neurons. Moreover microglial intracellular ROS produced by Nox are a key driver of self-propagating cycles of microglial-mediated neurodegeneration as Nox activation induces changes in microglia morphology and proinflammatory gene expression [116]. Given this dual effect of Nox activation on neurotoxicity, the role of Nox in increasing ROS level and the prevalence of Nox activation upon microglial activation suggested that microglial Nox could play a key role in neuronal death after TBI [117]. In the aged brain these effects are exacerbated as there is an exaggerated microglia activation in response to TBI with a Nox robust overexpression. In particular, in the injured cortex of aged mice a strong upregulation of the Nox subunits p22phox, and gp91phox has been observed [118].

Figure 1: Time related changes of Nox expression after TBI.

The expression of Nox isoforms is dependent on cell type and injury status [119]. In particular, Nox2 is primarily expressed by microglia and neurons, Nox3 is primarily expressed by neurons, and Nox4 is expressed by all three cell types. Further, Nox2 is the most responsive to injury.

TBI is a well-known epigenetic risk factor for the development of later neurodegenerative diseases [120]. Nox2 activation in brain tissue and Nox2-induced oxidative stress have emerged as a critical factor in the pathogenesis of Alzheimer’s disease [121, 122] and Parkinson’s disease [116, 123].

Alzheimer’s disease major hallmarks are the accumulation of β-amyloid and neurofibrillary tangles in the brain and the loss of neurons from the hippocampus and cerebral cortex [124]. It has been shown that TBI induces an accumulation of β-amyloid in the brain, which may explain the increased risk for cognitive decline and dementia in TBI patients [125, 126]. Interestingly, Nox inhibition by apocynin significantly attenuated the elevation of β-amyloid protein levels in the cortex following TBI, suggesting that Nox activation is involved in the induction of β-amyloid formation [18].

TBI was also found to induce overexpression of α-synuclein, the principal component of Lewy bodies, reported as a cause of Parkinson’s disease [127, 128]. A recent study of Acosta et al. suggested α-synuclein as the pathological link between chronic effects of TBI and PD symptoms [129]. It has been shown that the knockdown of Nox in the substantia nigra largely attenuated the increase of α-synuclein in a paraquat-induced Parkinson’s disease model, suggesting that Nox is involved in the mechanism responsible for generation of oxidative stress conditions implicated in increased α-synuclein expression and aggregation and dopaminergic neurodegeneration [130].

In summary, Nox upregulation occurs immediately after TBI and lasts for several days significantly contributing to oxidative stress damage and neuronal cell death. In particular, different lines of evidences suggest that Nox may be a causative factor in the onset of neurodegenerative disease related to TBI.

Although in terms of potential therapeutic strategies TBI treatment requires a deeper understanding of cerebral pathophysiology as well as of the neuroprotective responses toward therapeutic agents, targeting Nox isoforms could offer an intriguing hypothesis to decreasing/delaying the progression of temporary or permanent neurologic deficits that may result in lifelong impairment of physical, cognitive, and psychosocial functioning.

7. Conclusions

Accumulating evidence suggests that Nox-derived ROS play a crucial role in TBI. Nox upregulation occurs immediately after TBI and lasts for several days significantly contributing to oxidative stress damage and neuronal cell death. ROS produced by Nox contribute to diseases by means of distinct mechanisms, such as oxidation of macromolecules and consequent modulation of redox signaling pathways (Figure 2). Despite the progress made in the understanding of oxidative stress involvement in the pathology of several neurodegenerative diseases, much remains to be learned about how to counteract neurological damage following TBI.

Figure 2: Schematic representation of the proposed mechanisms triggering cell damage after TBI.

TBI is a well-known epigenetic risk factor for the development of later neurodegenerative diseases such as Parkinson and Alzheimer. Interestingly, Nox2-induced oxidative stress has emerged as a critical factor both in TBI secondary injury and in the pathogenesis of Alzheimer and Parkinson diseases suggesting that Nox2-generated ROS after TBI could be the cause of the increased neurodegenerative risks associated with TBI.

In summary, this review highlights the crucial role of Nox in TBI and suggests that selective and specific Nox inhibitor compounds could be useful for the development of novel therapeutic targets and strategies, allowing a fine correction of detrimental aspects of TBI.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Authors’ Contribution

Cristina Angeloni and Cecilia Prata contributed equally to this work.

Acknowledgments

This work was supported by MIUR-FIRB (project RBAP11HSZS) and “Fondazione del Monte di Bologna e Ravenna (Italy).”

References

  1. J. León-Carrión, M. D. R. Domínguez-Morales, J. M. Barroso y Martín, and F. Murillo-Cabezas, “Epidemiology of traumatic brain injury and subarachnoid hemorrhage,” Pituitary, vol. 8, no. 3-4, pp. 197–202, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. C. J. L. Murray and A. D. Lopez, “Alternative projections of mortality and disability by cause 1990-2020: global burden of disease study,” The Lancet, vol. 349, no. 9064, pp. 1498–1504, 1997. View at Publisher · View at Google Scholar · View at Scopus
  3. A. A. Hyder, C. A. Wunderlich, P. Puvanachandra, G. Gururaj, and O. C. Kobusingye, “The impact of traumatic brain injuries: a global perspective,” NeuroRehabilitation, vol. 22, no. 5, pp. 341–353, 2007. View at Google Scholar · View at Scopus
  4. F. Tagliaferri, C. Compagnone, M. Korsic, F. Servadei, and J. Kraus, “A systematic review of brain injury epidemiology in Europe,” Acta Neurochirurgica, vol. 148, no. 3, pp. 255–268, 2006. View at Publisher · View at Google Scholar · View at Scopus
  5. J. H. Adams, D. I. Graham, and T. A. Gennarelli, “Head injury in man and experimental animals: neuropathology,” Acta Neurochirurgica, Supplement, vol. 32, pp. 15–30, 1983. View at Publisher · View at Google Scholar · View at Scopus
  6. K. E. Saatman, A.-C. Duhaime, R. Bullock et al., “Classification of traumatic brain injury for targeted therapies,” Journal of Neurotrauma, vol. 25, no. 7, pp. 719–738, 2008. View at Publisher · View at Google Scholar · View at Scopus
  7. A. I. Maas, N. Stocchetti, and R. Bullock, “Moderate and severe traumatic brain injury in adults,” The Lancet Neurology, vol. 7, no. 8, pp. 728–741, 2008. View at Publisher · View at Google Scholar · View at Scopus
  8. J. J. Donkin and R. Vink, “Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments,” Current Opinion in Neurology, vol. 23, no. 3, pp. 293–299, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. E. Motori, J. Puyal, N. Toni et al., “Inflammation-induced alteration of astrocyte mitochondrial dynamics requires autophagy for mitochondrial network maintenance,” Cell Metabolism, vol. 18, no. 6, pp. 844–859, 2013. View at Publisher · View at Google Scholar · View at Scopus
  10. S. Signoretti, A. Marmarou, B. Tavazzi et al., “The protective effect of Cyclosporin A upon N-acetylaspartate and mitochondrial dysfunction following experimental diffuse traumatic brain injury,” Journal of Neurotrauma, vol. 21, no. 9, pp. 1154–1167, 2004. View at Publisher · View at Google Scholar · View at Scopus
  11. A. Lewén, P. Matz, and P. H. Chan, “Free radical pathways in CNS injury,” Journal of Neurotrauma, vol. 17, no. 10, pp. 871–890, 2000. View at Publisher · View at Google Scholar · View at Scopus
  12. R. A. Floyd and J. M. Carney, “Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress,” Annals of Neurology, vol. 32, pp. S22–S27, 1992. View at Publisher · View at Google Scholar · View at Scopus
  13. A. J. Lambert and M. D. Brand, “Reactive oxygen species production by mitochondria,” Methods in Molecular Biology, vol. 554, pp. 165–181, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. M. A. Ansari, K. N. Roberts, and S. W. Scheff, “A time course of NADPH-oxidase up-regulation and endothelial nitric oxide synthase activation in the hippocampus following neurotrauma,” Free Radical Biology and Medicine, vol. 77, pp. 21–29, 2014. View at Publisher · View at Google Scholar
  15. X.-Y. Lu, H.-D. Wang, J.-G. Xu, K. Ding, and T. Li, “NADPH oxidase inhibition improves neurological outcome in experimental traumatic brain injury,” Neurochemistry International, vol. 69, no. 1, pp. 14–19, 2014. View at Publisher · View at Google Scholar · View at Scopus
  16. I. N. Singh, P. G. Sullivan, Y. Deng, L. H. Mbye, and E. D. Hall, “Time course of post-traumatic mitochondrial oxidative damage and dysfunction in a mouse model of focal traumatic brain injury: implications for neuroprotective therapy,” Journal of Cerebral Blood Flow and Metabolism, vol. 26, no. 11, pp. 1407–1418, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. S.-X. Song, J.-L. Gao, K.-J. Wang et al., “Attenuation of brain edema and spatial learning deficits by the inhibition of NADPH oxidase activity using apocynin following diffuse traumatic brain injury in rats,” Molecular Medicine Reports, vol. 7, no. 1, pp. 327–331, 2013. View at Publisher · View at Google Scholar · View at Scopus
  18. Q. G. Zhang, M. D. Laird, D. Han et al., “Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury,” PLoS ONE, vol. 7, no. 4, Article ID e34504, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. B. Y. Choi, B. G. Jang, J. H. Kim et al., “Prevention of traumatic brain injury-induced neuronal death by inhibition of NADPH oxidase activation,” Brain Research, vol. 1481, pp. 49–58, 2012. View at Publisher · View at Google Scholar · View at Scopus
  20. C. L. Harrison and M. Dijkers, “Traumatic brain injury registries in the United States: an overview,” Brain Injury, vol. 6, no. 3, pp. 203–212, 1992. View at Publisher · View at Google Scholar · View at Scopus
  21. G. Teasdale and B. Jennett, “Assessment of coma and impaired consciousness. A practical scale,” The Lancet, vol. 2, no. 7872, pp. 81–84, 1974. View at Google Scholar · View at Scopus
  22. B. Jennett, “Epidemiology of head injury,” Journal of Neurology Neurosurgery and Psychiatry, vol. 60, no. 4, pp. 362–369, 1996. View at Publisher · View at Google Scholar · View at Scopus
  23. J. T. Povlishock and D. I. Katz, “Update of neuropathology and neurological recovery after traumatic brain injury,” Journal of Head Trauma Rehabilitation, vol. 20, no. 1, pp. 76–94, 2005. View at Publisher · View at Google Scholar · View at Scopus
  24. T. A. Gennarelli, L. E. Thibault, J. H. Adams, D. I. Graham, C. J. Thompson, and R. P. Marcincin, “Diffuse axonal injury and traumatic coma in the primate,” Annals of Neurology, vol. 12, no. 6, pp. 564–574, 1982. View at Publisher · View at Google Scholar · View at Scopus
  25. J. M. Meythaler, J. D. Peduzzi, E. Eleftheriou, and T. A. Novack, “Current concepts: diffuse axonal injury-associated traumatic brain injury,” Archives of Physical Medicine and Rehabilitation, vol. 82, no. 10, pp. 1461–1471, 2001. View at Publisher · View at Google Scholar · View at Scopus
  26. T. Skandsen, K. A. Kvistad, O. Solheim, I. H. Strand, M. Folvik, and V. Anne, “Prevalence and impact of diffuse axonal injury in patients with moderate and severe head injury: a cohort study of early magnetic resonance imaging findings and 1-year outcome: Clinical article,” Journal of Neurosurgery, vol. 113, no. 3, pp. 556–563, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. J. H. Adams, D. Doyle, I. Ford, T. A. Gennarelli, D. I. Graham, and D. R. McLellan, “Diffuse axonal injury in head injury: definition, diagnosis and grading,” Histopathology, vol. 15, no. 1, pp. 49–59, 1989. View at Publisher · View at Google Scholar · View at Scopus
  28. A. Büki and J. T. Povlishock, “All roads lead to disconnection?—Traumatic axonal injury revisited,” Acta Neurochirurgica, vol. 148, no. 2, pp. 181–193, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. J. Y. Wang, K. Bakhadirov, H. Abdi et al., “Longitudinal changes of structural connectivity in traumatic axonal injury,” Neurology, vol. 77, no. 9, pp. 818–826, 2011. View at Publisher · View at Google Scholar · View at Scopus
  30. C. B. Hutson, C. R. Lazo, F. Mortazavi, C. C. Giza, D. Hovda, and M. F. Chesselet, “Traumatic brain injury in adult rats causes progressive nigrostriatal dopaminergic cell loss and enhanced vulnerability to the pesticide paraquat,” Journal of Neurotrauma, vol. 28, no. 9, pp. 1783–1801, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. T. C. Lye and E. A. Shores, “Traumatic brain injury as a risk factor for Alzheimer's disease: a review,” Neuropsychology Review, vol. 10, no. 2, pp. 115–129, 2000. View at Publisher · View at Google Scholar · View at Scopus
  32. A. C. McKee, R. C. Cantu, C. J. Nowinski et al., “Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury,” Journal of Neuropathology & Experimental Neurology, vol. 68, no. 7, pp. 709–735, 2009. View at Publisher · View at Google Scholar · View at Scopus
  33. K. Beauchamp, H. Mutlak, W. R. Smith, E. Shohami, and P. F. Stahel, “Pharmacology of traumatic brain injury: where is the ‘golden bullet’?” Molecular Medicine, vol. 14, no. 11-12, pp. 731–740, 2008. View at Publisher · View at Google Scholar · View at Scopus
  34. H. Bayir, V. E. Kagan, R. S. B. Clark et al., “Neuronal NOS-mediated nitration and inactivation of manganese superoxide dismutase in brain after experimental and human brain injury,” Journal of Neurochemistry, vol. 101, no. 1, pp. 168–181, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. E. D. Hall, M. R. Detloff, K. Johnson, and N. C. Kupina, “Peroxynitrite-mediated protein nitration and lipid peroxidation in a mouse model of traumatic brain injury,” Journal of Neurotrauma, vol. 21, no. 1, pp. 9–20, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. G. Lotocki, J. P. de Rivero Vaccari, E. R. Perez et al., “Alterations in blood-brain barrier permeability to large and small molecules and leukocyte accumulation after traumatic brain injury: effects of post-traumatic hypothermia,” Journal of Neurotrauma, vol. 26, no. 7, pp. 1123–1134, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. P. B. L. Pun, J. Lu, and S. Moochhala, “Involvement of ROS in BBB dysfunction,” Free Radical Research, vol. 43, no. 4, pp. 348–364, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. H. Z. Toklu, T. Hakan, N. Biber, S. Solakoğlu, A. V. Öğünç, and G. Şener, “The protective effect of alpha lipoic acid against traumatic brain injury in rats,” Free Radical Research, vol. 43, no. 7, pp. 658–667, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. B. K. Siesjo, “Calcium-mediated processes in neuronal degeneration,” Annals of the New York Academy of Sciences, vol. 747, pp. 140–161, 1994. View at Google Scholar · View at Scopus
  40. A. Biegon, P. A. Fry, C. M. Paden, A. Alexandrovich, J. Tsenter, and E. Shohami, “Dynamic changes in N-methyl-D-aspartate receptors after closed head injury in mice: implications for treatment of neurological and cognitive deficits,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 14, pp. 5117–5122, 2004. View at Publisher · View at Google Scholar · View at Scopus
  41. A. W. Unterberg, J. Stover, B. Kress, and K. L. Kiening, “Edema and brain trauma,” Neuroscience, vol. 129, no. 4, pp. 1021–1029, 2004. View at Publisher · View at Google Scholar · View at Scopus
  42. B. Liu and J. S. Hong, “Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention,” Journal of Pharmacology and Experimental Therapeutics, vol. 304, no. 1, pp. 1–7, 2003. View at Publisher · View at Google Scholar · View at Scopus
  43. E. Shohami, R. Bass, D. Wallach, A. Yamin, and R. Gallily, “Inhibition of tumor necrosis factor alpha (TNFalpha) activity in rat brain is associated with cerebroprotection after closed head injury,” Journal of Cerebral Blood Flow and Metabolism, vol. 16, no. 3, pp. 378–384, 1996. View at Google Scholar · View at Scopus
  44. M. A. Ansari, K. N. Roberts, and S. W. Scheff, “Oxidative stress and modification of synaptic proteins in hippocampus after traumatic brain injury,” Free Radical Biology and Medicine, vol. 45, no. 4, pp. 443–452, 2008. View at Publisher · View at Google Scholar · View at Scopus
  45. C. Shao, K. N. Roberts, W. R. Markesbery, S. W. Scheff, and M. A. Lovell, “Oxidative stress in head trauma in aging,” Free Radical Biology and Medicine, vol. 41, no. 1, pp. 77–85, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. M. Prins, T. Greco, D. Alexander, and C. C. Giza, “The pathophysiology of traumatic brain injury at a glance,” Disease Models & Mechanisms, vol. 6, no. 6, pp. 1307–1315, 2013. View at Publisher · View at Google Scholar · View at Scopus
  47. U. Dirnagl, C. Iadecola, and M. A. Moskowitz, “Pathobiology of ischaemic stroke: an integrated view,” Trends in Neurosciences, vol. 22, no. 9, pp. 391–397, 1999. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Sahuquillo, M. A. Poca, and S. Amoros, “Current aspects of pathophysiology and cell dysfunction after severe head injury,” Current Pharmaceutical Design, vol. 7, no. 15, pp. 1475–1503, 2001. View at Publisher · View at Google Scholar · View at Scopus
  49. T. I. Peng and M. J. Jou, “Oxidative stress caused by mitochondrial calcium overload,” Annals of the New York Academy of Sciences, vol. 1201, pp. 183–188, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. Y. Xiong, Q. Gu, P. L. Peterson, J. P. Muizelaar, and C. P. Lee, “Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury,” Journal of Neurotrauma, vol. 14, no. 1, pp. 23–34, 1997. View at Publisher · View at Google Scholar · View at Scopus
  51. F. Clausen, H. Lundqvist, S. Ekmark, A. Lewén, T. Ebendal, and L. Hillered, “Oxygen free radical-dependent activation of extracellular signal-regulated kinase mediates apoptosis-like cell death after traumatic brain injury,” Journal of Neurotrauma, vol. 21, no. 9, pp. 1168–1182, 2004. View at Publisher · View at Google Scholar · View at Scopus
  52. N. Marklund, F. Clausen, T. Lewander, and L. Hillered, “Monitoring of reactive oxygen species production after traumatic brain injury in rats with microdialysis and the 4-hydroxybenzoic acid trapping method,” Journal of Neurotrauma, vol. 18, no. 11, pp. 1217–1227, 2001. View at Publisher · View at Google Scholar · View at Scopus
  53. J. D. Lambeth and A. S. Neish, “Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited,” Annual review of pathology, vol. 9, pp. 119–145, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. N. Chaudhari, P. Talwar, A. Parimisetty, C. Lefebvre d'Hellencourt, and P. Ravanan, “A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress,” Frontiers in Cellular Neuroscience, vol. 8, article 213, 2014. View at Publisher · View at Google Scholar
  55. B. Halliwell, “The role of oxygen radicals in human disease, with particular reference to the vascular system,” Haemostasis, vol. 23, supplement 1, pp. 118–126, 1993. View at Google Scholar · View at Scopus
  56. H. L. Hsieh and C. M. Yang, “Role of redox signaling in neuroinflammation and neurodegenerative diseases,” BioMed Research International, vol. 2013, Article ID 484613, 18 pages, 2013. View at Publisher · View at Google Scholar
  57. N. Kaludercic, S. Deshwal, and F. Di Lisa, “Reactive oxygen species and redox compartmentalization,” Frontiers in Physiology, vol. 5, article 285, 2014. View at Publisher · View at Google Scholar
  58. S. I. Liochev, “Free radical paradoxes,” Free Radical Biology and Medicine, vol. 65, pp. 232–233, 2013. View at Publisher · View at Google Scholar · View at Scopus
  59. B. Uttara, A. V. Singh, P. Zamboni, and R. T. Mahajan, “Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options,” Current Neuropharmacology, vol. 7, no. 1, pp. 65–74, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. M. L. Circu and T. Y. Aw, “Reactive oxygen species, cellular redox systems, and apoptosis,” Free Radical Biology and Medicine, vol. 48, no. 6, pp. 749–762, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. P. S. Hole, R. L. Darley, and A. Tonks, “Do reactive oxygen species play a role in myeloid leukemias?” Blood, vol. 117, no. 22, pp. 5816–5826, 2011. View at Publisher · View at Google Scholar · View at Scopus
  62. C. Cornelius, R. Crupi, V. Calabrese et al., “Traumatic brain injury: oxidative stress and neuroprotection,” Antioxidants & Redox Signaling, vol. 19, no. 8, pp. 836–853, 2013. View at Publisher · View at Google Scholar · View at Scopus
  63. K. Keyer, A. S. Gort, and J. A. Imlay, “Superoxide and the production of oxidative DNA damage,” Journal of Bacteriology, vol. 177, no. 23, pp. 6782–6790, 1995. View at Google Scholar · View at Scopus
  64. S. R. Thomas, P. K. Witting, and G. R. Drummond, “Redox control of endothelial function and dysfunction: molecular mechanisms and therapeutic opportunities,” Antioxidants and Redox Signaling, vol. 10, no. 10, pp. 1713–1765, 2008. View at Publisher · View at Google Scholar · View at Scopus
  65. T. Nishikawa, D. Edelstein, X. L. Du et al., “Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage,” Nature, vol. 404, no. 6779, pp. 787–790, 2000. View at Publisher · View at Google Scholar · View at Scopus
  66. T. Maraldi, “Natural compounds as modulators of NADPH oxidases,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 271602, 10 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  67. F. Vieceli Dalla Sega, L. Zambonin, D. Fiorentini et al., “Specific aquaporins facilitate Nox-produced hydrogen peroxide transport through plasma membrane in leukaemia cells,” Biochimica et Biophysica Acta, vol. 1843, no. 4, pp. 806–814, 2014. View at Publisher · View at Google Scholar · View at Scopus
  68. T. Finkel, “Signal transduction by reactive oxygen species,” The Journal of Cell Biology, vol. 194, no. 1, pp. 7–15, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. E. D. Hall and J. M. Braughler, “Free radicals in CNS injury,” Research Publications—Association for Research in Nervous and Mental Disease, vol. 71, pp. 81–105, 1993. View at Google Scholar · View at Scopus
  70. M. M. Zaleska and R. A. Floyd, “Regional lipid peroxidation in rat brain in vitro: possible role of endogenous iron,” Neurochemical Research, vol. 10, no. 3, pp. 397–410, 1985. View at Publisher · View at Google Scholar · View at Scopus
  71. A. Rodríguez-Rodríguez, J. J. Egea-Guerrero, F. Murillo-Cabezas, and A. Carrillo-Vico, “Oxidative stress in traumatic brain injury,” Current Medicinal Chemistry, vol. 21, no. 10, pp. 1201–1211, 2014. View at Publisher · View at Google Scholar · View at Scopus
  72. A. Tarozzi, C. Angeloni, M. Malaguti, F. Morroni, S. Hrelia, and P. Hrelia, “Sulforaphane as a potential protective phytochemical against neurodegenerative diseases,” Oxidative Medicine and Cellular Longevity, vol. 2013, Article ID 415078, 10 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  73. A. Minarini, A. Milelli, V. Tumiatti et al., “Cystamine-tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer's disease treatment,” Neuropharmacology, vol. 62, no. 2, pp. 997–1003, 2012. View at Publisher · View at Google Scholar · View at Scopus
  74. Z.-G. Xiong, X.-M. Zhu, X.-P. Chu et al., “Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels,” Cell, vol. 118, no. 6, pp. 687–698, 2004. View at Publisher · View at Google Scholar · View at Scopus
  75. C. Ikonomidou and L. Turski, “Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury?” The Lancet Neurology, vol. 1, no. 6, pp. 383–386, 2002. View at Publisher · View at Google Scholar · View at Scopus
  76. J. Sastre, F. V. Pallardo, and J. Vina, “The role of mitochondrial oxidative stress in aging,” Free Radical Biology & Medicine, vol. 35, no. 1, pp. 1–8, 2003. View at Google Scholar
  77. H. A. Kontos and J. T. Povlishock, “Oxygen radicals in brain injury,” Central Nervous System Trauma, vol. 3, no. 4, pp. 257–263, 1986. View at Google Scholar · View at Scopus
  78. H. A. Kontos and E. P. Wei, “Superoxide production in experimental brain injury,” Journal of Neurosurgery, vol. 64, no. 5, pp. 803–807, 1986. View at Publisher · View at Google Scholar · View at Scopus
  79. G. Barreto, R. E. White, Y. Ouyang, L. Xu, and R. G. Giffard, “Astrocytes: targets for neuroprotection in stroke,” Central Nervous System Agents in Medicinal Chemistry, vol. 11, no. 2, pp. 164–173, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. M. L. Block and J. S. Hong, “Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism,” Progress in Neurobiology, vol. 76, no. 2, pp. 77–98, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. J. M. C. Gutteridge, “Lipid peroxidation and antioxidants as biomarkers of tissue damage,” Clinical Chemistry, vol. 41, no. 12, pp. 1819–1828, 1995. View at Google Scholar · View at Scopus
  82. A. G. Mustafa, I. N. Singh, J. Wang, K. M. Carrico, and E. D. Hall, “Mitochondrial protection after traumatic brain injury by scavenging lipid peroxyl radicals,” Journal of Neurochemistry, vol. 114, no. 1, pp. 271–280, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. I. N. Singh, L. K. Gilmer, D. M. Miller, J. E. Cebak, J. A. Wang, and E. D. Hall, “Phenelzine mitochondrial functional preservation and neuroprotection after traumatic brain injury related to scavenging of the lipid peroxidation-derived aldehyde 4-hydroxy-2-nonenal,” Journal of Cerebral Blood Flow & Metabolism, vol. 33, no. 4, pp. 593–599, 2013. View at Publisher · View at Google Scholar · View at Scopus
  84. J. N. Keller, R. J. Mark, A. J. Bruce et al., “4-hydroxynonenal, an aldehydic product of membrane lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes,” Neuroscience, vol. 80, no. 3, pp. 685–696, 1997. View at Publisher · View at Google Scholar · View at Scopus
  85. W. A. Pedersen, N. R. Cashman, and M. P. Mattson, “The lipid peroxidation product 4-hydroxynonenal impairs glutamate and glucose transport and choline acetyltransferase activity in NSC-19 motor neuron cells,” Experimental Neurology, vol. 155, no. 1, pp. 1–10, 1999. View at Publisher · View at Google Scholar · View at Scopus
  86. R. Durmaz, G. Kanbak, F. Akyüz et al., “Lazaroid attenuates edema by stabilizing ATPase in the traumatized rat brain,” Canadian Journal of Neurological Sciences, vol. 30, no. 2, pp. 143–149, 2003. View at Google Scholar · View at Scopus
  87. P. Račay, P. Kaplán, V. Mézešová, and J. Lehotský, “Lipid peroxidation both inhibits Ca2+-ATPase and increases Ca2+ permeability of endoplasmic reticulum membrane,” Biochemistry and Molecular Biology International, vol. 41, no. 4, pp. 647–655, 1997. View at Google Scholar · View at Scopus
  88. K. Wada, K. Chatzipanteli, S. Kraydieh, R. Busto, and W. D. Dietrich, “Inducible nitric oxide synthase expression after traumatic brain injury and neuroprotection with aminoguanidine treatment in rats,” Neurosurgery, vol. 43, no. 6, pp. 1427–1436, 1998. View at Google Scholar · View at Scopus
  89. C. Mésenge, C. Charriaut-Marlangue, C. Verrecchia, M. Allix, R. R. Boulu, and M. Plotkine, “Reduction of tyrosine nitration after Nω-nitro-l-arginine-methylester treatment of mice with traumatic brain injury,” European Journal of Pharmacology, vol. 353, no. 1, pp. 53–57, 1998. View at Publisher · View at Google Scholar · View at Scopus
  90. Y. Deng-Bryant, I. N. Singh, K. M. Carrico, and E. D. Hall, “Neuroprotective effects of tempol, a catalytic scavenger of peroxynitrite-derived free radicals, in a mouse traumatic brain injury model,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 6, pp. 1114–1126, 2008. View at Publisher · View at Google Scholar · View at Scopus
  91. C. Gahm, S. Holmin, and T. Mathiesen, “Temporal profiles and cellular sources of three nitric oxide synthase isoforms in the brain after experimental contusion,” Neurosurgery, vol. 46, no. 1, pp. 169–177, 2000. View at Google Scholar · View at Scopus
  92. C. S. Cobbs, A. Fenoy, D. S. Bredt, and L. J. Noble, “Expression of nitric oxide synthase in the cerebral microvasculature after traumatic brain injury in the rat,” Brain Research, vol. 751, no. 2, pp. 336–338, 1997. View at Publisher · View at Google Scholar · View at Scopus
  93. V. L. Raghavendra Rao, A. Dogan, K. K. Bowen, and R. J. Dempsey, “Traumatic injury to rat brain upregulates neuronal nitric oxide synthase expression and l-[3H]nitroarginine binding,” Journal of Neurotrauma, vol. 16, no. 10, pp. 865–877, 1999. View at Publisher · View at Google Scholar · View at Scopus
  94. P. Ascenzi, A. Bocedi, P. Visca et al., “Hemoglobin and heme scavenging,” IUBMB Life, vol. 57, no. 11, pp. 749–759, 2005. View at Publisher · View at Google Scholar · View at Scopus
  95. T. Arai, N. Takeyama, and T. Tanaka, “Glutathione monoethyl ester and inhibition of the oxyhemoglobin-induced increase in cytosolic calcium in cultured smooth-muscle cells,” Journal of Neurosurgery, vol. 90, no. 3, pp. 527–532, 1999. View at Publisher · View at Google Scholar · View at Scopus
  96. T. Asano, “Oxyhemoglobin as the principal cause of cerebral vasospasm: a holistic view of its actions,” Critical Reviews in Neurosurgery, vol. 9, no. 5, pp. 303–318, 1999. View at Publisher · View at Google Scholar
  97. F. Marzatico, P. Gaetani, C. Cafe, G. Spanu, and R. Rodriguez y Baena, “Antioxidant enzymatic activities after experimental subarachnoid hemorrhage in rats,” Acta Neurologica Scandinavica, vol. 87, no. 1, pp. 62–66, 1993. View at Publisher · View at Google Scholar · View at Scopus
  98. F. Marzatico, P. Gaetani, V. Silvani, D. Lombardi, E. Sinforiani, and R. Baena, “Experimental isobaric subarachnoid hemorrhage: regional mitochondrial function during the acute and late phase,” Surgical Neurology, vol. 34, no. 5, pp. 294–300, 1990. View at Publisher · View at Google Scholar · View at Scopus
  99. E. D. Hall, R. A. Vaishnav, and A. G. Mustafa, “Antioxidant therapies for traumatic brain injury,” Neurotherapeutics, vol. 7, no. 1, pp. 51–61, 2010. View at Publisher · View at Google Scholar · View at Scopus
  100. S. Rehncrona, H. N. Hauge, and B. K. Siesjo, “Enhancement of iron-catalyzed free radical formation by acidosis in brain homogenates: differences in effect by lactic acid and CO2,” Journal of Cerebral Blood Flow and Metabolism, vol. 9, no. 1, pp. 65–70, 1989. View at Publisher · View at Google Scholar · View at Scopus
  101. J. D. Lambeth and A. S. Neish, “Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited,” Annual Review of Pathology, vol. 9, pp. 119–145, 2014. View at Publisher · View at Google Scholar · View at Scopus
  102. A. Panday, M. K. Sahoo, D. Osorio, and S. Batra, “NADPH oxidases: an overview from structure to innate immunity-associated pathologies,” Cellular and Molecular Immunology, vol. 12, no. 1, pp. 5–23, 2014. View at Publisher · View at Google Scholar
  103. H. Sumimoto, “Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species,” FEBS Journal, vol. 275, no. 13, pp. 3249–3277, 2008. View at Publisher · View at Google Scholar · View at Scopus
  104. K. Bedard and K.-H. Krause, “The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology,” Physiological Reviews, vol. 87, no. 1, pp. 245–313, 2007. View at Publisher · View at Google Scholar · View at Scopus
  105. S. Sorce and K. H. Krause, “NOX enzymes in the central nervous system: from signaling to disease,” Antioxidants and Redox Signaling, vol. 11, no. 10, pp. 2481–2504, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. A. Y. Abramov, J. Jacobson, F. Wientjes, J. Hothersall, L. Canevari, and M. R. Duchen, “Expression and modulation of an NADPH oxidase in mammalian astrocytes,” The Journal of Neuroscience, vol. 25, no. 40, pp. 9176–9184, 2005. View at Publisher · View at Google Scholar · View at Scopus
  107. S. H. Choi, Y. L. Da, U. K. Seung, and K. J. Byung, “Thrombin-induced oxidative stress contributes to the death of hippocampal neurons in vivo: role of microglial NADPH oxidase,” The Journal of Neuroscience, vol. 25, no. 16, pp. 4082–4090, 2005. View at Publisher · View at Google Scholar · View at Scopus
  108. A. P. O. Ferreira, F. S. Rodrigues, I. D. Della-Pace et al., “The effect of NADPH-oxidase inhibitor apocynin on cognitive impairment induced by moderate lateral fluid percussion injury: role of inflammatory and oxidative brain damage,” Neurochemistry International, vol. 63, no. 6, pp. 583–593, 2013. View at Publisher · View at Google Scholar · View at Scopus
  109. D. J. Loane, B. A. Stoica, K. R. Byrnes, W. Jeong, and A. I. Faden, “Activation of mGluR5 and inhibition of NADPH oxidase improves functional recovery after traumatic brain injury,” Journal of Neurotrauma, vol. 30, no. 5, pp. 403–412, 2013. View at Publisher · View at Google Scholar · View at Scopus
  110. K. Dohi, H. Ohtaki, T. Nakamachi et al., “Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury,” Journal of Neuroinflammation, vol. 7, article 41, 2010. View at Publisher · View at Google Scholar · View at Scopus
  111. J. Stolk, T. J. Hiltermann, J. H. Dijkman, and A. J. Verhoeven, “Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol,” American Journal of Respiratory Cell and Molecular Biology, vol. 11, no. 1, pp. 95–102, 1994. View at Publisher · View at Google Scholar · View at Scopus
  112. E. van den Worm, C. J. Beukelman, A. J. J. van den Berg, B. H. Kroes, R. P. Labadie, and H. van Dijk, “Effects of methoxylation of apocynin and analogs on the inhibition of reactive oxygen species production by stimulated human neutrophils,” European Journal of Pharmacology, vol. 433, no. 2-3, pp. 225–230, 2001. View at Publisher · View at Google Scholar · View at Scopus
  113. T. Hayashi, P. A. R. Juliet, H. Kano-Hayashi et al., “NADPH oxidase inhibitor, apocynin, restores the impaired endothelial-dependent and -independent responses and scavenges superoxide anion in rats with type 2 diabetes complicated by NO dysfunction,” Diabetes, Obesity and Metabolism, vol. 7, no. 4, pp. 334–343, 2005. View at Publisher · View at Google Scholar · View at Scopus
  114. Y. Jinnouchi, S.-I. Yamagishi, T. Matsui et al., “Administration of pigment epithelium-derived factor (PEDF) inhibits cold injury-induced brain edema in mice,” Brain Research, vol. 1167, no. 1, pp. 92–100, 2007. View at Publisher · View at Google Scholar · View at Scopus
  115. D. J. Loane, A. Kumar, B. A. Stoica, R. Cabatbat, and A. I. Faden, “Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation,” Journal of Neuropathology and Experimental Neurology, vol. 73, no. 1, pp. 14–29, 2014. View at Publisher · View at Google Scholar · View at Scopus
  116. L. Qin, Y. Liu, J. S. Hong, and F. T. Crews, “NADPH oxidase and aging drive microglial activation, oxidative stress, and dopaminergic neurodegeneration following systemic LPS administration,” Glia, vol. 61, no. 6, pp. 855–868, 2013. View at Publisher · View at Google Scholar · View at Scopus
  117. M. E. Lull and M. L. Block, “Microglial activation and chronic neurodegeneration,” Neurotherapeutics, vol. 7, no. 4, pp. 354–365, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. A. Kumar, B. A. Stoica, B. Sabirzhanov, M. P. Burns, A. I. Faden, and D. J. Loane, “Traumatic brain injury in aged animals increases lesion size and chronically alters microglial/macrophage classical and alternative activation states,” Neurobiology of Aging, vol. 34, no. 5, pp. 1397–1411, 2013. View at Publisher · View at Google Scholar · View at Scopus
  119. S. J. Cooney, S. L. Bermudez-Sabogal, and K. R. Byrnes, “Cellular and temporal expression of NADPH oxidase (NOX) isotypes after brain injury,” Journal of Neuroinflammation, vol. 10, article 155, 2013. View at Publisher · View at Google Scholar · View at Scopus
  120. N. B. Chauhan, “Chronic neurodegenerative consequences of traumatic brain injury,” Restorative Neurology and Neuroscience, vol. 32, no. 2, pp. 337–365, 2014. View at Google Scholar
  121. S. Shimohama, H. Tanino, N. Kawakami et al., “Activation of NADPH oxidase in Alzheimer's disease brains,” Biochemical and Biophysical Research Communications, vol. 273, no. 1, pp. 5–9, 2000. View at Publisher · View at Google Scholar · View at Scopus
  122. D. Zekry, T. Kay Epperson, and K.-H. Krause, “A role for NOX NADPH oxidases in Alzheimer's disease and other types of dementia?” IUBMB Life, vol. 55, no. 6, pp. 307–313, 2003. View at Publisher · View at Google Scholar · View at Scopus
  123. W. Zhang, T. Wang, L. Qin et al., “Neuroprotective effect of dextromethorphan in the MPTP Parkinson's disease model: role of NADPH oxidase,” The FASEB journal, vol. 18, no. 3, pp. 589–591, 2004. View at Google Scholar · View at Scopus
  124. C. Angeloni, L. Zambonin, and S. Hrelia, “Role of methylglyoxal in alzheimer's disease,” BioMed Research International, vol. 2014, Article ID 238485, 12 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  125. H. M. Bramlett and W. D. Dietrich, “Pathophysiology of cerebral ischemia and brain trauma: similarities and differences,” Journal of Cerebral Blood Flow & Metabolism, vol. 24, no. 2, pp. 133–150, 2004. View at Google Scholar · View at Scopus
  126. C. van den Heuvel, E. Thornton, and R. Vink, “Traumatic brain injury and Alzheimer's disease: a review,” Progress in Brain Research, vol. 161, pp. 303–316, 2007. View at Publisher · View at Google Scholar · View at Scopus
  127. K. Beyer, M. Domingo-Sàbat, and A. Ariza, “Molecular pathology of Lewy body diseases,” International Journal of Molecular Sciences, vol. 10, no. 3, pp. 724–745, 2009. View at Publisher · View at Google Scholar · View at Scopus
  128. T. Yasuda, Y. Nakata, and H. Mochizuki, “α-Synuclein and neuronal cell death,” Molecular neurobiology, vol. 47, no. 2, pp. 466–483, 2013. View at Publisher · View at Google Scholar · View at Scopus
  129. S. A. Acosta, N. Tajiri, I. de la Pena et al., “Alpha-synuclein as a pathological link between chronic traumatic brain injury and Parkinson's disease,” Journal of Cellular Physiology, vol. 230, no. 5, pp. 1024–1032, 2015. View at Publisher · View at Google Scholar
  130. A. C. Cristóvão, S. Guhathakurta, E. Bok et al., “Nadph oxidase 1 mediates alpha-synucleinopathy in Parkinson's disease,” The Journal of Neuroscience, vol. 32, no. 42, pp. 14465–14477, 2012. View at Publisher · View at Google Scholar · View at Scopus