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Review

Management of Traumatic Brain Injury: From Present to Future

by
Rosalia Crupi
1,†,
Marika Cordaro
2,†,
Salvatore Cuzzocrea
3,4,* and
Daniela Impellizzeri
3
1
Department of Veterinary Science, University of Messina, 98168 Messina, Italy
2
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98100 Messina, Italy
3
Department of Chemical, Biological, Pharmacological and Environmental Sciences, Messina University, Viale F. Stagno D’Alcontres 31, 98166 Messina, Italy
4
Department of Pharmacological and Physiological Science, Saint Louis University, Saint Louis, MO 63104, USA
*
Author to whom correspondence should be addressed.
†
The authors equally contributed to this work.
Antioxidants 2020, 9(4), 297; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9040297
Submission received: 3 March 2020 / Revised: 29 March 2020 / Accepted: 31 March 2020 / Published: 2 April 2020
(This article belongs to the Special Issue Cellular Oxidative Stress)
Browse Figure
Versions Notes

Abstract

:
TBI (traumatic brain injury) is a major cause of death among youth in industrialized societies. Brain damage following traumatic injury is a result of direct and indirect mechanisms; indirect or secondary injury involves the initiation of an acute inflammatory response, including the breakdown of the blood–brain barrier (BBB), brain edema, infiltration of peripheral blood cells, and activation of resident immunocompetent cells, as well as the release of numerous immune mediators such as interleukins and chemotactic factors. TBI can cause changes in molecular signaling and cellular functions and structures, in addition to tissue damage, such as hemorrhage, diffuse axonal damages, and contusions. TBI typically disturbs brain functions such as executive actions, cognitive grade, attention, memory data processing, and language abilities. Animal models have been developed to reproduce the different features of human TBI, better understand its pathophysiology, and discover potential new treatments. For many years, the first approach to manage TBI has been treatment of the injured tissue with interventions designed to reduce the complex secondary-injury cascade. Several studies in the literature have stressed the importance of more closely examining injuries, including endothelial, microglia, astroglia, oligodendroglia, and precursor cells. Significant effort has been invested in developing neuroprotective agents. The aim of this work is to review TBI pathophysiology and existing and potential new therapeutic strategies in the management of inflammatory events and behavioral deficits associated with TBI.

1. Introduction

Traumatic brain injury (TBI) is defined as damage to the brain sustained after the application of external physical force that causes temporary or permanent functional or structural damage to the brain. TBI stands as a major cause of death among youth in industrialized societies [1]. Brain injury can be mild, moderate, and severe. It is not a distinct unit but a heterogeneous group of pathologies that are initiated by diverse mechanisms and have different survival consequences. Head injuries can be typically classified as closed or penetrating. A closed head injury is normally used to describe automobile accidents, assaults, and falls, while a penetrating injury usually results from gunshot or stab wounds. The use of explosive devices in military conflict has generated a category known as blast injury, which is rare in injury pattern and consideration [2]. The early injury resulting from an external force creates brain tissue destruction with parenchymal impairment, intracerebral hemorrhage, and axonal cutting. Likewise, the primary insult provokes secondary neurometabolic and neurochemical events, including inflammation, cerebral edema, disruption of the blood–brain barrier (BBB), oxidative stress, excitotoxicity, and mitochondrial and metabolic dysfunctions, that can extremely modify the outcome and the recovery patterns, persisting for months to years post-injury [3]. While animal models do not replicate all the physiological, anatomical, and neurobehavioral qualities of human TBI, they do provide important insight into pathophysiological mechanisms and provide the opportunity for translational research and development of efficacious neurotherapeutic interventions [3]. Animal TBI models can be catalogued as penetrating or non-penetrating with the principal difference being the occurrence of a direct deformation of the brain in penetrating injuries, thus provoking a focal or diffused damage at the injury site. Several experimental TBI models that have been designed are listed in Table 1 [4].
The golden age of TBI research has been encouraged, thanks to the prominence of repetitive concussions or mild TBIs (mTBIs). Because of the failure of translational therapies focused on moderate to severe TBI, novel therapies have developed, defining two typical approaches. The traditional neuroprotection-based approach is based on the identification of key actions implicated in the advancement of secondary injury whether in mild or severe TBI. In this method, treatment is started as soon as possible after injury. Another methodology, more studied in clinical trials of mTBI patients, is one of targeting symptoms such as vestibular/oculomotor disturbances, headache, sleep illnesses, post-traumatic stress disorder (PTSD), cognitive dysfunction, or others [3,5]. Based on these findings, in this review, we describe the current therapeutic strategies and new therapeutic approaches for the treatment of neuroinflammatory phenomena and TBI symptom management.

2. The Pathophysiology of TBI

The pathological manifestations of TBI are characterized by BBB alteration arising from cerebral ischemia, inflammation, and redox imbalances [6]. The early phase of trauma is characterized by disruption of the BBB, reduced or altered blood flow, and neuronal and glial damage [6]. Secondary injury starts from this primary injury and emerges hours, days, or months later, involves various events such as oxidative stress, modified calcium homeostasis, inflammation, and axonal damage, terminating in cellular degeneration, disturbed neural circuits, and impaired synaptic transmission and synaptic plasticity [6]. Behaviorally, these alterations manifest as post traumatic headache, depression, individuality changes, anxiety, aggression, and deficits in attentiveness, cognition, sensory processing, and communication [7,8,9].

3. TBI and Neurotoxicity

The neuroinflammation process that characterizes TBI progression can mobilize astrocytes, cytokines, chemokines, and immune cells toward the inflamed area, generating a pro-inflammatory reaction against insult in the brain. Nevertheless, in the chronic step, excessive activation of inflammatory mediators contributes to an injury in the brain circuit, which mainly co-occurs with secondary cell death in TBI. Different secondary cell death mechanisms drive TBI. Among these, excitotoxicity is a process characterized by increased levels of neurotransmitters and glutamate in the synaptic space that stimulate the surrounding nerve cells’ N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [10]. These receptors remain activated, favoring the influx of both sodium and calcium ions into cells [10]. In the cytosol, a high concentration of calcium ions determines the activation of protein phosphatases, phospholipases, and proteases. This activation damages DNA, structures, and membranes. In addition to apoptosis and necrosis, other forms of cell death may be active such as necroptosis, autophagy, etc. Overexcitement of glutamate receptors stimulates the production of nitrogen oxide (NO), free radicals, and pro-death transcription factors [11].

4. TBI and Oxidative Stress

Another cell death episode that happens shortly after a TBI is oxidative stress, accompanied by accumulation of both reactive nitrogen species and reactive oxygen species (RNS and ROS) [12]. High ROS levels cause lipoperoxidation of the cellular membrane, leading to dysfunction of mitochondria and oxidizing proteins, which may cause the alteration in the structure of membrane pores [13]. After the primary injury, endogenous inflammatory responses are activated with the invasion of monocytes, neutrophils, and lymphocytes through the BBB [14]. These produce prostaglandins, proinflammatory cytokines, free radicals, and several inflammatory elements, which up-regulate the levels of cell adhesion molecules and chemokines [14]. TBI activates microglia cells, which release proinflammatory cytokines and astrocytes that can up-regulate brain-derived neurotrophic factors. These, in turn, support and guide axons in recovery, increase cell production, and stimulate the long-term persistence of neurons by stopping cell death [15]. Moreover, extracellular glutamate levels are regulated by astrocytes, which also reduce glutamate excitotoxicity to neurons and other cells [16]. The pathophysiological heterogeneity detected in TBI patients may result from the nature, severity, and location of the primary injury, as well as conditions such as age, gender, genetics, and medications [17].

5. Biomarkers in TBI

The development of biomarkers that reveal the pathogenicity of TBI could be clinically useful to establish both diagnosis and prognosis. In particular, blood levels of the neuronal marker ubiquitin C-terminal hydrolaseL1 (UCHL1) and the astroglial marker glial fibrillary acidic protein (GFAP) represent important TBI biomarkers to support drug development and efficacy. Neurofilaments (NFs) are a major element of the axonal cytoskeleton, and play a fundamental role in structural support and regulating axon diameter [18]. Several works suggested that a phosphorylated axonal form of the heavy neurofilament (pNF-H) subunit is released from damaged neurons and might be a sensitive marker of axonal injury following TBI. In that regard, serum pNF-H was reported as a diagnostic tool to predict injury severity in patients who have suffered mild TBI, and it was helpful in understanding which patients required further CT imaging. In a recent report, simvastatin monotherapy supported neurological and functional recovery after experimental TBI, maybe via decreasing axonal injury as verified by a significant increase in the density of NF-H-positive profiles [18]. Recently, another type of pharmacodynamic/response biomarker was identified, specifically, cerebrospinal fluid (CSF) pharmaco/metabolomics are used to evaluate the influence of the combination of antioxidant N-acetylcysteine (NAC) and probenecid on the glutathione pathway after severe TBI in children [5]. Although NAC crosses the BBB, its CSF levels were only a small portion of those in blood. This is partly because NAC is speedily transported back into blood by the organic acid transporters 1 and 3. Probenecid is able to inhibit those transporters, improving brain NAC levels. Thus, the combination of probenecid and NAC produced a significant change in the CSF metabolomic markers of TBI [5]. However, the most important mTBI biomarkers are summarized in Table 2 [19].

6. Review of Existing Drug Interventions

The main contributor to secondary injury is the neuroinflammatory process principally characterized by chronic microglial stimulation, astrocytes activation, pro-inflammatory cytokines release, and oxidative stress. It was reported that it is fundamental to start the therapeutic interventions immediately following TBI, in particular within 4 h post-injury, to realize the best promising neuroprotective outcome [45]. Different therapeutic drugs with anti-inflammatory action in some experimental TBI studies are summarized in Table 3.
In particular, minocycline, a tetracycline derivative, is pharmaceutically efficient in many models of central nervous system (CNS) illnesses and reduces inflammatory and apoptotic processes [70]. A single dose of minocycline decreases lesion volume and ameliorates neurological outcomes linked to diminished microgliosis and interleukin-1β expression in a murine model of closed head injury [59]. Administration of minocycline reduces cerebral edema and improves long-term neurological retrieval [58]. Synthetic peroxisome proliferator-activated receptor (PPAR) agonists also serve as a potent anti-inflammatory, therapeutic agents for TBI [71,72]. Fenofibrate, a PPARα receptor agonist, diminishes cerebral edema, oxidative stress, and inflammation by reducing behavioral deficits after TBI induction [60]. Pioglitazone and rosiglitazone, also PPARγ receptor agonists, diminish microglial activation, enhance neuroprotective antioxidant proteins, and change histological and behavioral outcomes after TBI [61]. Another TBI treatment approach is to block glial proliferation by cell cycle inhibition. Throughout cyclic-dependent kinase (CDK) inhibition, flavopiridol is effective at reducing lesion volume and promoting sensorimotor cognition and recovery after TBI [73]. Roscovitine, another cell cycle inhibitor, also modulates CDKs and has been shown to moderate post-injury neuroinflammation and neurodegeneration [74]. In addition, among anti-oxidants, NAC could also act as an anti-inflammatory drug. Interestingly, NAC repressed NF-κB, IL-1β, TNFα, IL-6, edema and breakdown of the BBB three days after TBI [62].

6.1. Clinical Trials of Drugs with Anti-Inflammatory Effect

Of the therapeutic strategies reported above in Table 3 for TBI management, some have already progressed into clinical trials. Erythropoietin (EPO) demonstrated potential neuroprotective proprieties in most animal models of TBI [75]. However, in a clinical trial with 200 patients presenting severe TBI, EPO administration failed to improve outcomes at 6 months [76]. Thus, although EPO has proven neuroprotective effects in preclinical animal models of TBI, its helpfulness as a medical approach is questionable [75]. In addition, a phase I/II clinical trial also showed the safety and usefulness of minocycline administration for human TBI (NCT01058395) [77,78]. Furthermore, statins, which inhibit cholesterol biosynthesis, also can promote functional recovery following TBI in rodents [79]. Simvastatin inhibits caspase-3 activation and apoptotic cell death, thereby increasing neuronal rescue after TBI [80]. Simvastatin enhances the expression of several growth factors and stimulates neurogenesis, controlling restoration of mental function [81] and supporting functional improvement after TBI (3 months) [82] in rats. However, the United States Food and Drug Administration reported cognitive side effects associated with statins treatment [83]. Given these conflicting findings, more clinical trials are needed to confirm the neuroprotective benefits of statin treatment after TBI. The effects of rosuvastatin on TBI-stimulated cytokine alteration were evaluated in a phase I/II trial (NCT00990028) [77].
A previous study also reported that the TNF-α antagonist, etanercept, has been given perispinally for back pain and sciatica treatment [84]. Twelve patients with chronic neurological dysfunction after TBI who were treated with etanercept showed improvements in many parameters of motor, cognitive, sensory, and psychological performance at several time points [85]. A case report also showed that a single dose of perispinal etanercept produced an important improvement in a patient with neurological dysfunction present for more than 3 years after acute brain injury [86]. Importantly, NAC also has shown potential in preventing sequelae from blast-induced mild TBI, apparently via its antioxidant capacity in the brain [87]. The safety and potential therapeutic efficacy of NAC was effectively evaluated in 41 military personnel who had a mild blast-induced TBI [87]. A phase I randomized clinical trial reported the effects of NAC in combination with an adjuvant probenecid for treatment of severe TBI in children [88].
Progesterone has also demonstrated helpful actions in animal models of TBI and clinical improvement in two phase II randomized, controlled trials [89]. Despite positive effects from preclinical studies and from two positive phase II clinical trials, two big phase III clinical trials of progesterone treatment of acute TBI ended with negative data, respectively, SYNAPSE (NCT01143064) and ProTECT III (NCT00822900) [89]; therefore, the results continue to fail in the field of TBI clinical trials.

6.2. Therapeutic Strategies to manage Neuronal Recovery and Neurobehavioral Sequelae after Injury

TBI progression affects the quality of life of a lot of people causing anxiety, agitation, memory deficiencies, and behavioral changes. Pharmacological compounds that increase cyclic 3’,5’-adenosine monophosphate (cAMP) signaling such as phosphodiesterase (PDE) inhibitors (rolipram, dipyridamole, BC11-38) [90,91], selective serotonin reuptake inhibitors (e.g., fluoxetine) [92], and serotonin-dopamine reuptake inhibitors (e.g., UWA-121), could help in brain repair, recovery of neuronal function [93], and alleviation of disabilities after injury including cognitive deficits, changes in personality, and increased rates of psychiatric illness. Table 4 gives an overview of the most frequently used treatments in the management of neuropsychiatric, neurocognitive, and neurobehavioral sequelae of injury to the brain [94].

7. New Therapeutic Strategies

Studying strategies to treat TBI-induced neuroinflammation requires understanding the usual mechanisms, including the tendency to protect against inflammation. Chronic inflammatory events can initiative a program of resolution that involves the release of lipid mediators capable of extinguishing inflammation [95]. Among these are fatty acid amides N-acylethanolamines (NAEs), including N-arachidonoylethanolamine (endocannabinoid), and the congeners N-stearoylethanolamine, N-oleoylethanolamine, and plus N-palmitoylethanolamine (PEA or palmitoylethanolamide) [96]. Several studies documented the positive effects of exogenously dispensed PEA in experimental models of TBI, spinal cord injuries, pain, cerebral ischemia, and Parkinson’s and Alzheimer diseases [97]. PEA has no unfavorable effects at pharmacological doses [97]. In addition, several experimental works showed the beneficial effects of new PEA formulations (micronized or ultramicronized) in carrageenan-induced inflammation [98] on cognitive decline associated to neuropathic pain [99] in an Alzheimer disease model [100], tibia fracture mouse model [101], and diabetic neuropathy [102]. Recent observational clinical studies reported the beneficial use of ultramicronized PEA as an add-on therapy in patients suffering from low back pain [103] as well as in patients suffering from fibromyalgia syndrome (FMS) [104]. In addition, interestingly, a co-ultramicronized PEA/luteolin (PEALUT) composite (10:1 mass ratio) displayed important neuroprotective effects in preclinical studies for various conditions (e.g., TBI, arthritis, depression, neurogenesis, Parkinson’s and Alzheimer’s diseases, and spinal cord injury) and, more recently, in experimental models of autism and vascular dementia [105,106,107,108,109,110,111,112,113]. In addition, Caltagirone et al. [114] showed that co-ultra PEALUT reduced brain injury in a rat model of Middle Cerebral Artery Occlusion (MCAO) and, more interestingly, in a clinical study. A group of 250 patients with stroke was administered a pharmaceutical formulation of co-ultraPEALut (Glialia®) for 60 days. At baseline and after 30 days of treatment, the patients showed improved neurological status, cognitive functions, spasticity, pain, and ability to perform activities of daily living. Despite its observational nature, the authors of [114] first described administration of co-ultraPEALut to human stroke patients, resulting in important clinical improvements. Inhibition of PEA degradation by affecting its primary catabolic enzyme, NAE-hydrolyzing acid amidase (NAAA), can also present an unconventional method to manage neuroinflammation. A recent study reported that pharmacological modulation and not blocking specific amidases for nacylamides, such as NAAA, can serve as a new approach to preserve the PEA function of maintaining cellular homeostasis through its quick, on-demand synthesis and correspondingly fast degradation. The most recent investigations reported that pharmacological changes in NAAA can be found with the oxazoline of PEA (PEA-OXA) [115]. In rat paws and the carrageenan (CAR) model, PEA-OXA accomplishes significantly better anti-inflammatory action than PEA [116]. In addition, Impellizzeri et al. [117] demonstrated the neuroprotective effects of PEA-OXA in spinal and brain injuries. PEA and new formulations of PEA, therefore, can present new therapeutic strategies in the management of neuroinflammation related to TBI and other CNS disorders.

8. Biologics

In addition to pharmacologic interventions for TBI, promising, innovative developments based on preclinical findings draw on the practice of biologics (e.g., gene therapy, eRNA, DNA, microRNA, antagomirs, peptide therapy, stem cells, exogenous growth factors, and peptides) [118]. Neural and mesenchymal stem cell therapy displays neuroregenerative and neurorestorative potential [119]. A recent work discussed novel associations in drug therapies that have been examined together with stem cells to overcome the restrictions allied with stem cell transplantation and to progress functional recuperation and brain repair post-TBI. To date, progesterone (clinical trials phase I and II), statins, and erythropoietin demonstrated the most encouraging results for the endogenous stem-cells-mediated repair [3].
Growth factors, moreover, draw significant attention for their neuroprotective and neuroregenerative efficiency. In particular, vascular endothelial growth factor (VEGF), human fibroblast growth factor 2 (FGF2), and brain-derived neurotrophic factor have been shown to improve neuronal survival when accompanying transplanted stem cells in unhealthy and injured models [120]. VEGF and FGF2 also improve functional outcomes in the preclinical model of TBI [121], while nerve growth factor decreases brain edema and reduces beta-amyloid production after TBI [122,123]. In addition, gene therapy and viral and non-viral-mediated delivery systems mark progress in managing neuronal injury. Adeno-associated viral vectors present attractive instruments for re-expressing and over-expressing genes in neurodegenerative disorders [124]. Micelles, polyethyleneimine (PEI)-coated micelles, and further micelle-like nanoparticles also might contain genetic material (DNA or RNA) and be an appealing approach for gene therapy due to their low or no immunogenicity. They can also be inserted into the brain via intranasal delivery, eliminating the need for direct intracerebral drug delivery. Nanoparticles, such as micelles, have been studied in a preclinical model of TBI to distribute DNA intranasally [125,126].

9. Neuropsychological Rehabilitation (NR) and Neurotherapy

TBI typically disturbs brain functions such as executive actions, cognitive grade, attention, memory, data processing, and language skills. Neuropsychological rehabilitation (NR) is aimed at ameliorating cognitive, emotional, psychosocial, and behavioral deficits caused by an insult to the brain. The NR of TBI patients represents a global problem, one with which modern medicine is grappling [127]. One of the central motives is the deficiency of strictly delineated theoretic supports for therapy and the means for the incessant repressing of their effects. Every brain damage causes conflicts with the so-called electric and chemical brain language, altering the space of prevailing networks and the action of neurotransmitters, which provoke a decline of the brain systems. Some studies confirmed that neurotherapy, also called neurofeedback therapy (NFT), can promote neuroplasticity [128]. NFT was shown to excite meaningful variants in structural and functional connectivity among young patients moderate TBI [127]. Transcranial magnetic stimulation (TMS) as a way of non-invasive direct modulation of neuronal activity is verysuitable for the treatment of TBI [127]. Recently, new tools for the evaluation of brain neuromarkers in TBI were developed. These include quantitative electroencephalography (EEG) to detect cortical self-regulation of the brain and event-related potentials for the flow of information in the brain [127]. Nevertheless, despite neurotherapy being very important for TBI management, more research projects are needed (Figure 1).

10. Conclusions

Neuroprotective approaches are the focus for TBI management, particularly methods to classify and target specific mechanisms involved in the complex secondary-injury cascade. The literature shows that neuroprotective approaches historically have been dominated by a neurocentric view, making alteration of neuronal-based injury mechanisms the primary or exclusive focus of neuroprotective strategies. The data in the literature, therefore, stress the relevance of more broadly viewing injury as comprising endothelial, microglia, astroglia, oligodendroglia, and precursor cells. Recent neuroprotection methods describe this multifaceted structure and interplay, highlighting therapeutic approaches that stimulate the recovery and optimal functioning of non-neuronal cells and inhibit the underlying mechanism of neuronal cell death. Several encouraging, recently developed treatments include neuroprotective, neurorestorative, and anti-inflammatory agents (for example PEA formulations or biologics). In addition, researchers have reported the need for developing new neurothechnologies and the neuromarkers of brain injuries to enable a correct diagnosis and, as a result, appropriate selection of methods for neuropsychological rehabilitation including neurotherapy. However, due to the difficulty and heterogeneity of brain injuries, post-TBI neural therapies are still facing several challenges.

Author Contributions

All authors have read and agreed to the published version of the manuscript. R.C. and D.I. were involved in the design and intellectual concept of the study; M.C. performed the literature search. S.C. designed the study and critically revised the manuscript.

Funding

This research received no external funding.

Acknowledgments

The writers would like to thank Maria Antonietta Medici for brilliant methodical assistance during this research, Francesco Soraci for office support and assistance, and also Valentina Malvagni for editorial assistance with the text.

Conflicts of Interest

Salvatore Cuzzocrea is a co-inventor on patent WO2013121449 A8 (Epitech Group Srl), which deals with methods and compositions for the modulation of amidases capable of hydrolyzing N-acylethanolamines that are employable in the treatment of inflammatory diseases. This invention is wholly unrelated to the present study. Moreover, Salvatore Cuzzocrea is also, with the Epitech Group, a co-inventor on the following patents: EP 2 821 083; MI2014 A001495; 102015000067344, that are unrelated to the study. The remaining authors report no conflict of interest.

References

  1. Kline, A.E.; Leary, J.B.; Radabaugh, H.L.; Cheng, J.P.; Bondi, C.O. Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better? Prog. Neurobiol. 2016, 142, 45–67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Logsdon, A.F.; Lucke-Wold, B.P.; Turner, R.C.; Huber, J.D.; Rosen, C.L.; Simpkins, J.W. Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury. Compr. Physiol. 2015, 5, 1147–1160. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Zibara, K.; Ballout, N.; Mondello, S.; Karnib, N.; Ramadan, N.; Omais, S.; Nabbouh, A.; Caliz, D.; Clavijo, A.; Hu, Z.; et al. Combination of drug and stem cells neurotherapy: Potential interventions in neurotrauma and traumatic brain injury. Neuropharmacology 2019, 145, 177–198. [Google Scholar] [CrossRef] [PubMed]
  4. Xiong, Y.; Mahmood, A.; Chopp, M. Animal models of traumatic brain injury. Nat. Rev. Neurosci. 2013, 14, 128–142. [Google Scholar] [CrossRef] [Green Version]
  5. Kochanek, P.M.; Jackson, T.C.; Jha, R.; Clark, R.S.B.; Okonkwo, D.O.; Bayir, H.; Poloyac, S.M.; Wagner, A.M.D.; Empey, P.E.; Conley, Y.P.; et al. Paths to successful translation of new therapies for severe TBI in the golden age of traumatic brain injury research: A Pittsburgh vision. J. Neurotrauma 2018. [Google Scholar] [CrossRef]
  6. Greve, M.W.; Zink, B.J. Pathophysiology of traumatic brain injury. Mt. Sinai J. Med. 2009, 76, 97–104. [Google Scholar] [CrossRef]
  7. Chan, T.L.H.; Woldeamanuel, Y.W. Exploring naturally occurring clinical subgroups of post-traumatic headache. J. Headache Pain 2020, 21, 12. [Google Scholar] [CrossRef]
  8. Larsen, E.L.; Ashina, H.; Iljazi, A.; Al-Khazali, H.M.; Seem, K.; Ashina, M.; Ashina, S.; Schytz, H.W. Acute and preventive pharmacological treatment of post-traumatic headache: A systematic review. J. Headache Pain 2019, 20, 98. [Google Scholar] [CrossRef]
  9. Bedaso, A.; Geja, E.; Ayalew, M.; Oltaye, Z.; Duko, B. Post-concussion syndrome among patients experiencing head injury attending emergency department of Hawassa University Comprehensive specialized hospital, Hawassa, southern Ethiopia. J. Headache Pain 2018, 19, 112. [Google Scholar] [CrossRef]
  10. Niyonkuru, C.; Wagner, A.K.; Ozawa, H.; Amin, K.; Goyal, A.; Fabio, A. Group-based trajectory analysis applications for prognostic biomarker model development in severe TBI: A practical example. J. Neurotrauma 2013, 30, 938–945. [Google Scholar] [CrossRef]
  11. Wang, Y.; Qin, Z.H. Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis Int. J. Program. Cell Death 2010, 15, 1382–1402. [Google Scholar] [CrossRef] [PubMed]
  12. Dasuri, K.; Zhang, L.; Keller, J.N. Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radic. Biol. Med. 2013, 62, 170–185. [Google Scholar] [CrossRef] [PubMed]
  13. Mutinati, M.; Pantaleo, M.; Roncetti, M.; Piccinno, M.; Rizzo, A.; Sciorsci, R.L. Oxidative stress in neonatology: A review. Reprod. Domest. Anim. 2014, 49, 7–16. [Google Scholar] [CrossRef] [PubMed]
  14. Fluiter, K.; Opperhuizen, A.L.; Morgan, B.P.; Baas, F.; Ramaglia, V. Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. J. Immunol. 2014, 192, 2339–2348. [Google Scholar] [CrossRef] [Green Version]
  15. Wu, L.Y.; Bao, X.Q.; Sun, H.; Zhang, D. Scavenger receptor on astrocytes and its relationship with neuroinflammation. Acta Acad. Med. Sin. 2014, 36, 330–335. [Google Scholar] [CrossRef]
  16. Kumar, A.; Loane, D.J. Neuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention. Brain Behav. Immun. 2012, 26, 1191–1201. [Google Scholar] [CrossRef]
  17. Margulies, S.; Hicks, R. Combination therapies for traumatic brain injury: Prospective considerations. J. Neurotrauma 2009, 26, 925–939. [Google Scholar] [CrossRef]
  18. Yang, Z.; Zhu, T.; Mondello, S.; Akel, M.; Wong, A.T.; Kothari, I.M.; Lin, F.; Shear, D.A.; Gilsdorf, J.S.; Leung, L.Y.; et al. Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury: An Operation Brain Trauma Therapy Study. J. Neurotrauma 2019, 36, 348–359. [Google Scholar] [CrossRef]
  19. Kim, H.J.; Tsao, J.W.; Stanfill, A.G. The current state of biomarkers of mild traumatic brain injury. JCI Insight 2018, 3. [Google Scholar] [CrossRef]
  20. Hagos, F.T.; Empey, P.E.; Wang, P.; Ma, X.; Poloyac, S.M.; Bayir, H.; Kochanek, P.M.; Bell, M.J.; Clark, R.S.B. Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury. Crit. Care Med. 2018, 46, 1471–1479. [Google Scholar] [CrossRef]
  21. Higashida, T.; Kreipke, C.W.; Rafols, J.A.; Peng, C.; Schafer, S.; Schafer, P.; Ding, J.Y.; Dornbos, D., 3rd; Li, X.; Guthikonda, M.; et al. The role of hypoxia-inducible factor-1alpha, aquaporin-4, and matrix metalloproteinase-9 in blood-brain barrier disruption and brain edema after traumatic brain injury. J. Neurosurg. 2011, 114, 92–101. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Pan, R.; Yu, K.; Weatherwax, T.; Zheng, H.; Liu, W.; Liu, K.J. Blood Occludin Level as a Potential Biomarker for Early Blood Brain Barrier Damage Following Ischemic Stroke. Sci. Rep. 2017, 7, 40331. [Google Scholar] [CrossRef] [PubMed]
  23. Zongo, D.; Ribereau-Gayon, R.; Masson, F.; Laborey, M.; Contrand, B.; Salmi, L.R.; Montaudon, D.; Beaudeux, J.L.; Meurin, A.; Dousset, V.; et al. S100-B protein as a screening tool for the early assessment of minor head injury. Ann. Emerg. Med. 2012, 59, 209–218. [Google Scholar] [CrossRef] [PubMed]
  24. Neher, M.D.; Keene, C.N.; Rich, M.C.; Moore, H.B.; Stahel, P.F. Serum biomarkers for traumatic brain injury. South. Med. J. 2014, 107, 248–255. [Google Scholar] [CrossRef]
  25. Kochanek, P.M.; Dixon, C.E.; Shellington, D.K.; Shin, S.S.; Bayir, H.; Jackson, E.K.; Kagan, V.E.; Yan, H.Q.; Swauger, P.V.; Parks, S.A.; 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. J. Neurotrauma 2013, 30, 920–937. [Google Scholar] [CrossRef] [Green Version]
  26. Pham, N.; Akonasu, H.; Shishkin, R.; Taghibiglou, C. Plasma soluble prion protein, a potential biomarker for sport-related concussions: A pilot study. PLoS ONE 2015, 10, e0117286. [Google Scholar] [CrossRef]
  27. Rubenstein, R.; Chang, B.; Yue, J.K.; Chiu, A.; Winkler, E.A.; Puccio, A.M.; Diaz-Arrastia, R.; Yuh, E.L.; Mukherjee, P.; Valadka, A.B.; et al. Comparing Plasma Phospho Tau, Total Tau, and Phospho Tau-Total Tau Ratio as Acute and Chronic Traumatic Brain Injury Biomarkers. JAMA Neurol. 2017, 74, 1063–1072. [Google Scholar] [CrossRef]
  28. Papa, L.; Lewis, L.M.; Silvestri, S.; Falk, J.L.; Giordano, P.; Brophy, G.M.; Demery, J.A.; Liu, M.C.; Mo, J.; Akinyi, L.; 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. J. Trauma Acute Care Surg. 2012, 72, 1335–1344. [Google Scholar] [CrossRef] [Green Version]
  29. Mondello, S.; Linnet, A.; Buki, A.; Robicsek, S.; Gabrielli, A.; Tepas, J.; Papa, L.; Brophy, G.M.; Tortella, F.; Hayes, R.L.; et al. Clinical utility of serum levels of ubiquitin C-terminal hydrolase as a biomarker for severe traumatic brain injury. Neurosurgery 2012, 70, 666–675. [Google Scholar] [CrossRef] [Green Version]
  30. Puvenna, V.; Brennan, C.; Shaw, G.; Yang, C.; Marchi, N.; Bazarian, J.J.; Merchant-Borna, K.; Janigro, D. Significance of ubiquitin carboxy-terminal hydrolase L1 elevations in athletes after sub-concussive head hits. PLoS ONE 2014, 9, e96296. [Google Scholar] [CrossRef] [Green Version]
  31. Gatson, J.W.; Barillas, J.; Hynan, L.S.; Diaz-Arrastia, R.; Wolf, S.E.; Minei, J.P. Detection of neurofilament-H in serum as a diagnostic tool to predict injury severity in patients who have suffered mild traumatic brain injury. J. Neurosurg. 2014, 121, 1232–1238. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Rossi, D.; Volanti, P.; Brambilla, L.; Colletti, T.; Spataro, R.; La Bella, V. CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis. J. Neurol. 2018, 265, 510–521. [Google Scholar] [CrossRef] [PubMed]
  33. Bohmer, A.E.; Oses, J.P.; Schmidt, A.P.; Peron, C.S.; Krebs, C.L.; Oppitz, P.P.; D’Avila, T.T.; Souza, D.O.; Portela, L.V.; Stefani, M.A. Neuron-specific enolase, S100B, and glial fibrillary acidic protein levels as outcome predictors in patients with severe traumatic brain injury. Neurosurgery 2011, 68, 1624–1630. [Google Scholar] [CrossRef] [PubMed]
  34. Lei, J.; Gao, G.; Feng, J.; Jin, Y.; Wang, C.; Mao, Q.; Jiang, J. Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: A prospective cohort study. Crit. Care 2015, 19, 362. [Google Scholar] [CrossRef] [Green Version]
  35. Berger, R.P.; Adelson, P.D.; Pierce, M.C.; Dulani, T.; Cassidy, L.D.; Kochanek, P.M. Serum neuron-specific enolase, S100B, and myelin basic protein concentrations after inflicted and noninflicted traumatic brain injury in children. J. Neurosurg. 2005, 103, 61–68. [Google Scholar] [CrossRef]
  36. Mondello, S.; Robicsek, S.A.; Gabrielli, A.; Brophy, G.M.; Papa, L.; Tepas, J.; Robertson, C.; Buki, A.; Scharf, D.; Jixiang, M.; et al. alphaII-spectrin breakdown products (SBDPs): Diagnosis and outcome in severe traumatic brain injury patients. J. Neurotrauma 2010, 27, 1203–1213. [Google Scholar] [CrossRef] [Green Version]
  37. Zhao, J.; Xi, G.; Wu, G.; Keep, R.F.; Hua, Y. Deferoxamine Attenuated the Upregulation of Lipocalin-2 Induced by Traumatic Brain Injury in Rats. Acta Neurochir. Suppl. 2016, 121, 291–294. [Google Scholar] [CrossRef]
  38. Zhao, J.; Chen, H.; Zhang, M.; Zhang, Y.; Qian, C.; Liu, Y.; He, S.; Zou, Y.; Liu, H. Early expression of serum neutrophil gelatinase-associated lipocalin (NGAL) is associated with neurological severity immediately after traumatic brain injury. J. Neurol. Sci. 2016, 368, 392–398. [Google Scholar] [CrossRef]
  39. Semple, B.D.; Bye, N.; Rancan, M.; Ziebell, J.M.; Morganti-Kossmann, M.C. Role of CCL2 (MCP-1) in traumatic brain injury (TBI): Evidence from severe TBI patients and CCL2-/- mice. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2010, 30, 769–782. [Google Scholar] [CrossRef]
  40. Buttram, S.D.; Wisniewski, S.R.; Jackson, E.K.; Adelson, P.D.; Feldman, K.; Bayir, H.; Berger, R.P.; Clark, R.S.; Kochanek, P.M. Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: Effects of moderate hypothermia. J. Neurotrauma 2007, 24, 1707–1717. [Google Scholar] [CrossRef]
  41. Berger, R.P.; Ta’asan, S.; Rand, A.; Lokshin, A.; Kochanek, P. Multiplex assessment of serum biomarker concentrations in well-appearing children with inflicted traumatic brain injury. Pediatric Res. 2009, 65, 97–102. [Google Scholar] [CrossRef] [PubMed]
  42. Oliver, J.; Abbas, K.; Lightfoot, J.T.; Baskin, K.; Collins, B.; Wier, D.; Bramhall, J.P.; Huang, J.; Puschett, J.B. Comparison of Neurocognitive Testing and the Measurement of Marinobufagenin in Mild Traumatic Brain Injury: A Preliminary Report. J. Exp. Neurosci. 2015, 9, 67–72. [Google Scholar] [CrossRef] [PubMed]
  43. Lee, H.H.; Yeh, C.T.; Ou, J.C.; Ma, H.P.; Chen, K.Y.; Chang, C.F.; Lai, J.H.; Liao, K.H.; Lin, C.M.; Lin, S.Y.; et al. The Association of Apolipoprotein E Allele 4 Polymorphism with the Recovery of Sleep Disturbance after Mild Traumatic Brain Injury. Acta Neurol. Taiwanica 2017, 26, 13–19. [Google Scholar]
  44. Hayes, J.P.; Reagan, A.; Logue, M.W.; Hayes, S.M.; Sadeh, N.; Miller, D.R.; Verfaellie, M.; Wolf, E.J.; McGlinchey, R.E.; Milberg, W.P.; et al. BDNF genotype is associated with hippocampal volume in mild traumatic brain injury. Genes Brain Behav. 2018, 17, 107–117. [Google Scholar] [CrossRef] [PubMed]
  45. Sullivan, P.G.; Sebastian, A.H.; Hall, E.D. Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury. J. Neurotrauma 2011, 28, 311–318. [Google Scholar] [CrossRef] [PubMed]
  46. Holmin, S.; Mathiesen, T. Dexamethasone and colchicine reduce inflammation and delayed oedema following experimental brain contusion. Acta Neurochir. 1996, 138, 418–424. [Google Scholar] [CrossRef]
  47. Zhang, Z.; Zhang, Z.; Artelt, M.; Burnet, M.; Schluesener, H.J. Dexamethasone attenuates early expression of three molecules associated with microglia/macrophages activation following rat traumatic brain injury. Acta Neuropathol. 2007, 113, 675–682. [Google Scholar] [CrossRef]
  48. Hakan, T.; Toklu, H.Z.; Biber, N.; Ozevren, H.; Solakoglu, S.; Demirturk, P.; Aker, F.V. Effect of COX-2 inhibitor meloxicam against traumatic brain injury-induced biochemical, histopathological changes and blood-brain barrier permeability. Neurol. Res. 2010, 32, 629–635. [Google Scholar] [CrossRef]
  49. Siopi, E.; Cho, A.H.; Homsi, S.; Croci, N.; Plotkine, M.; Marchand-Leroux, C.; Jafarian-Tehrani, M. Minocycline restores sAPPalpha levels and reduces the late histopathological consequences of traumatic brain injury in mice. J. Neurotrauma 2011, 28, 2135–2143. [Google Scholar] [CrossRef]
  50. Thau-Zuchman, O.; Shohami, E.; Alexandrovich, A.G.; Trembovler, V.; Leker, R.R. The anti-inflammatory drug carprofen improves long-term outcome and induces gliogenesis after traumatic brain injury. J. Neurotrauma 2012, 29, 375–384. [Google Scholar] [CrossRef]
  51. Chao, P.K.; Lu, K.T.; Jhu, J.Y.; Wo, Y.Y.; Huang, T.C.; Ro, L.S.; Yang, Y.L. Indomethacin protects rats from neuronal damage induced by traumatic brain injury and suppresses hippocampal IL-1beta release through the inhibition of Nogo-A expression. J. Neuroinflamm. 2012, 9, 121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Girgis, H.; Palmier, B.; Croci, N.; Soustrat, M.; Plotkine, M.; Marchand-Leroux, C. Effects of selective and non-selective cyclooxygenase inhibition against neurological deficit and brain oedema following closed head injury in mice. Brain Res. 2013, 1491, 78–87. [Google Scholar] [CrossRef] [PubMed]
  53. Clond, M.A.; Lee, B.S.; Yu, J.J.; Singer, M.B.; Amano, T.; Lamb, A.W.; Drazin, D.; Kateb, B.; Ley, E.J.; Yu, J.S. Reactive oxygen species-activated nanoprodrug of Ibuprofen for targeting traumatic brain injury in mice. PLoS ONE 2013, 8, e61819. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Cheong, C.U.; Chang, C.P.; Chao, C.M.; Cheng, B.C.; Yang, C.Z.; Chio, C.C. Etanercept attenuates traumatic brain injury in rats by reducing brain TNF- alpha contents and by stimulating newly formed neurogenesis. Mediat. Inflamm. 2013, 2013, 620837. [Google Scholar] [CrossRef] [Green Version]
  55. Campolo, M.; Ahmad, A.; Crupi, R.; Impellizzeri, D.; Morabito, R.; Esposito, E.; Cuzzocrea, S. Combination therapy with melatonin and dexamethasone in a mouse model of traumatic brain injury. J. Endocrinol. 2013, 217, 291–301. [Google Scholar] [CrossRef]
  56. Luo, C.L.; Li, Q.Q.; Chen, X.P.; Zhang, X.M.; Li, L.L.; Li, B.X.; Zhao, Z.Q.; Tao, L.Y. Lipoxin A4 attenuates brain damage and downregulates the production of pro-inflammatory cytokines and phosphorylated mitogen-activated protein kinases in a mouse model of traumatic brain injury. Brain Res. 2013, 1502, 1–10. [Google Scholar] [CrossRef]
  57. Harrison, J.L.; Rowe, R.K.; O’Hara, B.F.; Adelson, P.D.; Lifshitz, J. Acute over-the-counter pharmacological intervention does not adversely affect behavioral outcome following diffuse traumatic brain injury in the mouse. Exp. Brain Res. 2014, 232, 2709–2719. [Google Scholar] [CrossRef]
  58. Homsi, S.; Piaggio, T.; Croci, N.; Noble, F.; Plotkine, M.; Marchand-Leroux, C.; Jafarian-Tehrani, M. Blockade of acute microglial activation by minocycline promotes neuroprotection and reduces locomotor hyperactivity after closed head injury in mice: A twelve-week follow-up study. J. Neurotrauma 2010, 27, 911–921. [Google Scholar] [CrossRef]
  59. Bye, N.; Habgood, M.D.; Callaway, J.K.; Malakooti, N.; Potter, A.; Kossmann, T.; Morganti-Kossmann, M.C. Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration. Exp. Neurol. 2007, 204, 220–233. [Google Scholar] [CrossRef]
  60. Besson, V.C.; Chen, X.R.; Plotkine, M.; Marchand-Verrecchia, C. Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, exerts neuroprotective effects in traumatic brain injury. Neurosci. Lett. 2005, 388, 7–12. [Google Scholar] [CrossRef]
  61. Sauerbeck, A.; Gao, J.; Readnower, R.; Liu, M.; Pauly, J.R.; Bing, G.; Sullivan, P.G. Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury. Exp. Neurol. 2011, 227, 128–135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Chen, G.; Shi, J.; Hu, Z.; Hang, C. Inhibitory effect on cerebral inflammatory response following traumatic brain injury in rats: A potential neuroprotective mechanism of N-acetylcysteine. Mediat. Inflamm. 2008, 2008, 716458. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Bergold, P.J. Treatment of traumatic brain injury with anti-inflammatory drugs. Exp. Neurol. 2016, 275 Pt 3, 367–380. [Google Scholar] [CrossRef]
  64. Chen, G.; Shi, J.X.; Hang, C.H.; Xie, W.; Liu, J.; Liu, X. Inhibitory effect on cerebral inflammatory agents that accompany traumatic brain injury in a rat model: A potential neuroprotective mechanism of recombinant human erythropoietin (rhEPO). Neurosci. Lett. 2007, 425, 177–182. [Google Scholar] [CrossRef] [PubMed]
  65. Xu, F.; Yu, Z.Y.; Ding, L.; Zheng, S.Y. Experimental studies of erythropoietin protection following traumatic brain injury in rats. Exp. Med. 2012, 4, 977–982. [Google Scholar] [CrossRef] [Green Version]
  66. Chen, G.; Zhang, S.; Shi, J.; Ai, J.; Qi, M.; Hang, C. Simvastatin reduces secondary brain injury caused by cortical contusion in rats: Possible involvement of TLR4/NF-kappaB pathway. Exp. Neurol. 2009, 216, 398–406. [Google Scholar] [CrossRef]
  67. Li, B.; Mahmood, A.; Lu, D.; Wu, H.; Xiong, Y.; Qu, C.; Chopp, M. Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta level after traumatic brain injury. Neurosurgery 2009, 65, 179–185. [Google Scholar] [CrossRef] [Green Version]
  68. Si, D.; Li, J.; Liu, J.; Wang, X.; Wei, Z.; Tian, Q.; Wang, H.; Liu, G. Progesterone protects blood-brain barrier function and improves neurological outcome following traumatic brain injury in rats. Exp. Med. 2014, 8, 1010–1014. [Google Scholar] [CrossRef] [Green Version]
  69. Cutler, S.M.; Cekic, M.; Miller, D.M.; Wali, B.; VanLandingham, J.W.; Stein, D.G. Progesterone improves acute recovery after traumatic brain injury in the aged rat. J. Neurotrauma 2007, 24, 1475–1486. [Google Scholar] [CrossRef]
  70. Orsucci, D.; Calsolaro, V.; Mancuso, M.; Siciliano, G. Neuroprotective effects of tetracyclines: Molecular targets, animal models and human disease. CNS Neurol. Disord. Drug Targets 2009, 8, 222–231. [Google Scholar] [CrossRef]
  71. Villapol, S.; Yaszemski, A.K.; Logan, T.T.; Sanchez-Lemus, E.; Saavedra, J.M.; Symes, A.J. Candesartan, an angiotensin II AT(1)-receptor blocker and PPAR-gamma agonist, reduces lesion volume and improves motor and memory function after traumatic brain injury in mice. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 2012, 37, 2817–2829. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Mandrekar-Colucci, S.; Sauerbeck, A.; Popovich, P.G.; McTigue, D.M. PPAR agonists as therapeutics for CNS trauma and neurological diseases. ASN Neuro 2013, 5, e00129. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Di Giovanni, S.; Movsesyan, V.; Ahmed, F.; Cernak, I.; Schinelli, S.; Stoica, B.; Faden, A.I. Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury. Proc. Natl. Acad. Sci. USA 2005, 102, 8333–8338. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Kabadi, S.V.; Stoica, B.A.; Byrnes, K.R.; Hanscom, M.; Loane, D.J.; Faden, A.I. Selective CDK inhibitor limits neuroinflammation and progressive neurodegeneration after brain trauma. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2012, 32, 137–149. [Google Scholar] [CrossRef] [Green Version]
  75. Peng, W.; Xing, Z.; Yang, J.; Wang, Y.; Wang, W.; Huang, W. The efficacy of erythropoietin in treating experimental traumatic brain injury: A systematic review of controlled trials in animal models. J. Neurosurg. 2014, 121, 653–664. [Google Scholar] [CrossRef] [Green Version]
  76. Robertson, C.S.; Hannay, H.J.; Yamal, J.M.; Gopinath, S.; Goodman, J.C.; Tilley, B.C.; Epo Severe, T.B.I.T.I.; Baldwin, A.; Rivera Lara, L.; Saucedo-Crespo, H.; et al. Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: A randomized clinical trial. JAMA 2014, 312, 36–47. [Google Scholar] [CrossRef]
  77. Xiong, Y.; Zhang, Y.; Mahmood, A.; Chopp, M. Investigational agents for treatment of traumatic brain injury. Expert Opin. Investig. Drugs 2015, 24, 743–760. [Google Scholar] [CrossRef] [Green Version]
  78. Meythaler, J.; Fath, J.; Fuerst, D.; Zokary, H.; Freese, K.; Martin, H.B.; Reineke, J.; Peduzzi-Nelson, J.; Roskos, P.T. Safety and feasibility of minocycline in treatment of acute traumatic brain injury. Brain Inj. 2019, 33, 679–689. [Google Scholar] [CrossRef]
  79. Lu, D.; Goussev, A.; Chen, J.; Pannu, P.; Li, Y.; Mahmood, A.; Chopp, M. Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury. J. Neurotrauma 2004, 21, 21–32. [Google Scholar] [CrossRef]
  80. Wu, H.; Lu, D.; Jiang, H.; Xiong, Y.; Qu, C.; Li, B.; Mahmood, A.; Zhou, D.; Chopp, M. Increase in phosphorylation of Akt and its downstream signaling targets and suppression of apoptosis by simvastatin after traumatic brain injury. J. Neurosurg. 2008, 109, 691–698. [Google Scholar] [CrossRef]
  81. Wu, H.; Lu, D.; Jiang, H.; Xiong, Y.; Qu, C.; Li, B.; Mahmood, A.; Zhou, D.; Chopp, M. Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/Akt pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J. Neurotrauma 2008, 25, 130–139. [Google Scholar] [CrossRef] [PubMed]
  82. Mahmood, A.; Goussev, A.; Kazmi, H.; Qu, C.; Lu, D.; Chopp, M. Long-term benefits after treatment of traumatic brain injury with simvastatin in rats. Neurosurgery 2009, 65, 187–191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Head, B.P.; Patel, H.H.; Insel, P.A. Interaction of membrane/lipid rafts with the cytoskeleton: Impact on signaling and function: Membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim. Biophys. Acta 2014, 1838, 532–545. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Tobinick, E. Perispinal etanercept: A new therapeutic paradigm in neurology. Expert Rev. Neurother. 2010, 10, 985–1002. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Tobinick, E.; Kim, N.M.; Reyzin, G.; Rodriguez-Romanacce, H.; DePuy, V. Selective TNF inhibition for chronic stroke and traumatic brain injury: An observational study involving 629 consecutive patients treated with perispinal etanercept. CNS Drugs 2012, 26, 1051–1070. [Google Scholar] [CrossRef]
  86. Tobinick, E.; Rodriguez-Romanacce, H.; Levine, A.; Ignatowski, T.A.; Spengler, R.N. Immediate neurological recovery following perispinal etanercept years after brain injury. Clin. Drug Investig. 2014, 34, 361–366. [Google Scholar] [CrossRef]
  87. Hoffer, M.E.; Balaban, C.; Slade, M.D.; Tsao, J.W.; Hoffer, B. Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: A double-blind, placebo controlled study. PLoS ONE 2013, 8, e54163. [Google Scholar] [CrossRef] [Green Version]
  88. Clark, R.S.B.; Empey, P.E.; Bayir, H.; Rosario, B.L.; Poloyac, S.M.; Kochanek, P.M.; Nolin, T.D.; Au, A.K.; Horvat, C.M.; Wisniewski, S.R.; et al. Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children. PLoS ONE 2017, 12, e0180280. [Google Scholar] [CrossRef]
  89. Stein, D.G. Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 2015, 29, 1259–1272. [Google Scholar] [CrossRef]
  90. Atkins, C.M.; Oliva, A.A., Jr.; Alonso, O.F.; Pearse, D.D.; Bramlett, H.M.; Dietrich, W.D. Modulation of the cAMP signaling pathway after traumatic brain injury. Exp. Neurol. 2007, 208, 145–158. [Google Scholar] [CrossRef] [Green Version]
  91. Ceyhan, O.; Birsoy, K.; Hoffman, C.S. Identification of biologically active PDE11-selective inhibitors using a yeast-based high-throughput screen. Chem. Biol. 2012, 19, 155–163. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Kaminska, K.; Golembiowska, K.; Rogoz, Z. Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine, serotonin and noradrenaline in the rat frontal cortex. Pharmacol. Rep. Pr. 2013, 65, 1144–1151. [Google Scholar] [CrossRef]
  93. Huot, P.; Johnston, T.H.; Lewis, K.D.; Koprich, J.B.; Reyes, M.G.; Fox, S.H.; Piggott, M.J.; Brotchie, J.M. UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances L-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset. Neuropharmacology 2014, 82, 76–87. [Google Scholar] [CrossRef] [PubMed]
  94. Chew, E.; Zafonte, R.D. Pharmacological management of neurobehavioral disorders following traumatic brain injury--a state-of-the-art review. J. Rehabil. Res. Dev. 2009, 46, 851–879. [Google Scholar] [CrossRef] [PubMed]
  95. Buckley, C.D.; Gilroy, D.W.; Serhan, C.N.; Stockinger, B.; Tak, P.P. The resolution of inflammation. Nat. Rev. Immunol. 2013, 13, 59–66. [Google Scholar] [CrossRef]
  96. Pacher, P.; Batkai, S.; Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 2006, 58, 389–462. [Google Scholar] [CrossRef] [Green Version]
  97. Skaper, S.D.; Facci, L.; Giusti, P. Mast cells, glia and neuroinflammation: Partners in crime? Immunology 2014, 141, 314–327. [Google Scholar] [CrossRef]
  98. Impellizzeri, D.; Bruschetta, G.; Cordaro, M.; Crupi, R.; Siracusa, R.; Esposito, E.; Cuzzocrea, S. Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain. J. Neuroinflamm. 2014, 11, 136. [Google Scholar] [CrossRef] [Green Version]
  99. Boccella, S.; Marabese, I.; Iannotta, M.; Belardo, C.; Neugebauer, V.; Mazzitelli, M.; Pieretti, G.; Maione, S.; Palazzo, E. Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain. Int. J. Mol. Sci. 2019, 20. [Google Scholar] [CrossRef] [Green Version]
  100. Scuderi, C.; Bronzuoli, M.R.; Facchinetti, R.; Pace, L.; Ferraro, L.; Broad, K.D.; Serviddio, G.; Bellanti, F.; Palombelli, G.; Carpinelli, G.; et al. Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer’s disease by exerting anti-inflammatory and neuroprotective effects. Transl. Psychiatry 2018, 8, 32. [Google Scholar] [CrossRef]
  101. Fusco, R.; Gugliandolo, E.; Campolo, M.; Evangelista, M.; Di Paola, R.; Cuzzocrea, S. Effect of a new formulation of micronized and ultramicronized N-palmitoylethanolamine in a tibia fracture mouse model of complex regional pain syndrome. PLoS ONE 2017, 12, e0178553. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Impellizzeri, D.; Peritore, A.F.; Cordaro, M.; Gugliandolo, E.; Siracusa, R.; Crupi, R.; D’Amico, R.; Fusco, R.; Evangelista, M.; Cuzzocrea, S.; et al. The neuroprotective effects of micronized PEA (PEA-m) formulation on diabetic peripheral neuropathy in mice. FASEB J. 2019, 33, 11364–11380. [Google Scholar] [CrossRef] [PubMed]
  103. Passavanti, M.B.; Fiore, M.; Sansone, P.; Aurilio, C.; Pota, V.; Barbarisi, M.; Fierro, D.; Pace, M.C. The beneficial use of ultramicronized palmitoylethanolamide as add-on therapy to Tapentadol in the treatment of low back pain: A pilot study comparing prospective and retrospective observational arms. BMC Anesth. 2017, 17, 171. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Schweiger, V.; Martini, A.; Bellamoli, P.; Donadello, K.; Schievano, C.; Balzo, G.D.; Sarzi-Puttini, P.; Parolini, M.; Polati, E. Ultramicronized Palmitoylethanolamide (um-PEA) as Add-on Treatment in Fibromyalgia Syndrome (FMS): Retrospective Observational Study on 407 Patients. CNS Neurol. Disord. Drug Targets 2019, 18, 326–333. [Google Scholar] [CrossRef] [PubMed]
  105. Crupi, R.; Paterniti, I.; Ahmad, A.; Campolo, M.; Esposito, E.; Cuzzocrea, S. Effects of palmitoylethanolamide and luteolin in an animal model of anxiety/depression. CNS Neurol. Disord. Drug Targets 2013, 12, 989–1001. [Google Scholar] [CrossRef] [PubMed]
  106. Bertolino, B.; Crupi, R.; Impellizzeri, D.; Bruschetta, G.; Cordaro, M.; Siracusa, R.; Esposito, E.; Cuzzocrea, S. Beneficial Effects of Co-Ultramicronized Palmitoylethanolamide/Luteolin in a Mouse Model of Autism and in a Case Report of Autism. CNS Neurosci. Ther. 2017, 23, 87–98. [Google Scholar] [CrossRef] [Green Version]
  107. Crupi, R.; Impellizzeri, D.; Bruschetta, G.; Cordaro, M.; Paterniti, I.; Siracusa, R.; Cuzzocrea, S.; Esposito, E. Co-Ultramicronized Palmitoylethanolamide/Luteolin Promotes Neuronal Regeneration after Spinal Cord Injury. Front. Pharmacol. 2016, 7, 47. [Google Scholar] [CrossRef] [Green Version]
  108. Impellizzeri, D.; Esposito, E.; Di Paola, R.; Ahmad, A.; Campolo, M.; Peli, A.; Morittu, V.M.; Britti, D.; Cuzzocrea, S. Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagen type II in mice. Arthritis Res. Ther. 2013, 15, R192. [Google Scholar] [CrossRef] [Green Version]
  109. Paterniti, I.; Cordaro, M.; Campolo, M.; Siracusa, R.; Cornelius, C.; Navarra, M.; Cuzzocrea, S.; Esposito, E. Neuroprotection by association of palmitoylethanolamide with luteolin in experimental Alzheimer’s disease models: The control of neuroinflammation. CNS Neurol. Disord. Drug Targets 2014, 13, 1530–1541. [Google Scholar] [CrossRef]
  110. Paterniti, I.; Impellizzeri, D.; Di Paola, R.; Navarra, M.; Cuzzocrea, S.; Esposito, E. A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury. J. Neuroinflamm. 2013, 10, 91. [Google Scholar] [CrossRef] [Green Version]
  111. Siracusa, R.; Paterniti, I.; Impellizzeri, D.; Cordaro, M.; Crupi, R.; Navarra, M.; Cuzzocrea, S.; Esposito, E. The Association of Palmitoylethanolamide with Luteolin Decreases Neuroinflammation and Stimulates Autophagy in Parkinson’s Disease Model. CNS Neurol. Disord. Drug Targets 2015, 14, 1350–1365. [Google Scholar] [CrossRef] [PubMed]
  112. Cordaro, M.; Impellizzeri, D.; Paterniti, I.; Bruschetta, G.; Siracusa, R.; De Stefano, D.; Cuzzocrea, S.; Esposito, E. Neuroprotective Effects of Co-UltraPEALut on Secondary Inflammatory Process and Autophagy Involved in Traumatic Brain Injury. J. Neurotrauma 2016, 33, 132–146. [Google Scholar] [CrossRef] [PubMed]
  113. Siracusa, R.; Impellizzeri, D.; Cordaro, M.; Crupi, R.; Esposito, E.; Petrosino, S.; Cuzzocrea, S. Anti-Inflammatory and Neuroprotective Effects of Co-UltraPEALut in a Mouse Model of Vascular Dementia. Front. Neurol. 2017, 8, 233. [Google Scholar] [CrossRef] [PubMed]
  114. Caltagirone, C.; Cisari, C.; Schievano, C.; Di Paola, R.; Cordaro, M.; Bruschetta, G.; Esposito, E.; Cuzzocrea, S.; Stroke Study Group. Co-ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: From Rodent to Man. Transl. Stroke Res. 2016, 7, 54–69. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  115. Impellizzeri, D.; Cordaro, M.; Bruschetta, G.; Crupi, R.; Pascali, J.; Alfonsi, D.; Marcolongo, G.; Cuzzocrea, S. 2-pentadecyl-2-oxazoline: Identification in coffee, synthesis and activity in a rat model of carrageenan-induced hindpaw inflammation. Pharmacol. Res. 2016, 108, 23–30. [Google Scholar] [CrossRef] [PubMed]
  116. Petrosino, S.; Campolo, M.; Impellizzeri, D.; Paterniti, I.; Allara, M.; Gugliandolo, E.; D’Amico, R.; Siracusa, R.; Cordaro, M.; Esposito, E.; et al. 2-Pentadecyl-2-Oxazoline, the Oxazoline of Pea, Modulates Carrageenan-Induced Acute Inflammation. Front. Pharmacol. 2017, 8, 308. [Google Scholar] [CrossRef] [Green Version]
  117. Impellizzeri, D.; Cordaro, M.; Bruschetta, G.; Siracusa, R.; Crupi, R.; Esposito, E.; Cuzzocrea, S. N-Palmitoylethanolamine-Oxazoline as a New Therapeutic Strategy to Control Neuroinflammation: Neuroprotective Effects in Experimental Models of Spinal Cord and Brain Injury. J. Neurotrauma. 2017, 34, 2609–2623. [Google Scholar] [CrossRef]
  118. Mouhieddine, T.H.; Kobeissy, F.H.; Itani, M.; Nokkari, A.; Wang, K.K. Stem cells in neuroinjury and neurodegenerative disorders: Challenges and future neurotherapeutic prospects. Neural Regen. Res. 2014, 9, 901–906. [Google Scholar] [CrossRef]
  119. Liao, G.P.; Harting, M.T.; Hetz, R.A.; Walker, P.A.; Shah, S.K.; Corkins, C.J.; Hughes, T.G.; Jimenez, F.; Kosmach, S.C.; Day, M.C.; et al. Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children. Pediatr. Crit. Care Med. J. Soc. Crit. Care Med. World Fed. Pediatr. Intensive Crit. Care Soc. 2015, 16, 245–255. [Google Scholar] [CrossRef] [Green Version]
  120. Blaya, M.O.; Tsoulfas, P.; Bramlett, H.M.; Dietrich, W.D. Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury. Exp. Neurol. 2015, 264, 67–81. [Google Scholar] [CrossRef] [Green Version]
  121. Thau-Zuchman, O.; Shohami, E.; Alexandrovich, A.G.; Leker, R.R. Combination of vascular endothelial and fibroblast growth factor 2 for induction of neurogenesis and angiogenesis after traumatic brain injury. J. Mol. Neurosci. 2012, 47, 166–172. [Google Scholar] [CrossRef] [PubMed]
  122. Lv, Q.; Fan, X.; Xu, G.; Liu, Q.; Tian, L.; Cai, X.; Sun, W.; Wang, X.; Cai, Q.; Bao, Y.; et al. Intranasal delivery of nerve growth factor attenuates aquaporins-4-induced edema following traumatic brain injury in rats. Brain Res. 2013, 1493, 80–89. [Google Scholar] [CrossRef] [PubMed]
  123. Tian, L.; Guo, R.; Yue, X.; Lv, Q.; Ye, X.; Wang, Z.; Chen, Z.; Wu, B.; Xu, G.; Liu, X. Intranasal administration of nerve growth factor ameliorate beta-amyloid deposition after traumatic brain injury in rats. Brain Res. 2012, 1440, 47–55. [Google Scholar] [CrossRef] [PubMed]
  124. Murlidharan, G.; Samulski, R.J.; Asokan, A. Biology of adeno-associated viral vectors in the central nervous system. Front. Mol. Neurosci. 2014, 7, 76. [Google Scholar] [CrossRef] [Green Version]
  125. Das, M.; Wang, C.; Bedi, R.; Mohapatra, S.S.; Mohapatra, S. Magnetic micelles for DNA delivery to rat brains after mild traumatic brain injury. Nanomed. Nanotechnol. Biol. Med. 2014, 10, 1539–1548. [Google Scholar] [CrossRef] [Green Version]
  126. Harmon, B.T.; Aly, A.E.; Padegimas, L.; Sesenoglu-Laird, O.; Cooper, M.J.; Waszczak, B.L. Intranasal administration of plasmid DNA nanoparticles yields successful transfection and expression of a reporter protein in rat brain. Gene Ther. 2014, 21, 514–521. [Google Scholar] [CrossRef]
  127. Chantsoulis, M.; Mirski, A.; Rasmus, A.; Kropotov, J.D.; Pachalska, M. Neuropsychological rehabilitation for traumatic brain injury patients. Ann. Agric. Environ. Med. AAEM 2015, 22, 368–379. [Google Scholar] [CrossRef] [Green Version]
  128. Rostami, R.; Salamati, P.; Yarandi, K.K.; Khoshnevisan, A.; Saadat, S.; Kamali, Z.S.; Ghiasi, S.; Zaryabi, A.; Ghazi Mir Saeid, S.S.; Arjipour, M.; et al. Effects of neurofeedback on the short-term memory and continuous attention of patients with moderate traumatic brain injury: A preliminary randomized controlled clinical trial. Chin. J. Traumatol. 2017, 20, 278–282. [Google Scholar] [CrossRef]
Antioxidants 09 00297 g001 550
Figure 1. Pathophysiological heterogeneity detected in TBI.
Figure 1. Pathophysiological heterogeneity detected in TBI.
Antioxidants 09 00297 g001
Table
Table 1. Animal models of traumatic brain injury (TBI).
Table 1. Animal models of traumatic brain injury (TBI).
ModelInjury
FPIFocal/diffuse
LateralMixed
MiddleMixed
CCIPrimarily focal
PBBIPrimarily focal
BlastPrimarily diffuse
Weight DropFocal/diffuse
Repeated MildPrimarily diffuse
FPI: fluid percussion injury; CCI: controlled cortical impact; PBBI: penetrating ballistic-like brain injury.
Table
Table 2. Biomarkers in TBI.
Table 2. Biomarkers in TBI.
BiomarkersInjury FieldModelsReferences
CSF/serum albumin ratioBBB dysfunctionpatients with severe TBI[20]
Tight junction proteinsmTBI in rats
ischemic stroke in rats		[21,22]
S100Bpatients with minor head injury
patients with extracranial pathology		[23,24]
Plasma-soluble prion protein PrPcrat model of concussion
concussed athletes		[25,26]
Tau proteinsAxonal injurypatients with acute TBI[27]
UCHL1patients with mild or moderate TBI
patients with severe TBI
concussed athletes		[28,29,30]
Neurofilaments (NFs)rat models of TBI
patients with mTBI
patients with amyotrophic lateral sclerosis		[18,31,32]
NSEPatients with severe TBI[33]
GFAPRat TBI models
Patients with severe TBI		[18,34]
MBPChildren with TBI[35]
αII and βII-Spectrin breakdown productsPatients with severe TBI[36]
NGALRat model of TBI
Patients with severe TBI		[37,38]
IL-6, IL-8, IL-10NeuroinflammationAnimal and clinical models of TBI[39,40]
MMPmTBI patients[41]
MBG[42]
APOEGenetic variationsmTBI patients[43]
BDNF[44]
CSF, cerebrospinal fluid; UCHL1, deubiquitinase ubiquitin carboxyl-terminal hydrolase isoenzyme L1; NSE, glycolytic enzyme neuron-specific enolase; MBP, myelin basic protein; NGAL, neutrophil gelatinase-associated lipocalin; MBG, marinobufagenin; APOE, apolipoprotein E; BDNF, brain-derived neurotrophic factor, MMP, metalloproteinase, mTBI, mild traumatic brain injury.
Table
Table 3. Therapeutic drugs with anti-inflammatory action for TBI.
Table 3. Therapeutic drugs with anti-inflammatory action for TBI.
DrugRoute of AdministrationPreclinical ModelInflammatory EventsReferences
DexamethasoneI.P.WD⇓ Microglia (CD68, MHC II)
⇓ Microglia (Endothelial-Monocyte Activating Polypeptide II, P2X4 Receptor, Iba-1)		[46,47]
MeloxicamI.P.M-WD⇓ Lipid Peroxidation GSSH Nakatpase[48]
EtazolateI.P.WD⇓ IL-1β
⇓ Microglia (CD11b)		[49]
CarpofenS.C.WD⇓ Microglia (Iba-1)
⇓ IL-1β, ⇓ IL-6
⇔ IL-4, ⇔ IL-10		[50]
IndomethacinI.P.M-WD⇓ IL-1β, ⇓ 6-Keto PGF1α[51,52]
I.P.WD
NimesulideI.P.WD⇓ 6-Keto PGF1a[53]
CelecoxibI.P.WD⇓ Il-1β, ⇔ IL-10[52]
MeloxicamI.PWD⇓ 6-Keto PGF1a[52]
EtanerceptI.P.FPI⇓ TNF-α[54]
Dexamethasone MelatoninI.P.CCI⇓ MMP-2, ⇓ MMP-9, ⇓ Inos[55]
Lipoxin A4I.C.V.WD⇓ IL-1β, ⇓ IL-6, ⇓ TNFα, ⇓ GFAP
⇓ Microglia (CD11b)		[56]
IbuprofenI.P.FPI⇔ IL-4, ⇔ IL-10
⇔ TNFα ⇔ IL-1α⇔ IL-6		[57]
MinocyclineI.P.WD⇓ microglia (CD11b)[58]
I.P.WD⇓ microglia, ⇓ IL-1β[59]
FenofibrateP.O.LFP⇓ cerebral oedema
⇓ ICAM-1, ⇓ brain lesion		[60]
Pioglitazone and RosiglitazoneI.P.CCI⇓ activated microglia (OX-42)[61]
N-acetylcysteineI.P.WD⇓ NF-kB, ⇓ IL-1β
⇓ IL-6, ⇓ TNF-α		[62]
FlavopiridolI.P.LFP⇓ GFAP, ⇓ microglia[63]
RoscovitineI.C.V.CCI⇓ microglia (Iba-1)[63]
ErythropoietinI.P.CCI⇓ NF-kB, ⇓ ICAM-1, ⇓ IL-1β
⇓ TNF-α, ⇔ IL-6		[64]
I.P.WD⇓ CCL-2
⇓ microglia (CD-68)		[65]
SimvastatinP.O.CCI⇓ TLR4, ⇓ NF-κB
⇓ IL-1β, ⇓ TNFα
⇓ Il-6, ⇓ ICAM-1		[66]
⇓ Il-1β, ⇓ GFAP
⇓ IL-6, ⇓ TNF-α microglia (CD68)		[67]
ProgesteroneI.P.WDCOX-2, ⇓ PGE2, ⇓ NF-κB[68]
I.P./S.C.CCI⇓ IL-6, ⇓ COX-2, ⇓ NF-κB[69]
⇑, increase; ⇓, decrease; ⇔, no change, I.P., intraperitoneal; S.C., subcutaneous; I.C.V., intracerebroventricular; P.O., oral; FPI, fluid percussion injury; CCI, controlled cortical impact; WD, weight drop; M-WD, Marmarou weight drop; MHC, major histocompatibility complex; CD68, cluster of differentiation protein 68; IL, interleukin; TNF, tumor necrosis factor; LFP, lateral fluid percussion; ICAM-1, intercellular adhesion molecule, MMP, metalloproteinase, COX-2, cyclooxygenase-2; NF-kB, nuclear factor-kB; GSSH, oxidized glutathione; CCL2, C–C motif chemokine ligand 2.
Table
Table 4. Current drugs for neurobehavioral disorders after TBI.
Table 4. Current drugs for neurobehavioral disorders after TBI.
ClassDrugMechanismEffect
CNS stimulantsMethylphenidateacts as an NDRIamplified the speed of information processing in many neuropsychological tests
CNS stimulantsModafinilunknownraised alertness by the modulation of both noradrenergic and dopaminergic systems
Atypical antidepressantAgomelatinea melatonin receptor agonist and serotonin 5-HT2C and 5-HT2Bled to better sleep efficacy
AntiviralAmantadinereflect a growth in synthesis and discharge of dopaminedecreased the incidence and gravity of irritability
Antidepressant of the selective SNRI classVenlafaxineacts as an SNDRIincreased obsessive behaviors, irritability, and sadness symptoms
AnticonvulsantValproateblockade of voltage-gated sodium channels and increased brain levels of GABAhad benign neuropsychological effects, and is a safe drug to control recognized seizures or stabilize mood
Acetylcholinesterase inhibitorRivastigmineinhibits butyrylcholinesterase and acetylcholinesteraseencouraging in the subgroup of patients with moderate/severe memory weakening
Cholinesterase inhibitorGalantamineallosteric potentiating ligand of human nicotinic acetylcholine receptors (nAChRs) α4β2, α3β4, and α6β4 and chicken/mouse nAChRs α7/5-HT3 in some brain areasrefined fatigue, memory, attention, and initiative
Cholinesterase inhibitorDonepezildevelops cholinergic functionindorsed clinical improvement and metabolism
CNS, central nervous system; NDRI, norepinephrine–dopamine reuptake inhibitor; SNDRI, serotonin-norepinephrine-dopamine reuptake inhibitor; GABA, gamma-aminobutyric acid; SNRI., serotonin-norepinephrine reuptake inhibitor.

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Crupi, R.; Cordaro, M.; Cuzzocrea, S.; Impellizzeri, D. Management of Traumatic Brain Injury: From Present to Future. Antioxidants 2020, 9, 297. https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9040297

AMA Style

Crupi R, Cordaro M, Cuzzocrea S, Impellizzeri D. Management of Traumatic Brain Injury: From Present to Future. Antioxidants. 2020; 9(4):297. https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9040297

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Crupi, Rosalia, Marika Cordaro, Salvatore Cuzzocrea, and Daniela Impellizzeri. 2020. "Management of Traumatic Brain Injury: From Present to Future" Antioxidants 9, no. 4: 297. https://0-doi-org.brum.beds.ac.uk/10.3390/antiox9040297

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