Review Article | Open Access
André Mendes Arent, Luiz Felipe de Souza, Roger Walz, Alcir Luiz Dafre, "Perspectives on Molecular Biomarkers of Oxidative Stress and Antioxidant Strategies in Traumatic Brain Injury", BioMed Research International, vol. 2014, Article ID 723060, 18 pages, 2014. https://doi.org/10.1155/2014/723060
Perspectives on Molecular Biomarkers of Oxidative Stress and Antioxidant Strategies in Traumatic Brain Injury
Traumatic brain injury (TBI) is frequently associated with abnormal blood-brain barrier function, resulting in the release of factors that can be used as molecular biomarkers of TBI, among them GFAP, UCH-L1, S100B, and NSE. Although many experimental studies have been conducted, clinical consolidation of these biomarkers is still needed to increase the predictive power and reduce the poor outcome of TBI. Interestingly, several of these TBI biomarkers are oxidatively modified to carbonyl groups, indicating that markers of oxidative stress could be of predictive value for the selection of therapeutic strategies. Some drugs such as corticosteroids and progesterone have already been investigated in TBI neuroprotection but failed to demonstrate clinical applicability in advanced phases of the studies. Dietary antioxidants, such as curcumin, resveratrol, and sulforaphane, have been shown to attenuate TBI-induced damage in preclinical studies. These dietary antioxidants can increase antioxidant defenses via transcriptional activation of NRF2 and are also known as carbonyl scavengers, two potential mechanisms for neuroprotection. This paper reviews the relevance of redox biology in TBI, highlighting perspectives for future studies.
According to the World Health Organization, traumatic brain injury (TBI) is the leading cause of death in young adults. TBI will surpass many diseases and will become the third cause of death and disability in the general population by the year 2020 [1, 2]. The high medical costs of these patients can compromise the entire health care system .
The International Mission for Prognosis and Analysis of Critical Trials in TBI (IMPACT study) has developed a prognosis calculator based on admission data of more than 8500 patients ; validation studies has shown it to perform with reasonable accuracy . However, the predictive power of this outcome calculator can be improved by the use of brain injury biomarkers , while post-TBI prognosis itself can be improved through the development of new neuroprotective strategies. To determine a good biomarker it seems essential that pathophysiologic mechanisms involved in the initial phase of TBI should be known in detail, while a more extended understanding of regulatory mechanisms is also required for effectively promoting neuroprotection.
2.1. Clinical Parameters
The clinical outcomes of TBI are directly related to the severity of the primary and secondary lesions sustained by the patient. Primary lesions are those related to the initial impact (lacerations, contusion, fractures, and diffuse axonal injury). Secondary lesions are those which developed after the initial trauma, including hematomas, edema, and pathological processes cascades that cause ischemia resulting in a worsening of the clinical condition . The development of the secondary injury in TBI is a complex process involving oxidative stress, glutamate excitotoxicity, inflammatory damage, and the toxicity of metabolites that can be disseminated by the circulatory system [8, 9].
The therapeutic management of intracranial trauma aims to avoid the development of secondary lesions, and to this end, the control of physiological parameters such as cerebral perfusion pressure (CPP), intracranial pressure (ICP), and cerebral blood flow (CBF) is crucial to minimize ischemia and tissue damage . The clinical use of CPP as a clinical parameter is based on theoretical suggestions indicating that optimal cerebral blood flow is necessary to meet the metabolic needs of the injured brain . The therapeutic management goal is to keep the CBF stable and maintain a balance between CPP and ICP in order to rescue the ischemic penumbra area. Cells in this area are potentially salvable; therefore, they comprise the most essential area for medical intervention, making the prevention of secondary insults in this region crucial for a better outcome .
2.2. Brain Swelling
Among secondary injuries, cerebral edema is of special significance, as it can greatly aggravate brain damage and is the main condition related to increased ICP, excluding conditions potentially leading to surgical interventions, such as hematoma and contusion. Increased ICP leads to a decrease in CPP and CBF, worsening tissue damage as a consequence of brain ischemia. Edema occurs by two basic mechanisms, cytotoxic edema related to the depletion of cell energy and vasogenic edema related to disruption of the brain-blood barrier (BBB) [13, 14].
In vasogenic brain edema, BBB integrity is compromised by mechanical or autodigestive disruption, or functional breakdown of the endothelial cell layer of brain vessels, which is critical for maintenance of the BBB. Disintegration of the cerebral vascular endothelial wall allows for uncontrolled ion and protein transfer from the intravascular to the extracellular (interstitial) brain compartment, leading to fluid accumulation, which increases the volume of the extracellular space [15, 16]. The intact BBB prevents diffusion of most water-soluble molecules above 500 Da . However, when the BBB is disrupted, brain-related proteins can be measured in the peripheral circulation [18, 19]. The BBB leakage associated with TBI not only allows brain-related molecules to reach the bloodstream but also permits molecules from the periphery to enter cerebrospinal fluid (CSF). Both situations, either peripheral proteins entering the CSF or CSF leakage of proteins, can be used as biomarkers of TBI [20, 21].
Cytotoxic brain edema is characterized by intracellular water accumulation inside neurons, astrocytes, and microglia. This pathology is caused by an increased cell membrane permeability, ionic pump failure due to energy depletion, and intracellular accumulation of osmotically active solutes [16, 22]. This edema-driven energy impairment generates an “ischemia-like” pattern, which increases glycolysis flux, leading to lactic acid accumulation, associated with increased membrane permeability, intensifying edema, and the establishment of a destructive positive feed-back loop.
The next step of this pathophysiological cascade is characterized by excitoxicity. TBI is associated with a massive release of excitatory amino acid neurotransmitters, particularly glutamate [23, 24]. The extracellular glutamate availability affects neurons and astrocytes and results in overstimulation of ionotropic and metabotropic glutamate receptors, increasing Ca2+, Na+, and K+ influxes [25, 26]. Although these events trigger catabolic processes, the cellular attempt to compensate for ionic gradients increases Na+/K+-ATPase activity and therefore metabolic demand, creating a vicious circle of flow-metabolism uncoupling. This condition can destroy vascular and cellular structures and, ultimately, induces necrotic or programmed cell death .
3. Reactive Oxygen Species and Traumatic Brain Injury
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated during normal physiological processes. They are highly reactive molecules which can cause damage to key cellular components such as DNA, lipids, and proteins. Under physiological conditions, the endogenous defense system is able to prevent the formation of or scavenge these harmful molecules, protecting tissues from oxidative damage. In TBI there is a considerable increase in the production of free radicals, supporting the idea that oxidative stress plays a decisive role in the pathology [28, 29].
It is generally believed that 1-2% of the oxygen reduced by mitochondria is converted to superoxide anion () at the level of complex I or at the level of ubiquinone [30–32]. However, certain enzymatic components are loosely associated with the inner mitochondrial membrane and, under conditions of cellular stress, can be released or inactivated, greatly diminishing the reducing capacity of the electron transport chain (ETC). The electrons will subsequently be monoelectronically donated to oxygen (O2), yielding increased production of . Another important source of mitochondrial depends on Ca2+ influx, often secondary to glutamatergic excitotoxicity, which leads to structural alterations of the inner mitochondrial membrane. These alterations may increase ROS formation due to disorganization of the ETC . Under severe Ca2+ loads, however, opening of the mitochondrial permeability transition pore (mPTP) results in the extrusion of mitochondrial Ca2+ and other high- and low-molecular weight components. This catastrophic event discharges and uncouples the ETC, preventing ATP production, which can lead to necrotic or apoptotic cell death .
Other sources of free radicals in TBI, in addition to mitochondrial dysfunction and excitotoxicity mediated by glutamate, include the formation of bradykinin. This cytokine can activate phospholipase A2, releasing arachidonic acid that can serve as a source of free radicals [35, 36]. Arachidonic acid may also facilitate NADPH oxidase activity, thus further increasing ROS production . Apart from increasing arachidonic acid production from membrane phospholipids, bradykinin can induce free radical production by causing a Ca2+ overload . Another source of ROS in TBI may be macrophages/microglia and neutrophils activated as part of an inflammatory process triggered by the initial injury .
The extremely short half-life of ROS in biological systems makes direct measurement virtually impossible in a clinical setup. Therefore, several indirect approaches have been used for the estimation of ROS. These include measurement of (1) products of enzymes known to coproduce ROS, (2) stable adducts formed by the reaction between ROS and endogenous or exogenous trapping agents, and (3) endogenous scavengers . The brain is highly sensitive to oxidative stress because this 1300 g organ consumes about 20–30% of inspired oxygen and contains high levels of both polyunsaturated fatty acids and redox transition metals, making it an ideal target for a free radical attack .
Free radical acting on polyunsaturated fatty acids leads to the formation of highly reactive electrophilic aldehydes, including malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE), which are the most abundant products, and acrolein, the most reactive product [41–43]. Lipid peroxidation products, such as 4-HNE and thiobarbituric acid-reactive substances, are studied in order to identify an oxidative stress condition in experimental models of TBI [44–46]. Reactive aldehydes are a noxious byproduct of lipid peroxidation, which, among other things, increase BBB permeability , contribute to cytoskeletal changes in neurons , and affect glucose transport across membranes [49, 50].
Oxidative stress also damages nucleic acids, both by inducing DNA fragmentation, which consists of single- and double-stranded DNA breaks, the latter being irreversible and occurring a few hours after brain injury [51, 52], and via oxidative damage leading to modification and loss of DNA bases. The predominant base modification used as an index of DNA-oxidative damage is 8-hydroxy-2′-deoxyguanosine (8-OHdG). Single-strand breaks and base oxidation can be repaired , but an inefficient DNA repair may delay neurobehavioral recovery after TBI . Some experimental work has demonstrated that oxidative damage to DNA occurs early in TBI and can be targeted by therapeutic strategies [55, 56]. However, intriguingly, in a study using administration of the ROS scavenger alpha-phenyl-N-tert-butyl-nitrone, the authors found an improvement in memory (water maze task) accompanied by a paradoxical increase in neuronal DNA fragmentation. These data suggest that DNA fragmentation would not be a good marker for TBI . On the other hand, immunohistochemical analysis of DNA damage markers in autopsy samples has suggested the validity of single-strand breaks as markers of TBI. Given these findings, DNA single-stranded breaks may be more helpful when used in conjunction with other biomarkers such as glial fibrillary acidic protein (GFAP) and basic fibroblast growth factor (bFGF) in providing clues on different cell death mechanisms of succeeding TBI . However, there is a need for guidelines to support the use of DNA modifications as a marker of TBI.
4. Antioxidant Defenses
Antioxidants act in a concerted fashion in the normal brain and can be classified into two major groups: enzymes and low-molecular-weight antioxidants. The enzymes include a number of proteins, including SOD, catalase, and peroxidases, as well as some supporting enzymes. The expression of these enzymes and their activity diverge in different brain regions . The protective role of endogenous antioxidant enzymes in ischemic brain injury has been well established in the literature . Trauma not only interferes with the regulation of antioxidant mechanisms but may also convert these mechanisms into prooxidative ones through its ability to disrupt cell compartmentalization .
The low-molecular-weight antioxidants comprise a concerted system of water- and lipid-soluble molecules like glutathione (GSH), ascorbic acid, histidine-related compounds (carnosine, homocarnosine, and anserine), melatonin, uric acid, lipoic acid, and tocopherols . These are extremely important in minimizing oxidative stress. However, cells can synthesize only a limited number of these molecules (e.g., GSH and carnosine). The majority of low-molecular-weight antioxidants are derived from dietary sources. The concentration of ascorbate, which has a relatively high antioxidant potential, is unusually high in the brain, . However, there is a very limited literature about the importance of this antioxidant in TBI. Brain ascorbic acid was shown to be decreased in experimental blast-induced TBI and has been associated with decreases in GSH and protein thiols and an increase in oxidative markers [63–65].
Cells are equipped with enzymes that can eliminate peroxidation end products, such as the aldehyde 4-HNE. These enzymes include aldehyde dehydrogenases, aldo-keto reductases, carbonyl reductase, and glutathione S-transferases (GST) . GST is an enzyme that displays glutathione peroxidase activity and has, by far, the highest detoxifying capability of highly toxic aldehydes such as 4-HNE. Naturally occurring variation in the GST expression affects neurodegeneration after experimental TBI, confirming the importance of lipid peroxidation as an important pathophysiological mechanism in TBI .
5. Biomarkers of TBI
Biochemical biomarkers can be analyzed from serum or whole blood. Disadvantages of this approach include lack of specificity to brain tissue, high variability in the extent of BBB disruption, and low sensitivity to early injury. Alternatively, we can assess CSF markers that may be more specific to central nervous system (CNS) tissue and sensitive to early injury, although CSF collection is more invasive and not routinely available in medical practice. Another option would be the measurement of parenchymal interstitial fluid via microdialysis. High lactate to pyruvate ratio, increased levels of glycerol, and low levels of glucose have been correlated with poor clinical outcome. However, cutoff points for certain parameters are broad and poorly validated. One rational approach that may lead to identification of blood or CSF markers would be to evaluate biochemical processes known to play a central role in CNS injury, including markers of inflammation, glial activation, neuronal dysfunction, and oxidative stress .
TBI biomarkers can reveal structural brain damage but are also markers of secondary injury cascades. TBI promotes genomic, proteomic, and lipidomic changes, as well as oxidative stress, neurotransmitter dysfunction, mitochondrial failure, and other processes . Therefore, TBI biomarkers can also indicate appropriate therapeutic strategies to minimize secondary brain injury and long-term sequelae. Using TBI biomarkers increases the predictive value of outcome calculators and improves the development of individualized treatment courses, thereby reducing outcome severity . The detection of oxidatively modified biomolecules could be used as biomarkers to demonstrate the extension of cellular damage or changes in the cascade of secondary brain damage and repair [39, 65].
Several molecules have been investigated as biomarkers of TBI. CNS-specific molecules include creatine kinase [71, 72], lactate dehydrogenase [71, 72], glial fibrillary acid protein (GFAP) [72–75], myelin basic protein [72, 76], neuron-specific enolase [77–79], S-100β protein [72, 75, 80], brain and heart type fatty acid-binding proteins , tau proteins [82, 83], brain-derived neurotrophic factor (BDNF) [84, 85], and ubiquitin carboxy-terminal hydrolase-L1 [86, 87]. The most commonly used inflammatory serum biochemical markers include heat shock protein 70 kDa (Hsp70) , regulated on activation normal T cell expressed and secreted (RANTES) , tumor necrosis factor alpha (TNF-α), and interleukins .
N-acetylaspartate (NAA), a nervous system-specific metabolite, is synthesized from aspartate and acetyl-coenzyme A in neurons. NAA has been shown to be a marker with diagnostic relevance in monitoring metabolic state after TBI . NAA is the second most concentrated metabolite in the brain after the amino acid glutamate. It is only detected in adult brain neurons and is synthesized in the mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to α-ketoglutarate, which can enter the tricarboxylic acid cycle for energy production . Accumulating evidence in the last decade suggests that NAA is a marker of mitochondrial dysfunction in the brain. A close relationship has been demonstrated between trauma severity, depression of energy metabolism, and NAA [92, 93]. Alterations in NAA levels have also been demonstrated in many cerebral pathologies, and their noninvasive in vivo quantification by 1H-NMR spectroscopy makes them a particularly attractive biomarker [94–96].
The activity of the most studied antioxidant enzymes in TBI, CAT, SOD, and GPx presents random changes in animal models of TBI. In some cases an increase [97, 98] and in others a decrease [99, 100] or no change [101, 102]. The heterogeneity in sampling time points and animal models may be related to this lack of consistency across studies. Whatever the reason, to date there is little consistency in data regarding antioxidant enzymes to justify their use as markers of TBI and as a predictive tool of outcome.
Glutathione, the major nonprotein thiol of cells, usually decreases after TBI in rats [64, 99] but not in mice [64, 99, 103–105], demonstrating species-specific characteristics that should be taken into account when using information obtained from animal studies.
The peroxidation of membrane lipids can change the membrane function by modifying its fluidity, permeability, metabolic processes, and ionic equilibrium . Damage to mitochondrial membranes can also increase the production of ROS, besides generating mitochondrial dysfunction. The damage to brain membrane lipids is an early event. In thirty minutes after trauma, higher levels of MDA and 4-HNE can be detected, whose levels are maintained elevated 72 h after the injury onset [107–109]. Most studies analyzing the oxidative damage to lipids in animal models find a correlation between this parameter in conjunction with cognitive damage, installation of edema, and volume of injury. These data suggest that the damage to lipids of biological membranes can be an important event in this pathology [110, 111].
Oxidative damage to DNA is also an early event in TBI. In animal models, the appearance of 8-OHdG, oxidative marker of DNA damage, is increased within the first 15 minutes after trauma, demonstrating that the TBI-induced ROS production can interfere with the integrity of DNA . On the other hand, the administration of edaravone, an antioxidant, proved to be capable of blocking the DNA damage, resulting in improvement in behavioral tests in mice [112–114].
It has been shown that after a mild TBI, rats showed increased protein carbonylation, another marker of oxidative stress. This event correlated with poor performance in behavioral tests (Morris water maze test), accompanied by decrease in the levels of the neurotrophic factor BDNF. These alterations were neutralized by the administration of antioxidant vitamin E, showing that oxidative damage to proteins may have a key role in neuronal death in TBI . Evidence also points to the involvement of peroxynitrite on the pathophysiology of TBI. A number of studies showed precocious (1 h) increase in protein nitration markers, such as 3-nitrotyrosine [116, 117]. By contrast, protein carbonyl and lipid peroxidation levels were increased in mild TBI in different parts of the brain. However, these oxidative changes were not observed, or even decreased, in severe TBI . These results were somewhat corroborated by Schwarzbold and collaborators, showing that the oxidative damage does not completely correlate with the degree of trauma severity .
Several lines of evidence point to the occurrence of oxidative stress in brain trauma. Bayir and collaborators showed that children, who have suffered severe TBI, presented a clinical evolution that is marked by progressive impairment in antioxidant defenses and increase in lipid peroxidation. These findings correlate with the clinical evolution of these patients. Among the endpoints analyzed authors relate ascorbate depletion in the cerebrospinal fluid, followed by the ascorbyl radical formation, in addition to a decrease in the levels of GSH and antioxidant capacity . Arachidonic acid derivatives used as markers of lipid peroxidation, such as F2-isoprostanes, are found at high levels in cerebrospinal fluid after TBI. In fact, they are positively correlated with neuron-specific enolase, a marker of neuronal damage [119, 120]. However, the clinical applicability of this technique is limited, and not all patients can be analyzed due to the need of sampling of CSF.
The 8-iso-prostaglandin F2α (8-iso-PGF2α) is derived from either enzymatic, by cyclooxygenase, or nonenzymatic oxidation of arachidonic acid . This isoprostane is considered an excellent marker of oxidative stress in vivo. Recent data correlate plasma levels of this marker with the Glasgow coma scale (GCS). This finding is very important because it would be a predictive factor of mortality and outcome with sensitivity similar to GCS [122, 123]. Thus, this marker can be a tool in predicting the prognosis of patients with TBI and used as a marker of lipid peroxidation which can be dosed in peripheral blood sample.
Nitrosative stress, mainly detected by the presence of 3-NT, has been demonstrated in TBI [124, 125]. Darwish and collaborators  detected 3-NT in the CSF of 7 out of 10 TBI patients, but it was not found in control samples. High levels of 3-NT were also associated with a negative neurological outcome measured by the Glasgow outcome scale, but again, a marker obtained from the cerebrospinal fluid has limited applicability.
In spite of solid evidence of increased oxidative stress markers in TBI, the correlation of these changes with the severity of TBI, as measured by the GCS, is still controversial. For example, higher levels of lipid peroxidation, decrease in the levels of GSH, and increased activity of SOD were observed in erythrocyte of patients with severe TBI, compared to patients who are victims of mild TBI [127–129]. Another work of the same group, however, showed increased lipid peroxidation in erythrocytes of patients with TBI, but this was not correlated with GCS . Plasma levels of lipid peroxidation and protein carbonylation were also not predictive factors associated with hospital mortality or as cognitive impairment in TBI patients [131, 132].
Although the literature demonstrates the unequivocal correlation of markers of oxidative stress with trauma, the correlation of levels of 4-HNE and MDA with the outcome of the TBI presents divergent data necessitating further studies to determine if there is, in fact, some association with the prognosis and outcome. This divergence may be related to a higher incidence of ischemia reperfusion in the mild trauma compared to severe trauma . One of the main sources of ROS in TBI occurs during tissue reperfusion after ischemia, which is an event secondary to trauma. In severe trauma, however, there is a large area of primary tissue injury causing extensive cell death. However, in mild trauma more viable cells that can benefit from reperfusion present higher ROS production, which may favor the use of markers of lipid peroxidation as predictive biomarkers of outcome.
Overall, it seems that the oxidative stress occurs simultaneously in various conditions during and after the brain trauma, but its correlation with the severity and outcome is still not very well understood. Despite all the lines of evidence that indicate a central role of ROS in the cascades of secondary damage, the actual implication of them for neuronal death is not yet clear. As a general picture from the literature data, oxidative damage is not directly correlated with the severity of TBI. An area of study that may shed light on the use of oxidative stress biomarkers needs to take into account changes in redox signaling pathways, besides assessing direct oxidative damage to macromolecules, which may regulate determining factors that contribute to the final outcome.
6. Oxidative Stress-Mediated Factors in TBI
Age is another important factor in TBI. Elderly patients with TBI have a worse clinical outcome when compared to younger patients . The influence of oxidative stress on the development of aging has also been demonstrated. For instance, older rats showed higher levels of lipid peroxidation end product (4-HNE), along with lower antioxidant defenses . A worse cognitive outcome, also demonstrated in older rats, was correlated with lower mitochondrial antioxidant enzymes and high levels of 8-OHdG, 4-HNE, single-strand DNA breaks, and malondialdehyde, suggesting the involvement of ROS .
Post-TBI complications such as seizures and cognitive deficits also appear to be mediated by ROS in experimental models [136–138]. There is evidence that suggests that antioxidant therapy may reduce lesions induced by oxidative free radicals in some animal seizure models .
Interestingly, physical conditioning seems to decrease oxidative damage to lipids formed after TBI in rats . Both, the use of amphetamines, as well as physical exercise can reduce oxidative damage after TBI . There is preclinical evidence suggesting that exercise can improve cognitive outcomes in experimental TBI .
7. Antioxidant Strategies for Neuroprotection
The relationship between oxidative stress and TBI has generated considerable interest in the development of antioxidant therapies for neuroprotection. Despite the promising results in the treatment of TBI in animal models, evidence of successful antioxidant therapy in clinical practice is limited . There are a number of drawbacks to the use of exogenous antioxidants, for example, the limited penetrability through the BBB, the rapid metabolism and instability of these compounds, short therapeutic windows, and a very narrow therapeutic dosage range, resulting in toxicity at higher doses [143, 144]. Despite these limitations, natural antioxidants and modified antioxidants are promising candidates for future drugs to treat TBI.
7.1. Free Radicals Scavengers
Modified SOD has been used in different models as a scavenger of , as this radical has increased production after TBI. Lecithinized SOD displays high affinity to cell membranes and was able to increase neuronal counts in an animal model of TBI [145, 146]. Another superoxide scavenger, OPC-14117, reduced edema formation, neurological deficit, and infarct area caused by TBI [147–149].
Polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) has been tested in clinical trials. Initially, some benefits in a phase II study of PEG-SOD were demonstrated, including the reduction of persistent vegetative state and death outcomes when compared to placebo , but these observations were not confirmed in the phase III trial. Failures such as these have been attributed to a narrow therapeutic window . In this way, strategies aimed at directly scavenging ROS are restricted due to the extremely short half-life of free radicals and the small therapeutic window in a TBI event.
Nitrones and derivatives are used in neuroprotection models. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl) is a long-known radical scavenger that displays neuroprotective properties , including maintaining mitochondrial function in brain cells affected by TBI . Other radical scavengers, such as α-phenyl-N-tert-butyl nitrone (PBN), or its sulfated form, are able to improve cerebral blood flow and glucose metabolism, which are accompanied by improvement in neurologic scores [154–157]. However, the therapeutic window is relatively short due to initial burst of ROS in the first moments after the trauma. Therefore, strategies to increase the therapeutic windows are necessary to allow the efficient use of these radical scavengers .
The antioxidant α-tocopherol is hydrophobic and is able to prevent membrane lipids from undergoing peroxidation. The use of α-tocopherol contributed to a lower lipid peroxidation , edema [160, 161], and improvement in histological markers in experimental models of TBI .
Melatonin displays radical scavenger properties toward •OH, , singlet oxygen, and peroxynitrite . Administration of melatonin shortly after TBI decreases brain edema, neuronal death, and memory deficits [164, 165]. These changes are correlated with improvements in markers of oxidative damage (lipid peroxidation) and in the levels of low molecular weight antioxidants, such as vitamin C [166–169]. However, improvement is not always observed with the use of melatonin .
7.2. Carbonyl Scavengers
Besides the lipid peroxidation end products aldehydes, like MDA and 4-HNE, cells also produce continually a series of α-dicarbonyl species. For instance, methylglyoxal is continuously produced during glycolysis but can also be produced nonenzymatically from carbohydrates and glycation of proteins, besides other endogenous sources . The production of methylglyoxal, the main dicarbonyl byproduct of glycolysis, is responsible for significant portion of protein glycation and, consequently, the induction of cellular toxicity . Methylglyoxal modifies proteins to form advanced glycation end product (AGE) residues. These modified proteins can activate receptors of AGE (RAGE) leading to the upregulation and the expression of proinflammatory mediators [172, 173]. This proinflammatory cascade involving RAGE has been recently shown to be relevant to TBI. RAGE is upregulated in human brain as short as 30 min after TBI and maintained elevated up to 6 days, presenting maximal values at 24 h after TBI . Importantly, the inflammatory cytokine high-mobility group box 1 (HMGB1), a RAGE ligand, was increased in CSF and could be associated with poor outcome after TBI in infants and children . Since HMGB1 is released in the CSF, an anti-HMGB1 antibody strategy has proven to be effective in inhibiting fluid percussion-induced brain damage in mice .
This successful strategy brings attention to the potential importance of AGE on TBI. To prevent AGE production and consequent RAGE activation, α-dicarbonyls, like methylglyoxal, need to be eliminated or sequestered in order to avoid a negative impact in TBI outcome. Carbonyl scavengers have been used with the aim of reducing the “aldehyde load”  and have been investigated in vivo and in vitro regarding their effects on neuroprotection, but there is limited literature with regard to TBI [178, 179]. The carbonyl scavenger D-penicillamine binds primarily to aldehydes in an irreversible manner which inhibits their damaging effects and has also been shown to scavenge peroxynitrite as well . Acute penicillamine administration has previously been shown to improve neurological recovery in the mouse concussive head injury model  and to protect brain mitochondria . Carnosine is also a dicarbonyl scavenger with neuroprotective properties in TBI . Hydralazine, an acrolein scavenger, decreased cell membrane leakage and permeability in spinal cord injury . Aminoguanidine, another carbonyl scavenger and an inhibitor of inducible nitric oxide synthase (iNOS), was able to reduce carbonyl stress in diabetes, preserving neurological scores [184, 185], preventing the decrease in cortical necrotic neuron counts , and reducing infarct volume  in animal models of TBI. Aminoguanidine treatment is also able to reduce infarct size and preserve BBB in a middle cerebral artery occlusion model of ischemia  and reduce damage area in traumatic spinal cord injury , effects that are relevant to TBI.
7.3. Glutathione-Promoting Drugs
Strategies that aim at increasing the GSH levels have also been tested in animal models. GSH-promoting agents, like N-acetylcysteine (NAC) and γ-glutamylcysteine ethyl ester, are effective neuroprotectants in preclinical studies. Administration of γ-glutamylcysteine ethyl ester after TBI in mice preserves GSH, decreases autophagy, and improves both behavioral and histological outcomes . γ-glutamylcysteine ethyl ester decreased levels of protein carbonyls and 3-nitrotyrosine after sever TBI  as well as, preserved glutathione status, endotelial function, and BBB .
Studies with NAC showed efficacy of this drug in decreasing the TBI-mediated oxidative stress and limiting the volume of injury in rats . NAC also restored respiratory function and calcium transport when administrated 1 h after trauma . In contrast, this protective effect was not present when NAC was administrated 2 h after the lesion, indicating that it must act in the early stages of the lesion. NAC was able to restore brain GSH levels from 1 h to 14 days after TBI, suggesting that this protective effect may be related to the maintenance of the GSH levels. Other studies also showed anti-inflammatory properties of NAC. NAC administration decreased several inflammatory cytokines and the activation of NF-κB, which reduced brain edema, BBB permeability, and apoptotic index in the injured brain .
NAC was also tested in a randomized double blind, placebo-controlled study with soldiers who were exposed to ordnance blast and met the criteria for mild TBI. Patients received placebo or NAC for seven days, and the treatment showed improvement in symptoms such as dizziness, memory loss, and sleep disturbances . Given the fact that NAC is already approved by the FDA, this is a good candidate for future clinical trials.
Corticosteroids have been shown to inhibit the phospholipase A2, cyclooxygenase, and lipoxygenase pathways, limiting the release of arachidonic acid and its metabolites, downregulating proinflammatory cytokines, and dampening the inflammatory response . Methylprednisolone is able to attenuate cellular damage by a direct antioxidant effect, thereby inhibiting lipid peroxidation and protecting cellular membranes . Preclinical data showed that this steroid affects the outcome. Methylprednisolone was able to improve brain edema in rats, and this was dependent on dosing, time of administration, and method of treatment .
The indiscriminate use of corticosteroids was long performed without an evaluation of their devastating effects, as evidenced by clinical trials. However, The Brain Trauma Foundation guidelines published in 2000 state that “the use of corticosteroids is not recommended for improving outcome or reducing intracranial pressure in patients with severe brain injury” and “the major of available evidence indicates that steroids do nor improve outcome or lower ICP in severely head injured patients and the routine use of steroids for these purposes is not recommended” . In 2004 the corticosteroid randomization after significant head injury (CRASH) study demonstrated greater mortality in patients receiving high doses of methylprednisolone compared to placebo . A Cochrane meta-analysis correlated the use of corticosteroids with increased risk of gastrointestinal bleeding, hyperglycemia, and also higher mortality rates .
Preclinical studies, however, suggested a possible antioxidant and neuroprotective effect of physiological doses of sex hormones following TBI [200, 201]. Progesterone has been shown to decrease cerebral edema in a pluripotent manner, reducing lipid peroxidation, aquaporin expression, proinflammatory cytokine release, and complement activation . Unfortunately, studies in humans have not demonstrated a significant association between gender and prognosis [203, 204]. Nevertheless, clinical trials have demonstrated better outcomes in patients treated with progesterone [205, 206]. In a phase II study, progesterone showed significant reduction in mortality and improvement in the Glasgow outcome scale at 3 and 6 months after TBI; however, results from a phase III multicentre, randomized clinical trial are pending . A Cochrane systematic review concluded that “Progesterone may improve neurologic outcome of patients suffering TBI.” “evidence is insufficient and there is a need for further studies to support the use of progesterone in the management of TBI. Further large and multicentre clinical trials on progesterone are required to assess the effect of progesterone in people with acute TBI” .
Another strategy to prevent ROS-mediated damage is to block the propagation of lipid peroxidation. Lazaroids (21-aminosteroids) are a class of compounds with the membrane-stabilizing properties, similar to the effect of glucocorticoids. Tirilazad inhibits lipid peroxidation through its membrane-stabilizing properties, which prevent the propagation of the reaction between one oxidized fatty acid to the next, and through free radical scavenging.
In an animal model of TBI, administration of the lazaroid tirilazad improved neurological score and survival rate when administrated shortly after the trauma (5–60 min) . In a weight drop TBI model in rats, tirilazad also diminished neuron loss at 24 h and increased neuronal survival 14 days after the injury . Furthermore, administration of tirilazad reduced extracellular after TBI, which may contribute to its neuroprotective effect . The protective effect of tirilazad has also been demonstrated in animal models of ischemia and subarachnoid haemorrhage, both events linked with the secondary injury pathways in TBI .
Tirilazad attenuated cerebral edema after TBI  and protected against arachidonic acid-induced vasogenic brain edema in rats by inhibiting lipid peroxidation . Since tirilazad does not penetrate the BBB effectively, it is found mainly in the membranes of endothelial cells, where it could exert its action. However, it is possible that tirilazad can reach neuronal cells during the phase of increased permeability of the BBB in TBI, which can allow tirilazad to penetrate brain areas where it can act as a neuroprotectant .
In the 90s, tirilazad entered a phase III multicenter trial. The study comprised 1120 head-injured patients with moderate or severe TBI. Patients received tirilazad or placebo within 4 h after injury at a dose of 2.5 mg/kg every 6 h for 5 days. The trial failed to show a beneficial effect of the treatment in either moderate or severe injured groups. However, post hoc analysis showed that male patients that also had subarachnoid hemorrhage had significantly less mortality . Meta-analysis studies questioned the efficacy of tirilazad in subarachnoid hemorrhage [216, 217]. In other clinical studies, tirilazad significantly contributed to recovery after spinal cord injury , but recent studies are not available. The poor penetration through the BBB might be responsible for the negative result, as well as the nature of the head injury.
7.5. Calcium Blockers and Immunosuppressants
Calcium blockers and immunosuppressants that could limit the production of ROS/RNS by membrane stabilization or reduction of inflammation have also been investigated. Calcium-channel antagonists, such as nimodipine, would block the effects of the influx of calcium into the cell after TBI. Unfortunately, in an extensive Cochrane meta-analysis, nimodipine only reduced the risk of death in a subgroup of patients with subarachnoid hemorrhage . Cyclosporine A, a known immunosuppressant, is thought to mediate neuroprotection by decreasing the mitochondrial permeability and therefore the influx of Ca2+, organelle swelling, and cell death . Cyclosporine A also showed promising results in a phase II study; however, validation by a multicentre, randomized phase III clinical trial is pending .
7.6. Other Drugs
Interference of other pathways which result in the production of ROS/RNS has thus far failed to produce good clinical outcomes. Bradykinin antagonists such as Deltibant , modulators of excitotoxicity, and glutamate such as dexanabinol [221, 222], magnesium sulfate , and selfotel  have all been proven to be ineffective in clinical trials .
7.7. Nrf2/ARE: A Putative Therapeutic and Biomarker Route
Activation of the antioxidant response element (ARE) has been implicated in neuroprotection, as this induces expression of genes involved in decreasing oxidative stress, inflammatory damage, and accumulation of toxic metabolites . Several transcriptional factors can bind to ARE, including the nuclear factor-erythroid 2-related (Nrf2) protein that activates transcription in response to oxidative stress or electrophilic attack . Nrf2 is a basic leucine zipper redox-sensitive transcription factor reported to be a pleiotropic regulator of cell survival mechanisms . Recent studies have demonstrated that Nrf2 plays an indispensable role in the upregulation of Nrf2-dependent antioxidant enzymes and the reduction of oxidative damage after TBI . Under basal conditions, Nrf2 is sequestered in the cytoplasm by the cytosolic regulatory protein Keap1. In conditions of oxidative or xenobiotic stress, Nrf2 translocates to the nucleus where it binds to ARE, neutralizing the BACH1 competitive inhibition, activating this promoter, and resulting in transcription of a number of antioxidant proteins [229, 230].
Several antioxidants from the diet which have been studied for their neuroprotective properties are proposed to function via the activation of Nrf2/ARE. Caffeic acid phenethyl ester is an active component of bee propolis extracts which displays anti-inflammatory, immunomodulatory, antiproliferative, and antioxidant properties. Caffeic acid phenethyl ester treatment decreased MDA levels and increased GPx and SOD activity in a rat experimental model of TBI . Green tea is rich in polyphenols that have important antioxidant activity. Epigallocatechin gallate treatment in rat models of TBI decreased the free radical burden (e.g., and •OH) induced by brain injury. This antioxidant effect decreased tissue damage induced by free radicals, including a decrease of neuronal cell degeneration, apoptotic cell death around the damaged area, and improved brain function (water maze) [232–234]. Ginseng, from the root of Panax ginseng, is a well-known traditional herbal medicine that has been used widely for thousands of years. The ginseng saponins are generally considered as the principal bioactive ingredients. Preclinical studies suggested that the neuroprotective effects of ginseng saponins are potentially associated with protection against oxidative stress damage [235–238]. The flavonoid quercetin improved neuronal electrical activity and decreased proinflammatory effects in a model of TBI . Resveratrol is a polyphenolic compound enriched in grapes and red wine. Resveratrol has been shown to be a promising neuroprotective agent in TBI models, possibly inhibiting lipid peroxidation [240–242]. The use of resveratrol in an experimental model of TBI was able to counteract oxidative damage and prevent the depletion of the antioxidant glutathione and also resulted in a reduction of infarct area . Polyphenolic derivatives of curcumin have also been shown to protect the brain against the effects of experimental TBI by decreasing oxidative stress [44, 45, 243, 244]; however, the observed effects may be attributable not only to the antioxidant properties of flavonoids but also to a response occurring secondary to Nrf2/ARE activation. Sulforaphane, similar to other flavonoids, is an Nrf2/ARE signaling activator and is present in cruciferous vegetables such as broccoli. Nrf2/ARE activation by sulforaphane treatment after experimental TBI was confirmed by induction of target genes such as glutathione S-transferase α3 and heme oxigenase-1 and associated with an improvement in BBB integrity . The administration of sulforaphane is also neuroprotective in various animal models of TBI, specifically reducing cerebral edema and oxidative stress and thus decreasing cognitive deficits [246, 247]. In the spinal cord model, sulforaphane was able to produce both rapid (30 min) and long-lasting (3 days) responses, also corroborated by the induction of Nrf2/ARE target proteins, including the rate-limiting enzyme for glutathione synthesis (GCL), heme oxygenase 1, and NADPH quinonereductase-1, which cooperate to decrease levels of the proinflammatory markers TNF-α and IL-1β .
There is some evidence to support the idea that Nrf2 activation is able to protect against dicarbonyl stress by induction of glyoxalase 1 , the enzyme catalyzing the reaction of methylglyoxal with glutathione. It has been suggested that methylglyoxal and glyoxalase 1 can also modulate seizure intensity as metabolic sensors , which may have implications in TBI, since hyperglycolysis (high flux through anaerobic glycolysis) after TBI is associated with a negative outcome [251–253]. Hyperglycolysis may lead to increased production of methylglyoxal [254, 255]. Nrf2 activation would alleviate dicarbonyl stress by inducing glyoxalase 1 and glutathione synthesis . In fact, resveratrol was effective in protecting hepatic (Hep G2) cells against methylglyoxal toxicity due induction of Nrf2, which leads to increased expression of glyoxalase I and antioxidant defenses . The flavones Fisetin was highly protective against carbonyl stress in the Akita mice, a model of diabetes type 1, by inducing Nrf2-dependent enzymes such as glyoxalase and glutamate-cysteine ligase, the rate limiting enzyme in glutathione synthesis . Fisetin was also neuroprotective in an ischemia model . Quercetin displays a strong antiglycation action when albumin was incubated with methylglyoxal. Curcumin, despite being a potent Nrf2 inducer and effective as a neuroprotectant in TBI, is a strong inhibitor (IC(50) ~10 μM) of glyoxalase I , which would jeopardize its possible antiglycation properties. Nevertheless, curcumin is as potent dicarbonyl scavenger . Caffeic acid was effective in protecting proteins against AGE formation in vitro  and epigallocatechin-3-gallate has been proposed as a dicarbonyl scavenger , as well as other phenolic antioxidants . In this regard, flavonoids are added to the list of carbonyl scavengers, acting directly as scavenger or indirectly through activation Nrf2-dependent antiglycation enzymes such as glyoxalase I.
The use of antioxidants which sequester ROS and other harmful molecules is a promising strategy to increase neuroprotection in TBI [211, 240]; however, part of the antioxidant effect of such exogenous substances like flavonoids may be due to the induction of endogenous antioxidants. Nrf2 activators may be prime candidates for the attenuation of oxidative stress and subsequent neurotoxicity induced by TBI.
8. Concluding Remarks
Improving TBI outcomes will greatly reduce the heavy societal and economic burden currently associated with this condition. Oxidative stress appears to be a primary driver of TBI pathophysiology, and while several stress-related markers and new therapeutic drugs with distinct antioxidative stress mechanisms have been proposed for the diagnosis and treatment of TBI, clinical consolidation based on proven efficacy is still necessary. Research prospects for new biomarkers of TBI should focus on demonstration of functionality in converging pathways that can impact multiple pathophysiological cascades.
As part of a consistent and clinically applicable intervention, we believe it would be crucial to not only limit the development of secondary damage following TBI but also to activate major neuroprotective pathways. The identification of relevant biochemical markers along with successful therapeutic targeting in experimental models of TBI has demonstrated the importance of several regulatory pathways in neuroprotection, in particular Nrf2/ARE. This pathway is activated by oxidative stress and nitric oxide production, which are also both points of convergence in TBI-related pathophysiological cascades.
Regarding the inhibition of secondary damage, the toxic effect of aldehydes can be mitigated by aldehyde scavengers, but also by upregulation of endogenous detoxification and antioxidant defenses, which can limit damage to DNA, lipids, and proteins. However, other pathophysiological routes, like inflammation, also need to be targeted to reduce damage.
Our opinion is that the ideal, clinically feasible TBI therapy would involve the targeting of a pathway which converges on multiple pathophysiologic processes in TBI, such as Nrf2/ARE, and which can also be modulated by external factors like dietary substances. Such a pleiotropic drug would have the potential to usher in a new era of effective neuroprotection for traumatic brain injury.
Conflict of Interests
The authors have no actual or potential conflict of interests, including any financial, personal, or other relationships with relevant people or organizations. The work described has not been published previously, and it is not under consideration for publication elsewhere. The publication of this work is approved by the authors and, tacitly or explicitly, by the responsible authorities where the work was performed.
This work was supported by National Council for Research Development (CNPq) and Foundation for the Support of Scientific and Technological Research in the State of Santa Catarina (FAPESC). Alcir Luiz Dafre and Roger Walz are research fellows of CNPq. The authors also wish to thank Karen Chiang who kindly revised the paper. This work was supported by Programa de Apoio a Núcleos de Excelência PRONEX-FAPESC/CNPq (NENASC Project) and Programa de Pesquisa para o SUS PPSUS-FAPESC/MS-CNPq/SES-SC.
- 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.
- C. J. L. Murray and A. D. Lopez, “Global mortality, disability, and the contribution of risk factors: global burden of disease study,” The Lancet, vol. 349, no. 9063, pp. 1436–1442, 1997.
- 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. 255–267, 2006.
- E. W. Steyerberg, N. Mushkudiani, P. Perel et al., “Predicting outcome after traumatic brain injury: development and international validation of prognostic scores based on admission characteristics,” PLoS Medicine, vol. 5, no. 8, pp. 1251–1261, 2008.
- B. Roozenbeek, H. F. Lingsma, F. E. Lecky et al., “Prediction of outcome after moderate and severe traumatic brain injury: external validation of the international mission on prognosis and analysis of clinical trials (IMPACT) and corticoid randomisation after significant head injury (CRASH) prognostic models,” Critical Care Medicine, vol. 40, no. 5, pp. 1609–1617, 2012.
- E. Czeiter, S. Mondello, N. Kovacs et al., “Brain injury biomarkers may improve the predictive power of the IMPACT outcome calculator,” Journal of Neurotrauma, vol. 29, pp. 1770–1778, 2012.
- 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.
- P. Fernandez and D. Diaz, “Experimental animal models of traumatic brain injury: medical and biomechanical mechanism,” Critical Reviews in Neurosurgery, vol. 9, pp. 44–52, 1999.
- L. Wang, X. S. Ji, X. Y. Hong, Y. M. Chi, and R. Z. Qing, “The influence of subarachnoid hemorrhage on neurons: an animal model,” Annals of Clinical and Laboratory Science, vol. 35, no. 1, pp. 79–85, 2005.
- S. H. North, L. C. Shriver-Lake, C. R. Taitt, and F. S. Ligler, “Rapid analytical methods for on-site triage for traumatic brain injury,” Annual Review of Analytical Chemistry, vol. 5, pp. 35–56, 2012.
- G. S. F. Ling and C. J. Neal, “Maintaining cerebral perfusion pressure is a worthy clinical goal,” Neurocritical Care, vol. 2, no. 1, pp. 75–81, 2005.
- P.-O. Grände, P. Reinstrup, and B. Romner, “Active cooling in traumatic brain-injured patients: a questionable therapy?” Acta Anaesthesiologica Scandinavica, vol. 53, no. 10, pp. 1233–1238, 2009.
- H. Bayir, P. M. Kochanek, and R. S. B. Clark, “Traumatic brain injury in infants and children mechanisms of secondary damage and treatment in the intensive care unit,” Critical Care Clinics, vol. 19, no. 3, pp. 529–549, 2003.
- C. Werner and K. Engelhard, “Pathophysiology of traumatic brain injury,” British Journal of Anaesthesia, vol. 99, no. 1, pp. 4–9, 2007.
- D. S. Dewitt and D. S. Prough, “Traumatic cerebral vascular injury: the effects of concussive brain injury on the cerebral vasculature,” Journal of Neurotrauma, vol. 20, no. 9, pp. 795–825, 2003.
- A. W. Unterberg, J. Stover, B. Kress, and K. L. Kiening, “Edema and brain trauma,” Neuroscience, vol. 129, no. 4, pp. 1021–1029, 2004.
- B. J. Blyth, A. Farhavar, C. Gee et al., “Validation of serum markers for blood-brain barrier disruption in traumatic brain injury,” Journal of Neurotrauma, vol. 26, no. 9, pp. 1497–1507, 2009.
- A. Raabe, C. Grolms, M. Keller, J. Döhnert, O. Sorge, and V. Seifert, “Correlation of computed tomography findings and serum brain damage markers following severe head injury,” Acta Neurochirurgica, vol. 140, no. 8, pp. 787–792, 1998.
- A. Raabe, C. Grolms, and V. Seifert, “Serum markers of brain damage and outcome prediction in patients after severe head injury,” British Journal of Neurosurgery, vol. 13, no. 1, pp. 56–59, 1999.
- H. Reiber and J. B. Peter, “Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs,” Journal of the Neurological Sciences, vol. 184, no. 2, pp. 101–122, 2001.
- P. F. Stahel, M. C. Morganti-Kossmann, D. Perez et al., “Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood-brain barrier dysfunction in patients with traumatic brain injury,” Journal of Neurotrauma, vol. 18, no. 8, pp. 773–781, 2001.
- M. F. Stiefel, Y. Tomita, and A. Marmarou, “Secondary ischemia impairing the restoration of ion homeostasis following traumatic brain injury,” Journal of Neurosurgery, vol. 103, no. 4, pp. 707–714, 2005.
- R. Bullock, A. Zauner, J. J. Woodward et al., “Factors affecting excitatory amino acid release following severe human head injury,” Journal of Neurosurgery, vol. 89, no. 4, pp. 507–518, 1998.
- C. L. Robertson, M. J. Bell, P. M. Kochanek et al., “Increased adenosine in cerebrospinal fluid after severe traumatic brain injury in infants and children: association with severity of injury and excitotoxicity,” Critical Care Medicine, vol. 29, no. 12, pp. 2287–2293, 2001.
- C. L. Floyd, F. A. Gorin, and B. G. Lyeth, “Mechanical strain injury increases intracellular sodium and reverses Na+/Ca2+ exchange in cortical astrocytes,” GLIA, vol. 51, no. 1, pp. 35–46, 2005.
- J.-H. Yi and A. S. Hazell, “Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury,” Neurochemistry International, vol. 48, no. 5, pp. 394–403, 2006.
- C. Cornelius, R. Crupi, V. Calabrese et al., “Traumatic brain injury (TBI): oxidative stress and neuroprotection,” Antioxidants & Redox Signaling, vol. 19, pp. 836–853, 2013.
- 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.
- K. A. Hanafy and M. H. Selim, “Antioxidant strategies in neurocritical care,” Neurotherapeutics, vol. 9, no. 1, pp. 44–55, 2012.
- A. J. Kowaltowski and A. E. Vercesi, “Mitochondrial damage induced by conditions of oxidative stress,” Free Radical Biology and Medicine, vol. 26, no. 3-4, pp. 463–471, 1999.
- S. Dröse and U. Brandt, “Molecular mechanisms of superoxide production by the mitochondrial respiratory chain,” Advances in Experimental Medicine and Biology, vol. 748, pp. 145–169, 2012.
- A. Boveris, “Mitochondrial production of superoxide radical and hydrogen peroxide,” Advances in Experimental Medicine and Biology, vol. 78, pp. 67–82, 1977.
- A. J. Kowaltowski, R. F. Castilho, and A. E. Vercesi, “Ca2+-induced mitochondrial membrane permeabilization: role of coenzyme Q redox state,” American Journal of Physiology: Cell Physiology, vol. 269, no. 1, pp. C141–C147, 1995.
- P. G. Sullivan, A. G. Rabchevsky, P. C. Waldmeier, and J. E. Springer, “Mitochondrial permeability transition in CNS trauma: cause or effect of neuronal cell death?” Journal of Neuroscience Research, vol. 79, no. 1-2, pp. 231–239, 2005.
- S. M. Moochhala, J. Lu, M. C. K. Xing et al., “Mercaptoethylguanidine inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expressions induced in rats after fluid-percussion brain injury,” Journal of Trauma, vol. 59, no. 2, pp. 450–457, 2005.
- N. J. Abbott, “Inflammatory mediators and modulation of blood-brain barrier permeability,” Cellular and Molecular Neurobiology, vol. 20, no. 2, pp. 131–147, 2000.
- T. Rubinek and R. Levy, “Arachidonic acid increases the activity of the assembled NADPH oxidase in cytoplasmic membranes and endosomes,” Biochimica et Biophysica Acta, vol. 1176, no. 1-2, pp. 51–58, 1993.
- A. S. Easton and N. J. Abbott, “Bradykinin increases permeability by calcium and 5-lipoxygenase in the ECV304/C6 cell culture model of the blood-brain barrier,” Brain Research, vol. 953, no. 1-2, pp. 157–169, 2002.
- L. Hillered, P. M. Vespa, and D. A. Hovda, “Translational neurochemical research in acute human brain injury: the current status and potential future for cerebral microdialysis,” Journal of Neurotrauma, vol. 22, no. 1, pp. 3–41, 2005.
- R. Sultana, M. Perluigi, and D. A. Butterfield, “Lipid peroxidation triggers neurodegeneration: a redox proteomics view into the Alzheimer disease brain,” Free Radical Biology & Medicine, vol. 62, pp. 157–169, 2013.
- A. Loidl-Stahlhofen, K. Hannemann, and G. Spiteller, “Generation of α-hydroxyaldehydic compounds in the course of lipid peroxidation,” Biochimica et Biophysica Acta, vol. 1213, no. 2, pp. 140–148, 1994.
- W. A. Pryor and N. A. Porter, “Suggested mechanisms for the production of 4-hydroxy-2-nonenal from the autoxidation of polyunsaturated fatty acids,” Free Radical Biology and Medicine, vol. 8, no. 6, pp. 541–543, 1990.
- H. Esterbauer, R. J. Schaur, and H. Zollner, “Chemistry and Biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes,” Free Radical Biology and Medicine, vol. 11, no. 1, pp. 81–128, 1991.
- S. Sharma, Z. Ying, and F. Gomez-Pinilla, “A pyrazole curcumin derivative restores membrane homeostasis disrupted after brain trauma,” Experimental Neurology, vol. 226, no. 1, pp. 191–199, 2010.
- A. Wu, Z. Ying, and F. Gomez-Pinilla, “Dietary curcumin counteracts the outcome of traumatic brain injury on oxidative stress, synaptic plasticity, and cognition,” Experimental Neurology, vol. 197, no. 2, pp. 309–317, 2006.
- F. Petronilho, G. Feier, B. de Souza et al., “Oxidative stress in brain according to traumatic brain injury intensity,” Journal of Surgical Research, vol. 164, no. 2, pp. 316–320, 2010.
- K. Mertsch, I. Blasig, and T. Grune, “4-hydroxynonenal impairs the permeability of an in vitro rat blood-brain barrier,” Neuroscience Letters, vol. 314, no. 3, pp. 135–138, 2001.
- A. A. Farooqui, W.-Y. Ong, and L. A. Horrocks, “Biochemical aspects of neurodegeneration in human brain: involvement of neural membrane phospholipids and phospholipases A2,” Neurochemical Research, vol. 29, no. 11, pp. 1961–1977, 2004.
- 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.
- J. N. Keller, Z. Pang, J. W. Geddes et al., “Impairment of glucose and glutamate transport and induction of mitochondrial oxidative stress and dysfunction in synaptosomes by amyloid β- peptide: role of the lipid peroxidation product 4-hydroxynonenal,” Journal of Neurochemistry, vol. 69, no. 1, pp. 273–284, 1997.
- Y. Gavrieli, Y. Sherman, and S. A. Ben-Sasson, “Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation,” Journal of Cell Biology, vol. 119, no. 3, pp. 493–501, 1992.
- J. Chen, K. Jin, M. Chen et al., “Early detection of DNA strand breaks in the brain after transient focal ischemia: implications for the role of DNA damage in apoptosis and neuronal cell death,” Journal of Neurochemistry, vol. 69, no. 1, pp. 232–245, 1997.
- P. K. Liu, C. Y. Hsu, M. Dizdaroglu et al., “Damage, repair, and mutagenesis in nuclear genes after mouse forebrain ischemia-reperfusion,” The Journal of Neuroscience, vol. 16, no. 21, pp. 6795–6806, 1996.
- G. Tomasevic, H. L. Laurer, G. Mattiasson, H. Steeg, T. Wieloch, and T. K. McIntosh, “Delayed neuromotor recovery and increased memory acquisition dysfunction following experimental brain trauma in mice lacking the DNA repair gene XPA,” Journal of Neurosurgery, vol. 116, pp. 1368–1378, 2012.
- D. R. Mendez, L. Cherian, N. Moore, T. Arora, P. K. Liu, and C. S. Robertson, “Oxidative DNA lesions in a rodent model of traumatic brain injury,” Journal of Trauma, vol. 56, no. 6, pp. 1235–1240, 2004.
- J. A. Smith, S. Park, J. S. Krause, and N. L. Banik, “Oxidative stress, DNA damage, and the telomeric complex as therapeutic targets in acute neurodegeneration,” Neurochemistry International, vol. 62, pp. 764–775, 2013.
- A. Lewén, Y. Skoglösa, F. Clausen et al., “Paradoxical increase in neuronal DNA fragmentation after neuroprotective free radical scavenger treatment in experimental traumatic brain injury,” Journal of Cerebral Blood Flow and Metabolism, vol. 21, no. 4, pp. 344–350, 2001.
- Q. Wang, T. Ishikawa, T. Michiue, B.-L. Zhu, D.-W. Guan, and H. Maeda, “Evaluation of human brain damage in fatalities due to extreme environmental temperature by quantification of basic fibroblast growth factor (bFGF), glial fibrillary acidic protein (GFAP), S100β and single-stranded DNA (ssDNA) immunoreactivities,” Forensic Science International, vol. 221, pp. 142–151, 2012.
- B. D. Watson, “Evaluation of the concomitance of lipid peroxidation in experimental models of cerebral ischemia and stroke,” Progress in Brain Research, vol. 96, pp. 69–95, 1993.
- P. H. Chan, “Role of oxidants in ischemic brain damage,” Stroke, vol. 27, no. 6, pp. 1124–1129, 1996.
- H. Bayir, P. M. Kochanek, and V. E. Kagan, “Oxidative stress in immature brain after traumatic brain injury,” Developmental Neuroscience, vol. 28, no. 4-5, pp. 420–431, 2006.
- B. Halliwell, “Reactive oxygen species and the central nervous system,” Journal of Neurochemistry, vol. 59, no. 5, pp. 1609–1623, 1992.
- H. Bayir, V. E. Kagan, G. G. Borisenko et al., “Enhanced oxidative stress in iNOS-deficient mice after traumatic brain injury: support for a neuroprotective role of iNOS,” Journal of Cerebral Blood Flow and Metabolism, vol. 25, no. 6, pp. 673–684, 2005.
- P. M. Kochanek, C. E. Dixon, D. K. Shellington et al., “Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats,” Journal of Neurotrauma, vol. 30, pp. 920–937, 2013.
- B. Tavazzi, S. Signoretti, G. Lazzarino et al., “Cerebral oxidative stress and depression of energy metabolism correlate with severity of diffuse brain injury in rats,” Neurosurgery, vol. 56, no. 3, pp. 582–588, 2005.
- E. M. Ellis, “Reactive carbonyls and oxidative stress: potential for therapeutic intervention,” Pharmacology and Therapeutics, vol. 115, no. 1, pp. 13–24, 2007.
- F. Al Nimer, M. Ström, R. Lindblom et al., “Naturally occurring variation in the glutathione-s-transferase 4 gene determines neurodegeneration after traumatic brain injury,” Antioxidants & Redox Signaling, vol. 18, pp. 784–794, 2013.
- R. Sharma and D. T. Laskowitz, “Biomarkers in traumatic brain injury,” Current Neurology and Neuroscience Reports, vol. 12, pp. 560–569, 2012.
- P. M. Kochanek, R. P. Berger, H. Bayir, A. K. Wagner, L. W. Jenkins, and R. S. B. Clark, “Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making,” Current Opinion in Critical Care, vol. 14, no. 2, pp. 135–141, 2008.
- S. J. I. Sandler, A. A. Figaji, and P. D. Adelson, “Clinical applications of biomarkers in pediatric traumatic brain injury,” Child's Nervous System, vol. 26, no. 2, pp. 205–213, 2010.
- R. A. E. Bakay and A. A. Ward Jr., “Enzymatic changes in serum and cerebrospinal fluid in neurological injury,” Journal of Neurosurgery, vol. 58, no. 1, pp. 27–37, 1983.
- Z. Metting, N. Wilczak, L. A. Rodiger, J. M. Schaaf, and J. van der Naalt, “GFAP and S100B in the acute phase of mild traumatic brain injury,” Neurology, vol. 78, pp. 1428–1433, 2012.
- K. Nylén, M. Öst, L. Z. Csajbok et al., “Increased serum-GFAP in patients with severe traumatic brain injury is related to outcome,” Journal of the Neurological Sciences, vol. 240, no. 1-2, pp. 85–91, 2006.
- L. E. Pelinka, A. Kroepfl, R. Schmidhammer et al., “Glial fibrillary acidic protein in serum after traumatic brain injury and multiple trauma,” Journal of Trauma, vol. 57, no. 5, pp. 1006–1012, 2004.
- P. E. Vos, B. Jacobs, T. M. J. C. Andriessen et al., “GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study,” Neurology, vol. 75, no. 20, pp. 1786–1793, 2010.
- Y. Yamazaki, K. Yada, S. Morii, T. Kitahara, and T. Ohwada, “Diagnostic significance of serum neuron-specific enolase and myelin basic protein assay in patients with acute head injury,” Surgical Neurology, vol. 43, no. 3, pp. 267–271, 1995.
- E. Meric, A. Gunduz, S. Turedi, E. Cakir, and M. Yandi, “The prognostic value of neuron-specific enolase in head trauma patients,” Journal of Emergency Medicine, vol. 38, no. 3, pp. 297–301, 2010.
- T. Fridriksson, N. Kini, C. Walsh-Kelly, and H. Hennes, “Serum neuron-specific enolase as a predictor of intracranial lesions in children with head trauma: a pilot study,” Academic Emergency Medicine, vol. 7, no. 7, pp. 816–820, 2000.
- S. Bandyopadhyay, H. Hennes, M. H. Gorelick, R. G. Wells, and C. M. Walsh-Kelly, “Serum neuron-specific enolase as a predictor of short-term outcome in children with closed traumatic brain injury,” Academic Emergency Medicine, vol. 12, no. 8, pp. 732–738, 2005.
- M. Olivecrona, M. Rodling-Wahlström, S. Naredi, and L.-O. D. Koskinen, “S-100B and neuron specific enolase are poor outcome predictors in severe traumatic brain injury treated by an intracranial pressure targeted therapy,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 80, no. 11, pp. 1241–1247, 2009.
- M. M. A. L. Pelsers, T. Hanhoff, D. van der Voort et al., “Brain- and heart-type fatty acid-binding proteins in the brain: tissue distribution and clinical utility,” Clinical Chemistry, vol. 50, no. 9, pp. 1568–1575, 2004.
- M. Bulut, O. Koksal, S. Dogan et al., “Tau protein as a serum marker of brain damage in mild traumatic brain injury: preliminary results,” Advances in Therapy, vol. 23, no. 1, pp. 12–22, 2006.
- P.-C. Liliang, C.-L. Liang, H.-C. Weng et al., “τ proteins in serum predict outcome after severe traumatic brain injury,” Journal of Surgical Research, vol. 160, no. 2, pp. 302–307, 2010.
- A. Chiaretti, M. Piastra, G. Polidori et al., “Correlation between neurotrophic factor expression and outcome of children with severe traumatic brain injury,” Intensive Care Medicine, vol. 29, no. 8, pp. 1329–1338, 2003.
- S. Giacoppo, P. Bramanti, M. Barresi et al., “Predictive biomarkers of recovery in traumatic brain injury,” Neurocritical Care, vol. 16, pp. 470–477, 2012.
- S. Mondello, L. Papa, A. Buki et al., “Neuronal and glial markers are differently associated with computed tomography findings and outcome in patients with severe traumatic brain injury: a case control study,” Critical Care, vol. 15, no. 3, article R156, 2011.
- L. Papa, L. M. Lewis, S. Silvestri et al., “Serum levels of ubiquitin C-terminal hydrolase distinguish mild traumatic brain injury from trauma controls and are elevated in mild and moderate traumatic brain injury patients with intracranial lesions and neurosurgical intervention,” Journal of Trauma and Acute Care Surgery, vol. 72, pp. 1335–1344, 2012.
- A. B. Da Rocha, C. Zanoni, G. R. de Freitas et al., “Serum Hsp70 as an early predictor of fatal outcome after severe traumatic brain injury in males,” Journal of Neurotrauma, vol. 22, no. 9, pp. 966–977, 2005.
- K. Lumpkins, G. V. Bochicchio, B. Zagol et al., “Plasma levels of the beta chemokine regulated upon activation, normal T cell expressed, and secreted (RANTES) correlate with severe brain injury,” Journal of Trauma, vol. 64, no. 2, pp. 358–361, 2008.
- D. M. Stein, A. Lindell, K. R. Murdock et al., “Relationship of serum and cerebrospinal fluid biomarkers with intracranial hypertension and cerebral hypoperfusion after severe traumatic brain injury,” Journal of Trauma, vol. 70, no. 5, pp. 1096–1103, 2011.
- J. R. Moffett, B. Ross, P. Arun, C. N. Madhavarao, and A. M. A. Namboodiri, “N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology,” Progress in Neurobiology, vol. 81, no. 2, pp. 89–131, 2007.
- P. S. Ariyannur, C. N. Madhavarao, and A. M. A. Namboodiri, “N-acetylaspartate synthesis in the brain: mitochondria vs. microsomes,” Brain Research, vol. 1227, pp. 34–41, 2008.
- R. Vagnozzi, B. Tavazzi, S. Signoretti et al., “Temporal window of metabolic brain vulnerability to concussions: mitochondrial-related impairment—part I,” Neurosurgery, vol. 61, no. 2, pp. 379–389, 2007.
- A. Carpentier, D. Galanaud, L. Puybasset et al., “Early morphologic and spectroscopic magnetic resonance in severe traumatic brain injuries can detect “invisible brain stem damage” and predict ‘vegetative states’,” Journal of Neurotrauma, vol. 23, no. 5, pp. 674–685, 2006.
- B. A. Holshouser, K. A. Tong, and S. Ashwal, “Proton MR spectroscopic imaging depicts diffuse axonal injury in children with traumatic brain injury,” American Journal of Neuroradiology, vol. 26, no. 5, pp. 1276–1285, 2005.
- A. Marmarou, S. Signoretti, P. Fatouros, G. A. Aygok, and R. Bullock, “Mitochondrial injury measured by proton magnetic resonance spectroscopy in severe head trauma patients,” Acta Neurochirurgica, Supplementum, no. 95, pp. 149–151, 2005.
- S. T. DeKosky, K. M. Taffe, E. E. Abrahamson, C. E. Dixon, P. M. Kochanek, and M. D. Ikonomovic, “Time course analysis of hippocampal nerve growth factor and antioxidant enzyme activity following lateral controlled cortical impact brain injury in the rat,” Journal of Neurotrauma, vol. 21, no. 5, pp. 491–500, 2004.
- M. L. Schwarzbold, D. Rial, T. de Bem et al., “Effects of traumatic brain injury of different severities on emotional, cognitive, and oxidative stress-related parameters in mice,” Journal of Neurotrauma, vol. 27, no. 10, pp. 1883–1893, 2010.
- F. Dehghan, M. Khaksari Hadad, G. Asadikram, H. Najafipour, and N. Shahrokhi, “Effect of melatonin on intracranial pressure and brain edema following traumatic brain injury: role of oxidative stresses,” Archives of Medical Research, vol. 44, pp. 251–258, 2013.
- L. F. Silva, M. S. Hoffmann, R. Gerbatin Rda et al., “Treadmill exercise protects against pentylenetetrazol-induced seizures and oxidative stress after traumatic brain injury,” Journal of Neurotrauma, no. 30, pp. 1278–1287, 2013.
- E. Oztürk, S. Demirbilek, A. Köroğlu et al., “Propofol and erythropoietin antioxidant properties in rat brain injured tissue,” Progress in Neuro-Psychopharmacology & Biological Psychiatry, vol. 32, pp. 81–86, 2008.
- M. B. Potts, R. Rola, C. P. Claus, D. M. Ferriero, J. R. Fike, and L. J. Noble-Haeusslein, “Glutathione peroxidase overexpression does not rescue impaired neurogenesis in the injured immature brain,” Journal of Neuroscience Research, vol. 87, no. 8, pp. 1848–1857, 2009.
- B. Blasiole, H. Bayr, V. A. Vagni et al., “Effect of hyperoxia on resuscitation of experimental combined traumatic brain injury and hemorrhagic shock in mice,” Anesthesiology, pp. 649–663, 2013.
- S. Homsi, F. Federico, N. Croci et al., “Minocycline effects on cerebral edema: relations with inflammatory and oxidative stress markers following traumatic brain injury in mice,” Brain Research, vol. 1291, pp. 122–132, 2009.
- L. Lomnitski, S. Chapman, A. Hochman et al., “Antioxidant mechanisms in apolipoprotein E deficient mice prior to and following closed head injury,” Biochimica et Biophysica Acta, vol. 1453, no. 3, pp. 359–368, 1999.
- R. M. Adibhatla and J. F. Hatcher, “Phospholipase A2, reactive oxygen species, and lipid peroxidation in CNS pathologies,” Journal of Biochemistry and Molecular Biology, vol. 41, no. 8, pp. 560–567, 2008.
- X. Ji, W. Liu, K. Xie et al., “Beneficial effects of hydrogen gas in a rat model of traumatic brain injury via reducing oxidative stress,” Brain Research, vol. 1354, pp. 196–205, 2010.
- I. Solaroglu, O. Okutan, E. Kaptanoglu, E. Beskonakli, and K. Kilinc, “Increased xanthine oxidase activity after traumatic brain injury in rats,” Journal of Clinical Neuroscience, vol. 12, no. 3, pp. 273–275, 2005.
- P. G. Sullivan, J. N. Keller, M. P. Mattson, and S. W. Scheff, “Traumatic brain injury alters synaptic homeostasis: implications for impaired mitochondrial and transport function,” Journal of Neurotrauma, vol. 15, no. 10, pp. 789–798, 1998.
- O. Ates, S. Cayli, E. Altinoz et al., “Neuroprotection by resveratrol against traumatic brain injury in rats,” Molecular and Cellular Biochemistry, vol. 294, no. 1-2, pp. 137–144, 2007.
- M. Khan, H. Sakakima, T. S. Dhammu et al., “S-Nitrosoglutathione reduces oxidative injury and promotes mechanisms of neurorepair following traumatic brain injury in rats,” Journal of Neuroinflammation, vol. 8, article 78, 2011.
- K. Miyamoto, H. Ohtaki, K. Dohi et al., “Therapeutic time window for edaravone treatment of traumatic brain injury in mice,” BioMed Research International, vol. 2013, Article ID 379206, 13 pages, 2013.
- M. Ohta, Y. Higashi, T. Yawata et al., “Attenuation of axonal injury and oxidative stress by edaravone protects against cognitive impairments after traumatic brain injury,” Brain Research, vol. 1490, pp. 184–192, 2013.
- G.-H. Wang, Z.-L. Jiang, Y.-C. Li et al., “Free-radical scavenger edaravone treatment confers neuroprotection against traumatic brain injury in rats,” Journal of Neurotrauma, vol. 28, no. 10, pp. 2123–2134, 2011.
- A. Wu, Z. Ying, and F. Gomez-Pinilla, “Vitamin e protects against oxidative damage and learning disability after mild traumatic brain injury in rats,” Neurorehabilitation and Neural Repair, vol. 24, no. 3, pp. 290–298, 2010.
- Y. Deng, B. M. Thompson, X. Gao, and E. D. Hall, “Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury,” Experimental Neurology, vol. 205, no. 1, pp. 154–165, 2007.
- T. T. Reed, J. Owen, W. M. Pierce, A. Sebastian, P. G. Sullivan, and D. A. Butterfield, “Proteomic identification of nitrated brain proteins in traumatic brain-injured rats treated postinjury with gamma-glutamylcysteine ethyl ester: insights into the role of elevation of glutathione as a potential therapeutic strategy for traumatic brain injury,” Journal of Neuroscience Research, vol. 87, no. 2, pp. 408–417, 2009.
- H. Bayir, V. E. Kagan, Y. Y. Tyurina et al., “Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children,” Pediatric Research, vol. 51, no. 5, pp. 571–578, 2002.
- T. B. Corcoran, E. Mas, A. E. Barden et al., “Are isofurans and neuroprostanes increased after subarachnoid hemorrhage and traumatic brain injury?” Antioxidants and Redox Signaling, vol. 15, no. 10, pp. 2663–2667, 2011.
- S. Varma, K. L. Janesko, S. R. Wisniewski et al., “F2-isoprostane and neuron-specific enolase in cerebrospinal fluid after severe traumatic brain injury in infants and children,” Journal of Neurotrauma, vol. 20, no. 8, pp. 781–786, 2003.
- D. Praticò, E. M. Smyth, F. Violi, and G. A. FitzGerald, “Local amplification of platelet function by 8-epi prostaglandin F2α is not mediated by thromboxane receptor isoforms,” The Journal of Biological Chemistry, vol. 271, no. 25, pp. 14916–14924, 1996.
- F. Clausen, N. Marklund, A. Lewén, P. Enblad, S. Basu, and L. Hillered, “Interstitial F2-isoprostane 8-Iso-PGF2α as a biomarker of oxidative stress after severe human traumatic brain injury,” Journal of Neurotrauma, vol. 29, no. 5, pp. 766–775, 2012.
- G. F. Yu, Y. Q. Jie, A. Wu, Q. Huang, W. M. Dai, and X. F. Fan, “Increased plasma 8-iso-prostaglandin F2αconcentration in severe human traumatic brain injury,” Clinica Chimica Acta, vol. 421, pp. 7–11, 2013.
- 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.
- R. D. Readnower, M. Chavko, S. Adeeb et al., “Increase in blood-brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury,” Journal of Neuroscience Research, vol. 88, no. 16, pp. 3530–3539, 2010.
- R. S. Darwish, N. Amiridze, and B. Aarabi, “Nitrotyrosine as an oxidative stress marker: evidence for involvement in neurologic outcome in human traumatic brain injury,” Journal of Trauma, vol. 63, no. 2, pp. 439–442, 2007.
- C. Nayak, D. Nayak, A. Raja, and A. Rao, “Time-level relationship between indicators of oxidative stress and Glasgow Coma Scale scores of severe head injury patients,” Clinical Chemistry and Laboratory Medicine, vol. 44, no. 4, pp. 460–463, 2006.
- C. Nayak, D. Nayak, A. Raja, and A. Rao, “Time-relative changes in the erythrocyte antioxidant enzyme activities and their relationship with glasgow coma scale scores in severe head injury patients in the 21-day posttraumatic study period,” Indian Journal of Medical Sciences, vol. 61, no. 7, pp. 381–389, 2007.
- C. Nayak, D. Nayak, A. Raja, and A. Rao, “Erythrocyte indicators of oxidative changes in patients with graded traumatic head injury,” Neurology India, vol. 56, no. 1, pp. 31–35, 2008.
- C. Nayak, D. Nayak, A. Raja, and A. Rao, “Relationship between markers of lipid peroxidation, thiol oxidation and Glasgow coma scale scores of moderate head injury patients in the 7 day post-traumatic period,” Neurological Research, vol. 30, no. 5, pp. 461–464, 2008.
- A. Hohl, J. D. S. Gullo, C. C. P. Silva et al., “Plasma levels of oxidative stress biomarkers and hospital mortality in severe head injury: a multivariate analysis,” Journal of Critical Care, vol. 27, pp. 523.e11–523.e19, 2012.
- M. E. R. de Oliveira Thais, G. Cavallazzi, M. L. Schwarzbold et al., “Plasma levels of oxidative stress biomarkers and long-term cognitive performance after severe head injury,” CNS Neuroscience & Therapeutics, vol. 18, pp. 606–608, 2012.
- A. McIntyre, S. Mehta, J. Aubut, M. Dijkers, and R. W. Teasell, “Mortality among older adults after a traumatic brain injury: a meta-analysis,” Brain Injury, vol. 27, pp. 31–40, 2013.
- 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.
- T. Itoh, M. Imano, S. Nishida et al., “Increased apoptotic neuronal cell death and cognitive impairment at early phase after traumatic brain injury in aged rats,” Brain Structure and Function, vol. 218, pp. 209–220, 2013.
- L. F. A. Silva, M. S. Hoffmann, L. M. Rambo et al., “The involvement of Na+, K+-ATPase activity and free radical generation in the susceptibility to pentylenetetrazol-induced seizures after experimental traumatic brain injury,” Journal of the Neurological Sciences, vol. 308, no. 1-2, pp. 35–40, 2011.
- F. D. Lima, M. A. Souza, A. F. Furian et al., “Na+,K+-ATPase activity impairment after experimental traumatic brain injury: relationship to spatial learning deficits and oxidative stress,” Behavioural Brain Research, vol. 193, no. 2, pp. 306–310, 2008.
- A. L. L. Saraiva, A. P. O. Ferreira, L. F. A. Silva et al., “Creatine reduces oxidative stress markers but does not protect against seizure susceptibility after severe traumatic brain injury,” Brain Research Bulletin, vol. 87, no. 2-3, pp. 180–186, 2012.
- C. C. T. Aguiar, A. B. Almeida, P. V. P. Araujo et al., “Oxidative stress and epilepsy: literature review,” Oxidative Medicine and Cellular Longevity, vol. 2012, Article ID 795259, 12 pages, 2012.
- F. D. Lima, M. S. Oliveira, A. F. Furian et al., “Adaptation to oxidative challenge induced by chronic physical exercise prevents Na+,K+-ATPase activity inhibition after traumatic brain injury,” Brain Research, vol. 1279, pp. 147–155, 2009.
- G. S. Griesbach, D. A. Hovda, F. Gomez-Pinilla, and R. L. Sutton, “Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion injury in rats,” Neuroscience, vol. 154, no. 2, pp. 530–540, 2008.
- T. Itoh, M. Imano, S. Nishida et al., “Exercise inhibits neuronal apoptosis and improves cerebral function following rat traumatic brain injury,” Journal of Neural Transmission, vol. 118, no. 9, pp. 1263–1272, 2011.
- J. L. Rigg, E. P. Elovic, and B. D. Greenwald, “A review of the effectiveness of antioxidant therapy to reduce neuronal damage in acute traumatic brain injury,” Journal of Head Trauma Rehabilitation, vol. 20, no. 4, pp. 389–391, 2005.
- Y. Gilgun-Sherki, Z. Rosenbaum, E. Melamed, and D. Offen, “Antioxidant therapy in acute central nervous system injury: current state,” Pharmacological Reviews, vol. 54, no. 2, pp. 271–284, 2002.
- M. Yunoki, M. Kawauchi, N. Ukita et al., “Effects of lecithinized superoxide dismutase on traumatic brain injury in rats,” Journal of Neurotrauma, vol. 14, no. 10, pp. 739–746, 1997.
- M. Yunoki, M. Kawauchi, N. Ukita, T. Sugiura, and T. Ohmoto, “Effects of lecithinized superoxide dismutase on neuronal cell loss in CA3 hippocampus after traumatic brain injury in rats,” Surgical Neurology, vol. 59, no. 3, pp. 156–160, 2003.
- N. Aoyama, Y. Katayama, T. Kawamata et al., “Effects of antioxidant, OPC-14117, on secondary cellular damage and behavioral deficits following cortical contusion in the rat,” Brain Research, vol. 934, no. 2, pp. 117–124, 2002.
- T. Kawamata, Y. Katayama, T. Maeda et al., “Antioxidant, OPC-14117, attenuates edema formation and behavioral deficits following cortical contusion in rats,” Acta Neurochirurgica, Supplement, vol. 1997, no. 70, pp. 191–193, 1997.
- T. Mori, T. Kawamata, Y. Katayama et al., “Antioxidant, OPC-14117, attenuates edema formation, and subsequent tissue damage following cortical contusion in rats,” Acta Neurochirurgica, Supplement, vol. 1998, no. 71, pp. 120–122, 1998.
- J. P. Muizelaar, A. Marmarou, H. F. Young et al., “Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated superoxide dismutase: a Phase II trial,” Journal of Neurosurgery, vol. 78, no. 3, pp. 375–382, 1993.
- J. P. Muizelaar, J. W. Kupiec, and L. A. Rapp, “PEG-SOD after head injury,” Journal of Neurosurgery, vol. 83, no. 5, p. 942, 1995.
- R. Zhang, E. Shohami, E. Beit-Yannai, R. Bass, V. Trembovler, and A. Samuni, “Mechanism of brain protection by nitroxide radicals in experimental model of closed-head injury,” Free Radical Biology and Medicine, vol. 24, no. 2, pp. 332–340, 1998.
- 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.
- F. Clausen, N. Marklund, A. Lewén, and L. Hillered, “The nitrone free radical scavenger NXY-059 is neuroprotective when administered after traumatic brain injury in the rat,” Journal of Neurotrauma, vol. 25, no. 12, pp. 1449–1457, 2008.
- N. Marklund, S. Sihver, B. Långström, M. Bergström, and L. Hillered, “Effect of traumatic brain injury and nitrone radical scavengers on relative changes in regional cerebral blood flow and glucose uptake in rats,” Journal of Neurotrauma, vol. 19, no. 10, pp. 1139–1153, 2002.
- N. Marklund, F. Clausen, T. K. McIntosh, and L. Hillered, “Free radical scavenger posttreatment improves functional and morphological outcome after fluid percussion injury in the rat,” Journal of Neurotrauma, vol. 18, no. 8, pp. 821–832, 2001.
- N. Marklund, T. Lewander, F. Clausen, and L. Hillered, “Effects of the nitrone radical scavengers PBN and S-PBN on in vivo trapping of reactive oxygen species after traumatic brain injury in rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 21, no. 11, pp. 1259–1267, 2001.
- M. Fujita, Y. Oda, E. P. Wei, and J. T. Povlishock, “The combination of either tempol or FK506 with delayed hypothermia: implications for traumatically induced microvascular and axonal protection,” Journal of Neurotrauma, vol. 28, no. 7, pp. 1209–1218, 2011.
- S. Inci, O. E. Özcan, and K. Kilinç, “Time-level relationship for lipid peroxidation and the protective effect of α-tocopherol in experimental mild and severe brain injury,” Neurosurgery, vol. 43, no. 2, pp. 330–336, 1998.
- Y. Ikeda, Y. Mochizuki, Y. Nakamura et al., “Protective effect of a novel vitamin E derivative on experimental traumatic brain edema in rats–preliminary study,” Acta Neurochirurgica, Supplement, vol. 76, pp. 343–345, 2000.
- M. A. Petty, P. Poulet, A. Haas, I. J. Namer, and J. Wagner, “Reduction of traumatic brain injury-induced cerebral oedema by a free radical scavenger,” European Journal of Pharmacology, vol. 307, no. 2, pp. 149–155, 1996.
- J. Yang, Y. Han, W. Ye, F. Liu, K. Zhuang, and G. Wu, “Alpha tocopherol treatment reduces the expression of Nogo-A and NgR in rat brain after traumatic brain injury,” Journal of Surgical Research, vol. 182, pp. e69–e77, 2013.
- O. Ates, S. Cayli, I. Gurses et al., “Effect of pinealectomy and melatonin replacement on morphological and biochemical recovery after traumatic brain injury,” International Journal of Developmental Neuroscience, vol. 24, no. 6, pp. 357–363, 2006.
- A. Bayir, D. A. Kiresi, H. Kara et al., “The effects of mannitol and melatonin on MRI findings in an animal model of traumatic brain edema,” Acta Neurologica Belgica, vol. 108, no. 4, pp. 149–154, 2008.
- S. V. Kabadi and T. J. Maher, “Posttreatment with uridine and melatonin following traumatic brain injury reduces edema in various brain regions in rats,” Annals of the New York Academy of Sciences, vol. 1199, pp. 105–113, 2010.
- S. M. Beni, R. Kohen, R. J. Reiter, D.-X. Tan, and E. Shohami, “Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-kappaB and AP-1,” The FASEB Journal, vol. 18, no. 1, pp. 149–151, 2004.
- C. Mésenge, I. Margaill, C. Verrecchia, M. Allix, R. G. Boulu, and M. Plotkine, “Protective effect of melatonin in a model of traumatic brain injury in mice,” Journal of Pineal Research, vol. 25, no. 1, pp. 41–46, 1998.
- D. Ozdemir, N. Uysal, S. Gonenc et al., “Effect of melatonin on brain oxidative damage induced by traumatic brain injury in immature rats,” Physiological Research, vol. 54, no. 6, pp. 631–637, 2005.
- D. Ozdemir, K. Tugyan, N. Uysal et al., “Protective effect of melatonin against head trauma-induced hippocampal damage and spatial memory deficits in immature rats,” Neuroscience Letters, vol. 385, no. 3, pp. 234–239, 2005.
- M. L. Kelso, N. N. Scheff, S. W. Scheff, and J. R. Pauly, “Melatonin and minocycline for combinatorial therapy to improve functional and histopathological deficits following traumatic brain injury,” Neuroscience Letters, vol. 488, no. 1, pp. 60–64, 2011.
- M. P. Kalapos, “Where does plasma methylglyoxal originate from?” Diabetes Research and Clinical Practice, vol. 99, no. 3, pp. 260–271, 2013.
- N. Rabbani and P. J. Thornalley, “Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome,” Amino Acids, vol. 42, no. 4, pp. 1133–1142.
- R. Ramasamy, S. F. Yan, and A. M. Schmidt, “Advanced glycation endproducts: from precursors to RAGE: round and round we go,” Amino Acids, vol. 42, pp. 1151–1161, 2012.
- T. L. Gao, X. T. Yuan, D. Yang et al., “Expression of HMGB1 and RAGE in rat and human brains after traumatic brain injury,” Journal of Trauma and Acute Care Surgery, vol. 72, pp. 643–649, 2012.
- A. K. Au, R. K. Aneja, M. J. Bell et al., “Cerebrospinal fluid levels of high-mobility group box 1 and cytochrome C predict outcome after pediatric traumatic brain injury,” Journal of Neurotrauma, vol. 29, pp. 2013–2021, 2012.
- Y. Okuma, K. Liu, H. Wake et al., “Anti-high mobility group box-1 antibody therapy for traumatic brain injury,” Annals of Neurology, vol. 72, no. 3, pp. 373–384, 2012.
- G. Aldini, I. Dalle-Donne, R. M. Facino, A. Milzani, and M. Carini, “Intervention strategies to inhibit protein carbonylation by lipoxidation-derived reactive carbonyls,” Medicinal Research Reviews, vol. 27, no. 6, pp. 817–868, 2007.
- P. L. Wood, M. A. Khan, S. R. Kulow, S. A. Mahmood, and J. R. Moskal, “Neurotoxicity of reactive aldehydes: the concept of “aldehyde load” as demonstrated by neuroprotection with hydroxylamines,” Brain Research, vol. 1095, no. 1, pp. 190–199, 2006.
- B. Saletu, H. V. Semlitsch, P. Anderer, F. Resch, O. Presslich, and P. Schuster, “Psychophysiological research in psychiatry and neuropsychopharmacology. II. The investigation of antihypoxidotic/nootropic drugs (tenilsetam and co-dergocrine-mesylate) in elderlies with the Viennese Psychophysiological Test-System (VPTS),” Methods and Findings in Experimental and Clinical Pharmacology, vol. 11, no. 1, pp. 43–55, 1989.
- I. N. Singh, P. G. Sullivan, and E. D. Hall, “Peroxynitrite-mediated oxidative damage to brain mitochondria: protective effects of peroxynitrite scavengers,” Journal of Neuroscience Research, vol. 85, no. 10, pp. 2216–2223, 2007.
- E. D. Hall, N. C. Kupina, and J. S. Althaus, “Peroxynitrite scavengers for the acute treatment of traumatic brain injury,” Annals of the New York Academy of Sciences, vol. 890, pp. 462–468, 1999.
- X. Pei, K. Ni, Y. Zhou et al., “Protective effects of carnosine against closed head injury in mice,” Journal of Zhejiang University Science, vol. 42, pp. 291–296, 2013.
- K. Hamann, A. Durkes, H. Ouyang, K. Uchida, A. Pond, and R. Shi, “Critical role of acrolein in secondary injury following ex vivo spinal cord trauma,” Journal of Neurochemistry, vol. 107, no. 3, pp. 712–721, 2008.
- G. Louin, C. Marchand-Verrecchia, B. Palmier, M. Plotkine, and M. Jafarian-Tehrani, “Selective inhibition of inducible nitric oxide synthase reduces neurological deficit but not cerebral edema following traumatic brain injury,” Neuropharmacology, vol. 50, no. 2, pp. 182–190, 2006.
- J. Lu, S. Moochhala, M. Shirhan et al., “Neuroprotection by aminoguanidine after lateral fluid-percussive brain injury in rats: a combined magnetic resonance imaging, histopathologic and functional study,” Neuropharmacology, vol. 44, no. 2, pp. 253–263, 2003.
- 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.
- A. Vakili, F. Hosseinzadeh, and T. Sadogh, “Effect of aminoguanidine on post-ischemic brain edema in transient model of focal cerebral ischemia,” Brain Research, vol. 1170, pp. 97–102, 2007.
- K. Chatzipanteli, R. Garcia, A. E. Marcillo, K. E. Loor, S. Kraydieh, and W. D. Dietrich, “Temporal and segmental distribution of constitutive and inducible nitric oxide synthases after traumatic spinal cord injury: effect of aminoguanidine treatment,” Journal of Neurotrauma, vol. 19, no. 5, pp. 639–651, 2002.
- R. S. B. Clark, H. Bayir, C. T. Chu, S. M. Alber, P. M. Kochanek, and S. C. Watkins, “Autophagy is increased in mice after traumatic brain injury and is detectable in human brain after trauma and critical illness,” Autophagy, vol. 4, no. 1, pp. 88–90, 2008.
- J. Lok, W. Leung, S. Zhao et al., “Gamma-glutamylcysteine ethyl ester protects cerebral endothelial cells during injury and decreases blood-brain barrier permeability after experimental brain trauma,” Journal of Neurochemistry, vol. 118, no. 2, pp. 248–255, 2011.
- J.-H. Yi and A. S. Hazell, “N-acetylcysteine attenuates early induction of heme oxygenase-1 following traumatic brain injury,” Brain Research, vol. 1033, no. 1, pp. 13–19, 2005.
- Y. Xiong, P. L. Peterson, and C. P. Lee, “Effect of N-acetylcysteine on mitochondrial function following traumatic brain injury in rats,” Journal of Neurotrauma, vol. 16, no. 11, pp. 1067–1082, 1999.
- G. Chen, J. Shi, Z. Hu, and C. Hang, “Inhibitory effect on cerebral inflammatory response following traumatic brain injury in rats: a potential neuroprotective mechanism of N-acetylcysteine,” Mediators of Inflammation, vol. 2008, Article ID 716458, 8 pages, 2008.
- M. E. Hoffer, C. Balaban, M. D. Slade, J. W. Tsao, and B. Hoffer, “Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a double-blind, placebo controlled study,” PloS One, vol. 8, Article ID e54163, 2013.
- M. Segatore, “Corticosteroids and traumatic brain injury: status at the end of the decade of the brain,” The Journal of Neuroscience Nursing, vol. 31, no. 4, pp. 239–250, 1999.
- C. O. Park, “The effects of methylprednisolone on prevention of brain edema after experimental moderate diffuse brain injury in rats—Comparison between dosage, injection time, and treatment methods,” Yonsei Medical Journal, vol. 39, no. 5, pp. 395–403, 1998.
- “The Brain Trauma Foundation. The American Association of Neurological Surgeons. The joint section on neurotrauma and critical care. Role of steroids,” Journal of Neurotrauma, vol. 17, pp. 531–535, 2000.
- I. Roberts, D. Yates, P. Sandercock et al., “Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial,” The Lancet, vol. 364, pp. 1321–1328, 2004.
- P. Alderson and I. Roberts, “Corticosteroids for acute traumatic brain injury,” Cochrane Database of Systematic Reviews, Article ID CD000196, 2005.
- N. Shahrokhi, M. K. Haddad, S. Joukar, M. Shabani, Z. Keshavarzi, and B. Shahozehi, “Neuroprotective antioxidant effect of sex steroid hormones in traumatic brain injury,” Pakistan Journal of Pharmaceutical Sciences, vol. 25, no. 1, pp. 219–225, 2012.
- H. Bayir, D. W. Marion, A. M. Puccio et al., “Marked gender effect on lipid peroxidation after severe traumatic brain injury in adult patients,” Journal of Neurotrauma, vol. 21, no. 1, pp. 1–8, 2004.
- D. G. Stein, “Progesterone exerts neuroprotective effects after brain injury,” Brain Research Reviews, vol. 57, no. 2, pp. 386–397, 2008.
- J. Leitgeb, W. Mauritz, A. Brazinova et al., “Effects of gender on outcomes after traumatic brain injury,” Journal of Trauma, vol. 71, no. 6, pp. 1620–1626, 2011.
- C. Renner, H. Hummelsheim, A. Kopczak et al., “The influence of gender on the injury severity, course and outcome of traumatic brain injury,” Brain Injury, vol. 26, pp. 1360–1371, 2012.
- G. Xiao, J. Wei, W. Yan, W. Wang, and Z. Lu, “Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial,” Critical Care, vol. 12, no. 2, article R61, 2008.
- J. Ma, S. Huang, S. Qin, and C. You, “Progesterone for acute traumatic brain injury,” Cochrane Database of Systematic Reviews, vol. 10, Article ID 008409, 2012.
- K. W. McConeghy, J. Hatton, L. Hughes, and A. M. Cook, “A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury,” CNS Drugs, vol. 26, pp. 613–636, 2012.
- E. D. Hall, P. A. Yonkers, J. M. McCall, and J. M. Braughler, “Effects of the 21-aminosteroid U74006F on experimental head injury in mice,” Journal of Neurosurgery, vol. 68, no. 3, pp. 456–461, 1988.
- C. Gahm, S. Holmin, S. Rudehill, and T. Mathiesen, “Neuronal degeneration and iNOS expression in experimental brain contusion following treatment with colchicine, dexamethasone, tirilazad mesylate and nimodipine,” Acta Neurochirurgica, vol. 147, no. 10, pp. 1071–1084, 2005.
- R. H. Fabian, D. S. Dewitt, and T. A. Kent, “The 21-aminosteroid U-74389G reduces cerebral superoxide anion concentration following fluid percussion injury of the brain,” Journal of Neurotrauma, vol. 15, no. 6, pp. 433–440, 1998.
- M. Bains and E. D. Hall, “Antioxidant therapies in traumatic brain and spinal cord injury,” Biochimica et Biophysica Acta, vol. 1822, no. 5, pp. 675–684, 2012.
- T. K. McIntosh, M. Thomas, D. Smith, and M. Banbury, “The novel 21-aminosteroid U74006F attenuates cerebral edema and improves survival after brain injury in the rat,” Journal of Neurotrauma, vol. 9, no. 1, pp. 33–46, 1992.
- E. D. Hall and M. A. Travis, “Inhibition of arachidonic acid-induced vasogenic brain edema by the non-glucocorticoid 21-aminosteroid U74006F,” Brain Research, vol. 451, no. 1-2, pp. 350–352, 1988.
- R. J. Kavanagh and K. P. C. A. Kam P.C.A, “Lazaroids: efficacy and mechanism of action of the 21-aminosteroids in neuroprotection,” British Journal of Anaesthesia, vol. 86, no. 1, pp. 110–119, 2001.
- L. F. Marshall, A. I. R. Maas, S. B. Marshall et al., “A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury,” Journal of Neurosurgery, vol. 89, no. 4, pp. 519–525, 1998.
- G. J. Velat, M. M. Kimball, J. D. Mocco, and B. L. Hoh, “Vasospasm after aneurysmal subarachnoid hemorrhage: review of randomized controlled trials and meta-analyses in the literature,” World Neurosurgery, vol. 76, no. 5, pp. 446–454, 2011.
- D. Ilodigwe, G. D. Murray, N. F. Kassell et al., “Sliding dichotomy compared with fixed dichotomization of ordinal outcome scales in subarachnoid hemorrhage trials Clinical article,” Journal of Neurosurgery, vol. 118, pp. 3–12, 2013.
- M. B. Bracken, M. J. Shepard, T. R. Holford et al., “Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury: results of the third national acute spinal cord injury randomized controlled trial,” The Journal of the American Medical Association, vol. 277, no. 20, pp. 1597–1604, 1997.
- J. Langham, C. Goldfrad, G. Teasdale, D. Shaw, and K. Rowan, “Calcium channel blockers for acute traumatic brain injury,” Cochrane Database of Systematic Reviews, Article ID CD000565, 2003.
- A. Marmarou, J. Nichols, J. Burgess et al., “Effects of the bradykinin antagonist Bradycor(TM) (Deltibant, CP-1027) in severe traumatic brain injury: results of a multi-center, randomized, placebo-controlled trial,” Journal of Neurotrauma, vol. 16, no. 6, pp. 431–444, 1999.
- A. I. R. Maas, G. Murray, H. Henney III et al., “Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial,” The Lancet Neurology, vol. 5, no. 1, pp. 38–45, 2006.
- N. Knoller, L. Levi, I. Shoshan et al., “Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial,” Critical Care Medicine, vol. 30, no. 3, pp. 548–554, 2002.
- N. R. Temkin, G. D. Anderson, H. R. Winn et al., “Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial,” The Lancet Neurology, vol. 6, no. 1, pp. 29–38, 2007.
- G. F. Morris, R. Bullock, S. B. Marshall, A. Marmarou, A. Maas, and L. F. Marshall, “Failure of the competitive N-methyl-D-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: results of two phase III clinical trials,” Journal of Neurosurgery, vol. 91, no. 5, pp. 737–743, 1999.
- W. Yan, H.-D. Wang, Z.-G. Hu, Q.-F. Wang, and H.-X. Yin, “Activation of Nrf2-ARE pathway in brain after traumatic brain injury,” Neuroscience Letters, vol. 431, no. 2, pp. 150–154, 2008.
- K. Itoh, T. Chiba, S. Takahashi et al., “An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements,” Biochemical and Biophysical Research Communications, vol. 236, no. 2, pp. 313–322, 1997.
- E. D. Owuor and A.-N. T. Kong, “Antioxidants and oxidants regulated signal transduction pathways,” Biochemical Pharmacology, vol. 64, no. 5-6, pp. 765–770, 2002.
- J.-M. Zhang, Y. Hong, W. Yan, S. Chen, and C.-R. Sun, “The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumatic brain injury in rats and mice,” Acta Pharmacologica Sinica, vol. 31, no. 11, pp. 1421–1430, 2010.
- A. K. Jain, D. A. Bloom, and A. K. Jaiswal, “Nuclear import and export signals in control of Nrf2,” The Journal of Biological Chemistry, vol. 280, no. 32, pp. 29158–29168, 2005.
- W. O. Osburn, N. Wakabayashi, V. Misra et al., “Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion,” Archives of Biochemistry and Biophysics, vol. 454, no. 1, pp. 7–15, 2006.
- M. Kerman, M. Kanter, K. K. Coşkun, M. Erboga, and A. Gurel, “Neuroprotective effects of Caffeic acid phenethyl ester on experimental traumatic brain injury in rats,” Journal of Molecular Histology, vol. 43, no. 1, pp. 49–57, 2012.
- T. Itoh, M. Imano, S. Nishida et al., “(-)-Epigallocatechin-3-gallate increases the number of neural stem cells around the damaged area after rat traumatic brain injury,” Journal of Neural Transmission, vol. 119, pp. 877–890, 2012.
- T. Itoh, M. Imano, S. Nishida et al., “(-)-Epigallocatechin-3-gallate protects against neuronal cell death and improves cerebral function after traumatic brain injury in rats,” NeuroMolecular Medicine, vol. 13, no. 4, pp. 300–309, 2011.
- T. Itoh, M. Imano, S. Nishida et al., “(-)-Epigallocatechin-3-gallate increases the number of neural stem cells around the damaged area after rat traumatic brain injury,” Journal of Neural Transmission, pp. 1–14, 2011.
- L. Xia, Z.-L. Jiang, G.-H. Wang, B.-Y. Hu, and K.-F. Ke, “Treatment with ginseng total saponins reduces the secondary brain injury in rat after cortical impact,” Journal of Neuroscience Research, vol. 90, pp. 1424–1436, 2012.
- B. Y. Hu, Z. L. Jiang, G. H. Wang, X. Li, and H. M. Shen, “Effective dose and time window of ginseng total saponins treatment in rat after traumatic brain injury,” Chinese Journal of Applied Physiology, vol. 28, pp. 179–183, 2012.
- L. Xia, Q. Chen, and G. Cheng, “Effects of ginseng total saponin on traumatic brain edema of rats,” Chinese Journal of Integrated Traditional and Western Medicine, vol. 32, pp. 1671–1674, 2012.
- Y. C. Ji, Y. B. Kim, S. W. Park et al., “Neuroprotective effect of ginseng total saponins in experimental traumatic brain injury,” Journal of Korean Medical Science, vol. 20, no. 2, pp. 291–296, 2005.
- E. Schültke, H. Kamencic, M. Zhao et al., “Neuroprotection following fluid percussion brain trauma: a pilot study using quercetin,” Journal of Neurotrauma, vol. 22, no. 12, pp. 1475–1484, 2005.
- 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.
- R. H. Singleton, H. Q. Yan, W. Fellows-Mayle, and C. E. Dixon, “Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury,” Journal of Neurotrauma, vol. 27, no. 6, pp. 1091–1099, 2010.
- Ü. Sönmez, A. Sönmez, G. Erbil, I. Tekmen, and B. Baykara, “Neuroprotective effects of resveratrol against traumatic brain injury in immature rats,” Neuroscience Letters, vol. 420, no. 2, pp. 133–137, 2007.
- S. Sharma, Y. Zhuang, Z. Ying, A. Wu, and F. Gomez-Pinilla, “Dietary curcumin supplementation counteracts reduction in levels of molecules involved in energy homeostasis after brain trauma,” Neuroscience, vol. 161, no. 4, pp. 1037–1044, 2009.
- A. Wu, Z. Ying, D. Schubert, and F. Gomez-Pinilla, “Brain and spinal cord interaction: a dietary curcumin derivative counteracts locomotor and cognitive deficits after brain trauma,” Neurorehabilitation and Neural Repair, vol. 25, no. 4, pp. 332–342, 2011.
- J. Zhao, A. N. Moore, J. B. Redell, and P. K. Dash, “Enhancing expression of Nrf2-driven genes protects the blood-brain barrier after brain injury,” The Journal of Neuroscience, vol. 27, no. 38, pp. 10240–10248, 2007.
- P. K. Dash, J. Zhao, S. A. Orsi, M. Zhang, and A. N. Moore, “Sulforaphane improves cognitive function administered following traumatic brain injury,” Neuroscience Letters, vol. 460, no. 2, pp. 103–107, 2009.
- J. Zhao, A. N. Moore, G. L. Clifton, and P. K. Dash, “Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury,” Journal of Neuroscience Research, vol. 82, no. 4, pp. 499–506, 2005.
- X. Wang, J. P. de Rivero Vaccari, H. Wang et al., “Activation of the nuclear factor E2-related factor 2/antioxidant response element pathway is neuroprotective after spinal cord injury,” Journal of Neurotrauma, vol. 29, no. 5, pp. 936–945, 2012.
- M. Xue, N. Rabbani, H. Momiji et al., “Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation,” Biochemical Journal, vol. 443, no. 1, pp. 213–222, 2012.
- M. G. Distler, N. Gorfinkle, L. A. Papale et al., “Glyoxalase 1 and its substrate methylglyoxal are novel regulators of seizure susceptibility,” Epilepsia, vol. 54, pp. 649–657, 2013.
- M. Bergsneider, D. A. Hovda, E. Shalmon et al., “Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study,” Journal of Neurosurgery, vol. 86, no. 2, pp. 241–251, 1997.
- P. J. Hutchinson, M. T. O'Connell, A. Seal et al., “A combined microdialysis and FDG-PET study of glucose metabolism in head injury,” Acta Neurochirurgica, vol. 151, no. 1, pp. 51–61, 2009.
- K. D. Statler, K. L. Janesko, J. A. Melick, R. S. B. Clark, L. W. Jenkins, and P. M. Kochanek, “Hyperglycolysis is exacerbated after traumatic brain injury with fentanyl vs. isoflurane anesthesia in rats,” Brain Research, vol. 994, no. 1, pp. 37–43, 2003.
- D. Schubert, “Glucose metabolism and Alzheimer's disease,” Ageing Research Reviews, vol. 4, no. 2, pp. 240–257, 2005.
- A. Sartori and E. J. H. Bechara, “Is methylglyoxal an endogenous toxin?” Quimica Nova, vol. 33, no. 10, pp. 2193–2201, 2010.
- A. S. Cheng, Y. H. Cheng, C. H. Chiou, and T. L. Chang, “Resveratrol upregulates Nrf2 expression to attenuate methylglyoxal-induced insulin resistance in Hep G2 cells,” Journal of Agricultural and Food Chemistry, vol. 60, pp. 9180–9187, 2012.
- P. Maher, R. Dargusch, J. L. Ehren, S. Okada, K. Sharma, and D. Schubert, “Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes,” PLoS ONE, vol. 6, no. 6, Article ID e21226, 2011.
- M. Gelderblom, F. Leypoldt, J. Lewerenz et al., “The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 5, pp. 835–843, 2012.
- M. Liu, M. Yuan, M. Luo, X. Bu, H.-B. Luo, and X. Hu, “Binding of curcumin with glyoxalase I: molecular docking, molecular dynamics simulations, and kinetics analysis,” Biophysical Chemistry, vol. 147, no. 1-2, pp. 28–34, 2010.
- T.-Y. Hu, C.-L. Liu, C.-C. Chyau, and M. L. Hu, “Trapping of methylglyoxal by curcumin in cell-free systems and in human umbilical vein endothelial cells,” Journal of Agricultural and Food Chemistry, vol. 60, pp. 8190–8196, 2012.
- A. Gugliucci, D. H. M. Bastos, J. Schulze, and M. F. F. Souza, “Caffeic and chlorogenic acids in Ilex paraguariensis extracts are the main inhibitors of AGE generation by methylglyoxal in model proteins,” Fitoterapia, vol. 80, no. 6, pp. 339–344, 2009.
- S. Sang, X. Shao, N. Bai, C.-Y. Lo, C. S. Yang, and C.-T. Ho, “Tea polyphenol (-)-epigallocatechin-3-gallate: a new trapping agent of reactive dicarbonyl species,” Chemical Research in Toxicology, vol. 20, no. 12, pp. 1862–1870, 2007.
- Y. Xie and X. Chen, “Structures required of polyphenols for inhibiting advanced glycation end products formation,” Current Drug Metabolism, vol. 14, pp. 414–431, 2013.
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