{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:07:48Z","timestamp":1792458468396,"version":"4.5.0"},"reference-count":128,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T00:00:00Z","timestamp":1585785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>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\u2013brain 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.<\/jats:p>","DOI":"10.3390\/antiox9040297","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T10:33:58Z","timestamp":1585823638000},"page":"297","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Management of Traumatic Brain Injury: From Present to Future"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7629-3132","authenticated-orcid":false,"given":"Rosalia","family":"Crupi","sequence":"first","affiliation":[{"name":"Department of Veterinary Science, University of Messina, 98168 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3980-0043","authenticated-orcid":false,"given":"Marika","family":"Cordaro","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Via Consolare Valeria 1, 98100 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6131-3690","authenticated-orcid":false,"given":"Salvatore","family":"Cuzzocrea","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmacological and Environmental Sciences, Messina University, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"},{"name":"Department of Pharmacological and Physiological Science, Saint Louis University, Saint Louis, MO 63104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Impellizzeri","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmacological and Environmental Sciences, Messina University, Viale F. Stagno D\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.pneurobio.2016.05.002","article-title":"Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?","volume":"142","author":"Kline","year":"2016","journal-title":"Prog. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1002\/cphy.c140057","article-title":"Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury","volume":"5","author":"Logsdon","year":"2015","journal-title":"Compr. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.neuropharm.2018.09.032","article-title":"Combination of drug and stem cells neurotherapy: Potential interventions in neurotrauma and traumatic brain injury","volume":"145","author":"Zibara","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/nrn3407","article-title":"Animal models of traumatic brain injury","volume":"14","author":"Xiong","year":"2013","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_5","unstructured":"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., and Conley, Y.P. (2018). Paths to successful translation of new therapies for severe TBI in the golden age of traumatic brain injury research: A Pittsburgh vision. J. Neurotrauma."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/msj.20104","article-title":"Pathophysiology of traumatic brain injury","volume":"76","author":"Greve","year":"2009","journal-title":"Mt. Sinai J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s10194-020-1080-2","article-title":"Exploring naturally occurring clinical subgroups of post-traumatic headache","volume":"21","author":"Chan","year":"2020","journal-title":"J. Headache Pain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s10194-019-1051-7","article-title":"Acute and preventive pharmacological treatment of post-traumatic headache: A systematic review","volume":"20","author":"Larsen","year":"2019","journal-title":"J. Headache Pain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/s10194-018-0945-0","article-title":"Post-concussion syndrome among patients experiencing head injury attending emergency department of Hawassa University Comprehensive specialized hospital, Hawassa, southern Ethiopia","volume":"19","author":"Bedaso","year":"2018","journal-title":"J. Headache Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1089\/neu.2012.2578","article-title":"Group-based trajectory analysis applications for prognostic biomarker model development in severe TBI: A practical example","volume":"30","author":"Niyonkuru","year":"2013","journal-title":"J. Neurotrauma"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1007\/s10495-010-0481-0","article-title":"Molecular and cellular mechanisms of excitotoxic neuronal death","volume":"15","author":"Wang","year":"2010","journal-title":"Apoptosis Int. J. Program. Cell Death"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.freeradbiomed.2012.09.016","article-title":"Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis","volume":"62","author":"Dasuri","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/rda.12230","article-title":"Oxidative stress in neonatology: A review","volume":"49","author":"Mutinati","year":"2014","journal-title":"Reprod. Domest. Anim."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.4049\/jimmunol.1302793","article-title":"Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice","volume":"192","author":"Fluiter","year":"2014","journal-title":"J. Immunol."},{"key":"ref_15","first-page":"330","article-title":"Scavenger receptor on astrocytes and its relationship with neuroinflammation","volume":"36","author":"Wu","year":"2014","journal-title":"Acta Acad. Med. Sin."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.bbi.2012.06.008","article-title":"Neuroinflammation after traumatic brain injury: Opportunities for therapeutic intervention","volume":"26","author":"Kumar","year":"2012","journal-title":"Brain Behav. Immun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1089\/neu.2008.0794","article-title":"Combination therapies for traumatic brain injury: Prospective considerations","volume":"26","author":"Margulies","year":"2009","journal-title":"J. Neurotrauma"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1089\/neu.2017.5586","article-title":"Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury: An Operation Brain Trauma Therapy Study","volume":"36","author":"Yang","year":"2019","journal-title":"J. Neurotrauma"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kim, H.J., Tsao, J.W., and Stanfill, A.G. (2018). The current state of biomarkers of mild traumatic brain injury. JCI Insight, 3.","DOI":"10.1172\/jci.insight.97105"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1097\/CCM.0000000000003203","article-title":"Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury","volume":"46","author":"Hagos","year":"2018","journal-title":"Crit. Care Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"92","DOI":"10.3171\/2010.6.JNS10207","article-title":"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","volume":"114","author":"Higashida","year":"2011","journal-title":"J. Neurosurg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"40331","DOI":"10.1038\/srep40331","article-title":"Blood Occludin Level as a Potential Biomarker for Early Blood Brain Barrier Damage Following Ischemic Stroke","volume":"7","author":"Pan","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.annemergmed.2011.07.027","article-title":"S100-B protein as a screening tool for the early assessment of minor head injury","volume":"59","author":"Zongo","year":"2012","journal-title":"Ann. Emerg. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1097\/SMJ.0000000000000086","article-title":"Serum biomarkers for traumatic brain injury","volume":"107","author":"Neher","year":"2014","journal-title":"South. Med. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1089\/neu.2013.2862","article-title":"Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats","volume":"30","author":"Kochanek","year":"2013","journal-title":"J. Neurotrauma"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pham, N., Akonasu, H., Shishkin, R., and Taghibiglou, C. (2015). Plasma soluble prion protein, a potential biomarker for sport-related concussions: A pilot study. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0117286"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1001\/jamaneurol.2017.0655","article-title":"Comparing Plasma Phospho Tau, Total Tau, and Phospho Tau-Total Tau Ratio as Acute and Chronic Traumatic Brain Injury Biomarkers","volume":"74","author":"Rubenstein","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1097\/TA.0b013e3182491e3d","article-title":"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","volume":"72","author":"Papa","year":"2012","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_29","first-page":"666","article-title":"Clinical utility of serum levels of ubiquitin C-terminal hydrolase as a biomarker for severe traumatic brain injury","volume":"70","author":"Mondello","year":"2012","journal-title":"Neurosurgery"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Puvenna, V., Brennan, C., Shaw, G., Yang, C., Marchi, N., Bazarian, J.J., Merchant-Borna, K., and Janigro, D. (2014). Significance of ubiquitin carboxy-terminal hydrolase L1 elevations in athletes after sub-concussive head hits. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096296"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.3171\/2014.7.JNS132474","article-title":"Detection of neurofilament-H in serum as a diagnostic tool to predict injury severity in patients who have suffered mild traumatic brain injury","volume":"121","author":"Gatson","year":"2014","journal-title":"J. Neurosurg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1007\/s00415-017-8730-6","article-title":"CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis","volume":"265","author":"Rossi","year":"2018","journal-title":"J. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1227\/NEU.0b013e318214a81f","article-title":"Neuron-specific enolase, S100B, and glial fibrillary acidic protein levels as outcome predictors in patients with severe traumatic brain injury","volume":"68","author":"Bohmer","year":"2011","journal-title":"Neurosurgery"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1186\/s13054-015-1081-8","article-title":"Glial fibrillary acidic protein as a biomarker in severe traumatic brain injury patients: A prospective cohort study","volume":"19","author":"Lei","year":"2015","journal-title":"Crit. Care"},{"key":"ref_35","first-page":"61","article-title":"Serum neuron-specific enolase, S100B, and myelin basic protein concentrations after inflicted and noninflicted traumatic brain injury in children","volume":"103","author":"Berger","year":"2005","journal-title":"J. Neurosurg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1089\/neu.2010.1278","article-title":"alphaII-spectrin breakdown products (SBDPs): Diagnosis and outcome in severe traumatic brain injury patients","volume":"27","author":"Mondello","year":"2010","journal-title":"J. Neurotrauma"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/978-3-319-18497-5_50","article-title":"Deferoxamine Attenuated the Upregulation of Lipocalin-2 Induced by Traumatic Brain Injury in Rats","volume":"121","author":"Zhao","year":"2016","journal-title":"Acta Neurochir. Suppl."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.jns.2016.07.060","article-title":"Early expression of serum neutrophil gelatinase-associated lipocalin (NGAL) is associated with neurological severity immediately after traumatic brain injury","volume":"368","author":"Zhao","year":"2016","journal-title":"J. Neurol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/jcbfm.2009.262","article-title":"Role of CCL2 (MCP-1) in traumatic brain injury (TBI): Evidence from severe TBI patients and CCL2-\/- mice","volume":"30","author":"Semple","year":"2010","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1089\/neu.2007.0349","article-title":"Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: Effects of moderate hypothermia","volume":"24","author":"Buttram","year":"2007","journal-title":"J. Neurotrauma"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1203\/PDR.0b013e31818c7e27","article-title":"Multiplex assessment of serum biomarker concentrations in well-appearing children with inflicted traumatic brain injury","volume":"65","author":"Berger","year":"2009","journal-title":"Pediatric Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4137\/JEN.S27921","article-title":"Comparison of Neurocognitive Testing and the Measurement of Marinobufagenin in Mild Traumatic Brain Injury: A Preliminary Report","volume":"9","author":"Oliver","year":"2015","journal-title":"J. Exp. Neurosci."},{"key":"ref_43","first-page":"13","article-title":"The Association of Apolipoprotein E Allele 4 Polymorphism with the Recovery of Sleep Disturbance after Mild Traumatic Brain Injury","volume":"26","author":"Lee","year":"2017","journal-title":"Acta Neurol. Taiwanica"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/gbb.12403","article-title":"BDNF genotype is associated with hippocampal volume in mild traumatic brain injury","volume":"17","author":"Hayes","year":"2018","journal-title":"Genes Brain Behav."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1089\/neu.2010.1646","article-title":"Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury","volume":"28","author":"Sullivan","year":"2011","journal-title":"J. Neurotrauma"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1007\/BF01420304","article-title":"Dexamethasone and colchicine reduce inflammation and delayed oedema following experimental brain contusion","volume":"138","author":"Holmin","year":"1996","journal-title":"Acta Neurochir."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1007\/s00401-007-0195-8","article-title":"Dexamethasone attenuates early expression of three molecules associated with microglia\/macrophages activation following rat traumatic brain injury","volume":"113","author":"Zhang","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1179\/016164109X12464612122731","article-title":"Effect of COX-2 inhibitor meloxicam against traumatic brain injury-induced biochemical, histopathological changes and blood-brain barrier permeability","volume":"32","author":"Hakan","year":"2010","journal-title":"Neurol. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1089\/neu.2010.1738","article-title":"Minocycline restores sAPPalpha levels and reduces the late histopathological consequences of traumatic brain injury in mice","volume":"28","author":"Siopi","year":"2011","journal-title":"J. Neurotrauma"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1089\/neu.2010.1673","article-title":"The anti-inflammatory drug carprofen improves long-term outcome and induces gliogenesis after traumatic brain injury","volume":"29","author":"Shohami","year":"2012","journal-title":"J. Neurotrauma"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/1742-2094-9-121","article-title":"Indomethacin protects rats from neuronal damage induced by traumatic brain injury and suppresses hippocampal IL-1beta release through the inhibition of Nogo-A expression","volume":"9","author":"Chao","year":"2012","journal-title":"J. Neuroinflamm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.brainres.2012.10.049","article-title":"Effects of selective and non-selective cyclooxygenase inhibition against neurological deficit and brain oedema following closed head injury in mice","volume":"1491","author":"Girgis","year":"2013","journal-title":"Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Clond, M.A., Lee, B.S., Yu, J.J., Singer, M.B., Amano, T., Lamb, A.W., Drazin, D., Kateb, B., Ley, E.J., and Yu, J.S. (2013). Reactive oxygen species-activated nanoprodrug of Ibuprofen for targeting traumatic brain injury in mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061819"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"620837","DOI":"10.1155\/2013\/620837","article-title":"Etanercept attenuates traumatic brain injury in rats by reducing brain TNF- alpha contents and by stimulating newly formed neurogenesis","volume":"2013","author":"Cheong","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1530\/JOE-13-0022","article-title":"Combination therapy with melatonin and dexamethasone in a mouse model of traumatic brain injury","volume":"217","author":"Campolo","year":"2013","journal-title":"J. Endocrinol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2013.01.037","article-title":"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","volume":"1502","author":"Luo","year":"2013","journal-title":"Brain Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1007\/s00221-014-3948-3","article-title":"Acute over-the-counter pharmacological intervention does not adversely affect behavioral outcome following diffuse traumatic brain injury in the mouse","volume":"232","author":"Harrison","year":"2014","journal-title":"Exp. Brain Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1089\/neu.2009.1223","article-title":"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","volume":"27","author":"Homsi","year":"2010","journal-title":"J. Neurotrauma"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.expneurol.2006.10.013","article-title":"Transient neuroprotection by minocycline following traumatic brain injury is associated with attenuated microglial activation but no changes in cell apoptosis or neutrophil infiltration","volume":"204","author":"Bye","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.neulet.2005.06.019","article-title":"Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, exerts neuroprotective effects in traumatic brain injury","volume":"388","author":"Besson","year":"2005","journal-title":"Neurosci. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.expneurol.2010.10.003","article-title":"Pioglitazone attenuates mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation following traumatic brain injury","volume":"227","author":"Sauerbeck","year":"2011","journal-title":"Exp. Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"716458","DOI":"10.1155\/2008\/716458","article-title":"Inhibitory effect on cerebral inflammatory response following traumatic brain injury in rats: A potential neuroprotective mechanism of N-acetylcysteine","volume":"2008","author":"Chen","year":"2008","journal-title":"Mediat. Inflamm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.expneurol.2015.05.024","article-title":"Treatment of traumatic brain injury with anti-inflammatory drugs","volume":"275 Pt 3","author":"Bergold","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.neulet.2007.08.022","article-title":"Inhibitory effect on cerebral inflammatory agents that accompany traumatic brain injury in a rat model: A potential neuroprotective mechanism of recombinant human erythropoietin (rhEPO)","volume":"425","author":"Chen","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"977","DOI":"10.3892\/etm.2012.723","article-title":"Experimental studies of erythropoietin protection following traumatic brain injury in rats","volume":"4","author":"Xu","year":"2012","journal-title":"Exp. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.expneurol.2008.12.019","article-title":"Simvastatin reduces secondary brain injury caused by cortical contusion in rats: Possible involvement of TLR4\/NF-kappaB pathway","volume":"216","author":"Chen","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1227\/01.NEU.0000346272.76537.DC","article-title":"Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta level after traumatic brain injury","volume":"65","author":"Li","year":"2009","journal-title":"Neurosurgery"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.3892\/etm.2014.1840","article-title":"Progesterone protects blood-brain barrier function and improves neurological outcome following traumatic brain injury in rats","volume":"8","author":"Si","year":"2014","journal-title":"Exp. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1089\/neu.2007.0294","article-title":"Progesterone improves acute recovery after traumatic brain injury in the aged rat","volume":"24","author":"Cutler","year":"2007","journal-title":"J. Neurotrauma"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"222","DOI":"10.2174\/187152709788680689","article-title":"Neuroprotective effects of tetracyclines: Molecular targets, animal models and human disease","volume":"8","author":"Orsucci","year":"2009","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1038\/npp.2012.152","article-title":"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","volume":"37","author":"Villapol","year":"2012","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_72","first-page":"e00129","article-title":"PPAR agonists as therapeutics for CNS trauma and neurological diseases","volume":"5","author":"Sauerbeck","year":"2013","journal-title":"ASN Neuro"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"8333","DOI":"10.1073\/pnas.0500989102","article-title":"Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury","volume":"102","author":"Movsesyan","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/jcbfm.2011.117","article-title":"Selective CDK inhibitor limits neuroinflammation and progressive neurodegeneration after brain trauma","volume":"32","author":"Kabadi","year":"2012","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"653","DOI":"10.3171\/2014.6.JNS132577","article-title":"The efficacy of erythropoietin in treating experimental traumatic brain injury: A systematic review of controlled trials in animal models","volume":"121","author":"Peng","year":"2014","journal-title":"J. Neurosurg."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1001\/jama.2014.6490","article-title":"Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: A randomized clinical trial","volume":"312","author":"Robertson","year":"2014","journal-title":"JAMA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1517\/13543784.2015.1021919","article-title":"Investigational agents for treatment of traumatic brain injury","volume":"24","author":"Xiong","year":"2015","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1080\/02699052.2019.1566968","article-title":"Safety and feasibility of minocycline in treatment of acute traumatic brain injury","volume":"33","author":"Meythaler","year":"2019","journal-title":"Brain Inj."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1089\/089771504772695913","article-title":"Atorvastatin reduces neurological deficit and increases synaptogenesis, angiogenesis, and neuronal survival in rats subjected to traumatic brain injury","volume":"21","author":"Lu","year":"2004","journal-title":"J. Neurotrauma"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"691","DOI":"10.3171\/JNS\/2008\/109\/10\/0691","article-title":"Increase in phosphorylation of Akt and its downstream signaling targets and suppression of apoptosis by simvastatin after traumatic brain injury","volume":"109","author":"Wu","year":"2008","journal-title":"J. Neurosurg."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1089\/neu.2007.0369","article-title":"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","volume":"25","author":"Wu","year":"2008","journal-title":"J. Neurotrauma"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1227\/01.NEU.0000343540.24780.D6","article-title":"Long-term benefits after treatment of traumatic brain injury with simvastatin in rats","volume":"65","author":"Mahmood","year":"2009","journal-title":"Neurosurgery"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.bbamem.2013.07.018","article-title":"Interaction of membrane\/lipid rafts with the cytoskeleton: Impact on signaling and function: Membrane\/lipid rafts, mediators of cytoskeletal arrangement and cell signaling","volume":"1838","author":"Head","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1586\/ern.10.52","article-title":"Perispinal etanercept: A new therapeutic paradigm in neurology","volume":"10","author":"Tobinick","year":"2010","journal-title":"Expert Rev. Neurother."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1007\/s40263-012-0013-2","article-title":"Selective TNF inhibition for chronic stroke and traumatic brain injury: An observational study involving 629 consecutive patients treated with perispinal etanercept","volume":"26","author":"Tobinick","year":"2012","journal-title":"CNS Drugs"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1007\/s40261-014-0186-1","article-title":"Immediate neurological recovery following perispinal etanercept years after brain injury","volume":"34","author":"Tobinick","year":"2014","journal-title":"Clin. Drug Investig."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Hoffer, M.E., Balaban, C., Slade, M.D., Tsao, J.W., and Hoffer, B. (2013). Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: A double-blind, placebo controlled study. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054163"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"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., and Wisniewski, S.R. (2017). 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, 12.","DOI":"10.1371\/journal.pone.0180280"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.3109\/02699052.2015.1065344","article-title":"Embracing failure: What the Phase III progesterone studies can teach about TBI clinical trials","volume":"29","author":"Stein","year":"2015","journal-title":"Brain Inj."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.expneurol.2007.08.011","article-title":"Modulation of the cAMP signaling pathway after traumatic brain injury","volume":"208","author":"Atkins","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.chembiol.2011.12.010","article-title":"Identification of biologically active PDE11-selective inhibitors using a yeast-based high-throughput screen","volume":"19","author":"Ceyhan","year":"2012","journal-title":"Chem. Biol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1016\/S1734-1140(13)71472-5","article-title":"Effect of risperidone on the fluoxetine-induced changes in extracellular dopamine, serotonin and noradrenaline in the rat frontal cortex","volume":"65","author":"Kaminska","year":"2013","journal-title":"Pharmacol. Rep. Pr."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.neuropharm.2014.01.012","article-title":"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","volume":"82","author":"Huot","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1682\/JRRD.2008.09.0120","article-title":"Pharmacological management of neurobehavioral disorders following traumatic brain injury--a state-of-the-art review","volume":"46","author":"Chew","year":"2009","journal-title":"J. Rehabil. Res. Dev."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/nri3362","article-title":"The resolution of inflammation","volume":"13","author":"Buckley","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1124\/pr.58.3.2","article-title":"The endocannabinoid system as an emerging target of pharmacotherapy","volume":"58","author":"Pacher","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1111\/imm.12170","article-title":"Mast cells, glia and neuroinflammation: Partners in crime?","volume":"141","author":"Skaper","year":"2014","journal-title":"Immunology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12974-014-0136-0","article-title":"Micronized\/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain","volume":"11","author":"Impellizzeri","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Boccella, S., Marabese, I., Iannotta, M., Belardo, C., Neugebauer, V., Mazzitelli, M., Pieretti, G., Maione, S., and Palazzo, E. (2019). Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain. Int. J. Mol. Sci.","DOI":"10.3390\/ijms20071757"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41398-017-0076-4","article-title":"Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer\u2019s disease by exerting anti-inflammatory and neuroprotective effects","volume":"8","author":"Scuderi","year":"2018","journal-title":"Transl. Psychiatry"},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Fusco, R., Gugliandolo, E., Campolo, M., Evangelista, M., Di Paola, R., and Cuzzocrea, S. (2017). Effect of a new formulation of micronized and ultramicronized N-palmitoylethanolamine in a tibia fracture mouse model of complex regional pain syndrome. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178553"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"11364","DOI":"10.1096\/fj.201900538R","article-title":"The neuroprotective effects of micronized PEA (PEA-m) formulation on diabetic peripheral neuropathy in mice","volume":"33","author":"Impellizzeri","year":"2019","journal-title":"FASEB J."},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Passavanti, M.B., Fiore, M., Sansone, P., Aurilio, C., Pota, V., Barbarisi, M., Fierro, D., and Pace, M.C. (2017). 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., 17.","DOI":"10.1186\/s12871-017-0461-9"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"326","DOI":"10.2174\/1871527318666190227205359","article-title":"Ultramicronized Palmitoylethanolamide (um-PEA) as Add-on Treatment in Fibromyalgia Syndrome (FMS): Retrospective Observational Study on 407 Patients","volume":"18","author":"Schweiger","year":"2019","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"989","DOI":"10.2174\/18715273113129990084","article-title":"Effects of palmitoylethanolamide and luteolin in an animal model of anxiety\/depression","volume":"12","author":"Crupi","year":"2013","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1111\/cns.12648","article-title":"Beneficial Effects of Co-Ultramicronized Palmitoylethanolamide\/Luteolin in a Mouse Model of Autism and in a Case Report of Autism","volume":"23","author":"Bertolino","year":"2017","journal-title":"CNS Neurosci. Ther."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"47","DOI":"10.3389\/fphar.2016.00047","article-title":"Co-Ultramicronized Palmitoylethanolamide\/Luteolin Promotes Neuronal Regeneration after Spinal Cord Injury","volume":"7","author":"Crupi","year":"2016","journal-title":"Front. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"R192","DOI":"10.1186\/ar4382","article-title":"Palmitoylethanolamide and luteolin ameliorate development of arthritis caused by injection of collagen type II in mice","volume":"15","author":"Impellizzeri","year":"2013","journal-title":"Arthritis Res. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.2174\/1871527313666140806124322","article-title":"Neuroprotection by association of palmitoylethanolamide with luteolin in experimental Alzheimer\u2019s disease models: The control of neuroinflammation","volume":"13","author":"Paterniti","year":"2014","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/1742-2094-10-91","article-title":"A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury","volume":"10","author":"Paterniti","year":"2013","journal-title":"J. Neuroinflamm."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.2174\/1871527314666150821102823","article-title":"The Association of Palmitoylethanolamide with Luteolin Decreases Neuroinflammation and Stimulates Autophagy in Parkinson\u2019s Disease Model","volume":"14","author":"Siracusa","year":"2015","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1089\/neu.2014.3460","article-title":"Neuroprotective Effects of Co-UltraPEALut on Secondary Inflammatory Process and Autophagy Involved in Traumatic Brain Injury","volume":"33","author":"Cordaro","year":"2016","journal-title":"J. Neurotrauma"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"233","DOI":"10.3389\/fneur.2017.00233","article-title":"Anti-Inflammatory and Neuroprotective Effects of Co-UltraPEALut in a Mouse Model of Vascular Dementia","volume":"8","author":"Siracusa","year":"2017","journal-title":"Front. Neurol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1007\/s12975-015-0440-8","article-title":"Co-ultramicronized Palmitoylethanolamide\/Luteolin in the Treatment of Cerebral Ischemia: From Rodent to Man","volume":"7","author":"Caltagirone","year":"2016","journal-title":"Transl. Stroke Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.phrs.2016.04.007","article-title":"2-pentadecyl-2-oxazoline: Identification in coffee, synthesis and activity in a rat model of carrageenan-induced hindpaw inflammation","volume":"108","author":"Impellizzeri","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"308","DOI":"10.3389\/fphar.2017.00308","article-title":"2-Pentadecyl-2-Oxazoline, the Oxazoline of Pea, Modulates Carrageenan-Induced Acute Inflammation","volume":"8","author":"Petrosino","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1089\/neu.2016.4808","article-title":"N-Palmitoylethanolamine-Oxazoline as a New Therapeutic Strategy to Control Neuroinflammation: Neuroprotective Effects in Experimental Models of Spinal Cord and Brain Injury","volume":"34","author":"Impellizzeri","year":"2017","journal-title":"J. Neurotrauma."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"901","DOI":"10.4103\/1673-5374.133129","article-title":"Stem cells in neuroinjury and neurodegenerative disorders: Challenges and future neurotherapeutic prospects","volume":"9","author":"Mouhieddine","year":"2014","journal-title":"Neural Regen. Res."},{"key":"ref_119","first-page":"245","article-title":"Autologous bone marrow mononuclear cells reduce therapeutic intensity for severe traumatic brain injury in children","volume":"16","author":"Liao","year":"2015","journal-title":"Pediatr. Crit. Care Med. J. Soc. Crit. Care Med. World Fed. Pediatr. Intensive Crit. Care Soc."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.expneurol.2014.11.014","article-title":"Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury","volume":"264","author":"Blaya","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1007\/s12031-012-9706-8","article-title":"Combination of vascular endothelial and fibroblast growth factor 2 for induction of neurogenesis and angiogenesis after traumatic brain injury","volume":"47","author":"Shohami","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.brainres.2012.11.028","article-title":"Intranasal delivery of nerve growth factor attenuates aquaporins-4-induced edema following traumatic brain injury in rats","volume":"1493","author":"Lv","year":"2013","journal-title":"Brain Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.brainres.2011.12.059","article-title":"Intranasal administration of nerve growth factor ameliorate beta-amyloid deposition after traumatic brain injury in rats","volume":"1440","author":"Tian","year":"2012","journal-title":"Brain Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3389\/fnmol.2014.00076","article-title":"Biology of adeno-associated viral vectors in the central nervous system","volume":"7","author":"Murlidharan","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.nano.2014.01.003","article-title":"Magnetic micelles for DNA delivery to rat brains after mild traumatic brain injury","volume":"10","author":"Das","year":"2014","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1038\/gt.2014.28","article-title":"Intranasal administration of plasmid DNA nanoparticles yields successful transfection and expression of a reporter protein in rat brain","volume":"21","author":"Harmon","year":"2014","journal-title":"Gene Ther."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"368","DOI":"10.5604\/12321966.1152097","article-title":"Neuropsychological rehabilitation for traumatic brain injury patients","volume":"22","author":"Chantsoulis","year":"2015","journal-title":"Ann. Agric. Environ. Med. AAEM"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.cjtee.2016.11.007","article-title":"Effects of neurofeedback on the short-term memory and continuous attention of patients with moderate traumatic brain injury: A preliminary randomized controlled clinical trial","volume":"20","author":"Rostami","year":"2017","journal-title":"Chin. J. Traumatol."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/4\/297\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:14:45Z","timestamp":1760174085000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/9\/4\/297"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,2]]},"references-count":128,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["antiox9040297"],"URL":"https:\/\/doi.org\/10.3390\/antiox9040297","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,2]]}}}