{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:40Z","timestamp":1787028460903,"version":"build-2736575974"},"reference-count":94,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["272249"],"award-info":[{"award-number":["272249"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["273909"],"award-info":[{"award-number":["273909"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["2285733-9"],"award-info":[{"award-number":["2285733-9"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["307866"],"award-info":[{"award-number":["307866"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["0000"],"award-info":[{"award-number":["0000"]}],"id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Strategic Neuroscience Funding of the University of Eastern Finland","award":["0000"],"award-info":[{"award-number":["0000"]}]},{"name":"FP7-HEALTH project 602102 (EPITARGET)","award":["602102"],"award-info":[{"award-number":["602102"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>We assessed the effect of antioxidant therapy using the Food and Drug Administration-approved respiratory drug N-acetylcysteine (NAC) or sulforaphane (SFN) as monotherapies or duotherapy in vitro in neuron-BV2 microglial co-cultures and validated the results in a lateral fluid-percussion model of TBI in rats. As in vitro measures, we assessed neuronal viability by microtubule-associated-protein 2 immunostaining, neuroinflammation by monitoring tumor necrosis factor (TNF) levels, and neurotoxicity by measuring nitrite levels. In vitro, duotherapy with NAC and SFN reduced nitrite levels to 40% (p &lt; 0.001) and neuroinflammation to \u201329% (p &lt; 0.001) compared with untreated culture. The treatment also improved neuronal viability up to 72% of that in a positive control (p &lt; 0.001). The effect of NAC was negligible, however, compared with SFN. In vivo, antioxidant duotherapy slightly improved performance in the beam walking test. Interestingly, duotherapy treatment decreased the plasma interleukin-6 and TNF levels in sham-operated controls (p &lt; 0.05). After TBI, no treatment effect on HMGB1 or plasma cytokine levels was detected. Also, no treatment effects on the composite neuroscore or cortical lesion area were detected. The robust favorable effect of duotherapy on neuroprotection, neuroinflammation, and oxidative stress in neuron-BV2 microglial co-cultures translated to modest favorable in vivo effects in a severe TBI model.<\/jats:p>","DOI":"10.3390\/ijms221910555","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:03:42Z","timestamp":1632960222000},"page":"10555","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Targeting Oxidative Stress with Antioxidant Duotherapy after Experimental Traumatic Brain Injury"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8396-6921","authenticated-orcid":false,"given":"Jenni","family":"Kyyri\u00e4inen","sequence":"first","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natallie","family":"Kajevu","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1474-3513","authenticated-orcid":false,"given":"Ivette","family":"Ba\u00f1uelos","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4617-2580","authenticated-orcid":false,"given":"Leonardo","family":"Lara","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4403-9084","authenticated-orcid":false,"given":"Anssi","family":"Lipponen","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland"},{"name":"Department of Health Security, Finnish Institute for Health and Welfare, FI-70701 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Balosso","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6869-2574","authenticated-orcid":false,"given":"Elina","family":"H\u00e4m\u00e4l\u00e4inen","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini","family":"Das Gupta","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noora","family":"Puhakka","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teemu","family":"Natunen","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9578-018X","authenticated-orcid":false,"given":"Teresa","family":"Ravizza","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Vezzani","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mario Negri Institute for Pharmacological Research IRCCS, 20156 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3566-4096","authenticated-orcid":false,"given":"Mikko","family":"Hiltunen","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8163-5416","authenticated-orcid":false,"given":"Asla","family":"Pitk\u00e4nen","sequence":"additional","affiliation":[{"name":"A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, FI-70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1016\/j.apmr.2010.05.017","article-title":"Demographics and Clinical Assessment Working Group of the International and Interagency Initiative toward Common Data Elements for Research on Traumatic Brain Injury and Psychological Health. Position Statement: Definition of Traumatic Brain Injury","volume":"91","author":"Menon","year":"2010","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_2","unstructured":"(2021, August 25). CENTER-TBI Website. Available online: https:\/\/www.center-tbi.eu\/."},{"key":"ref_3","unstructured":"(2021, August 25). Center for Disease Control and Prevention Website, Available online: https:\/\/www.cdc.gov\/traumaticbraininjury\/."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1176\/appi.psy.50.3.198","article-title":"Neuropsychiatric Problems After Traumatic Brain Injury: Unraveling the Silent Epidemic","volume":"50","author":"Vaishnavi","year":"2009","journal-title":"Psychosomatics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.yebeh.2017.06.001","article-title":"Post-Traumatic Epilepsy Associations with Mental Health Outcomes in the First Two Years After Moderate to Severe TBI: A TBI Model Systems Analysis","volume":"73","author":"Juengst","year":"2017","journal-title":"Epilepsy Behav."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s10571-016-0400-1","article-title":"Pathophysiology Associated with Traumatic Brain Injury: Current Treatments and Potential Novel Therapeutics","volume":"37","author":"Pearn","year":"2017","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/jnr.24132","article-title":"Non-Invasive Diagnosis and Treatment Strategies for Traumatic Brain Injury: An Update","volume":"96","author":"Joseph","year":"2018","journal-title":"J. Neurosci. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1089\/neu.2011.2122","article-title":"Hemorrhagic Progression of a Contusion After Traumatic Brain Injury: A Review","volume":"29","author":"Kurland","year":"2012","journal-title":"J. Neurotrauma"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/bph.13125","article-title":"The Contribution of Astrocytes and Microglia to Traumatic Brain Injury","volume":"173","author":"Karve","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/B978-0-444-52892-6.00005-2","article-title":"Cellular and Molecular Mechanisms of Injury and Spontaneous Recovery","volume":"127","author":"McGinn","year":"2015","journal-title":"Handb. Clin. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.neuropharm.2018.08.005","article-title":"Newer Pharmacological Approaches for Antioxidant Neuroprotection in Traumatic Brain Injury","volume":"145","author":"Hall","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_12","unstructured":"(2021, August 25). European Framework 7-Funded Consortium EPITARGET Website. Available online: https:\/\/www.epitarget.eu\/."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e39","DOI":"10.1093\/brain\/awz130","article-title":"Targeting Oxidative Stress Improves Disease Outcomes in a Rat Model of Acquired Epilepsy","volume":"142","author":"Pauletti","year":"2019","journal-title":"Brain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.brainres.2004.10.055","article-title":"N-Acetylcysteine Attenuates Early Induction of Heme Oxygenase-1 Following Traumatic Brain Injury","volume":"1033","author":"Yi","year":"2005","journal-title":"Brain Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1089\/neu.2006.23.86","article-title":"Early, Transient Increase in Complexin I and Complexin II in the Cerebral Cortex Following Traumatic Brain Injury is Attenuated by N-Acetylcysteine","volume":"23","author":"Yi","year":"2006","journal-title":"J. Neurotrauma"},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s11064-014-1255-9","article-title":"N-Acetylcysteine and Selenium Modulate Oxidative Stress, Antioxidant Vitamin and Cytokine Values in Traumatic Brain Injury-Induced Rats","volume":"39","author":"Senol","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1007\/s10571-014-0069-2","article-title":"Neuroprotection Induced by N-Acetylcysteine and Selenium Against Traumatic Brain Injury-Induced Apoptosis and Calcium Entry in Hippocampus of Rat","volume":"34","author":"Senol","year":"2014","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1089\/neu.1999.16.1067","article-title":"Effect of N-Acetylcysteine on Mitochondrial Function Following Traumatic Brain Injury in Rats","volume":"16","author":"Xiong","year":"1999","journal-title":"J. Neurotrauma"},{"key":"ref_20","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_21","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.exger.2015.11.004","article-title":"Sulforaphane Induces Nrf2 Target Genes and Attenuates Inflammatory Gene Expression in Microglia from Brain of Young Adult and Aged Mice","volume":"73","author":"Townsend","year":"2016","journal-title":"Exp. Gerontol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ejphar.2019.03.010","article-title":"Effects of Sulforaphane in the Central Nervous System","volume":"853","author":"Huang","year":"2019","journal-title":"Eur. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11624","DOI":"10.1038\/ncomms11624","article-title":"Nrf2 Suppresses Macrophage Inflammatory Response by Blocking Proinflammatory Cytokine Transcription","volume":"7","author":"Kobayashi","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41573-018-0008-x","article-title":"Therapeutic Targeting of the NRF2 and KEAP1 Partnership in Chronic Diseases","volume":"18","author":"Cuadrado","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Vomund, S., Sch\u00e4fer, A., Parnham, M.J., Br\u00fcne, B., and von Knethen, A. (2017). Nrf2, the Master Regulator of Anti-Oxidative Responses. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122772"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1002\/jnr.22307","article-title":"Sulforaphane Protects Immature Hippocampal Neurons Against Death Caused by Exposure to Hemin Or to Oxygen and Glucose Deprivation","volume":"88","author":"Soane","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1038\/aps.2010.101","article-title":"The Role of Nrf2 Signaling in the Regulation of Antioxidants and Detoxifying Enzymes After Traumatic Brain Injury in Rats and Mice","volume":"31","author":"Hong","year":"2010","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/S0304-3940(99)00315-8","article-title":"Quantification of Neuron Survival in Monolayer Cultures using an Enzyme-Linked Immunosorbent Assay Approach, rather than by Cell Counting","volume":"267","author":"Brooke","year":"1999","journal-title":"Neurosci. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1002\/glia.23094","article-title":"Dynamics of PDGFR\u03b2 Expression in Different Cell Types After Brain Injury","volume":"65","year":"2017","journal-title":"Glia"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/bja\/aem131","article-title":"Pathophysiology of Traumatic Brain Injury","volume":"99","author":"Werner","year":"2007","journal-title":"Br. J. Anaesth."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1523\/JNEUROSCI.3817-03.2004","article-title":"Nuclear Factor E2-Related Factor 2-Dependent Antioxidant Response Element Activation by Tert-Butylhydroquinone and Sulforaphane Occurring Preferentially in Astrocytes Conditions Neurons Against Oxidative Insult","volume":"24","author":"Kraft","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s12264-012-1273-z","article-title":"Sulforaphane Protects Primary Cultures of Cortical Neurons Against Injury Induced by Oxygen-Glucose deprivation\/reoxygenation Via Antiapoptosis","volume":"28","author":"Wu","year":"2012","journal-title":"Neurosci. Bull."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00011-009-0116-5","article-title":"Sulforaphane Suppresses LPS-Induced Inflammation in Primary Rat Microglia","volume":"59","author":"Brandenburg","year":"2010","journal-title":"Inflamm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.phrs.2018.01.014","article-title":"Sulforaphane Attenuates Microglia-Mediated Neuronal Necroptosis through Down-Regulation of MAPK\/NF-\u03baB Signaling Pathways in LPS-Activated BV-2 Microglia","volume":"133","author":"Qin","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"32373","DOI":"10.1038\/srep32373","article-title":"N-Acetylcysteine Attenuates Lipopolysaccharide-Induced Impairment in Lamination of Ctip2-and Tbr1-Expressing Cortical Neurons in the Developing Rat Fetal Brain","volume":"6","author":"Chao","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.1021\/acs.molpharmaceut.6b01028","article-title":"Redox Potential-Sensitive N-Acetyl Cysteine-Prodrug Nanoparticles Inhibit the Activation of Microglia and Improve Neuronal Survival","volume":"14","author":"Markoutsa","year":"2017","journal-title":"Mol. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s11064-006-9040-z","article-title":"Neuroprotective Effects of N-Acetylcysteine on Experimental Closed Head Trauma in Rats","volume":"31","author":"Hicdonmez","year":"2006","journal-title":"Neurochem. Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Eakin, K., Baratz-Goldstein, R., Pick, C.G., Zindel, O., Balaban, C.D., Hoffer, M.E., Lockwood, M., Miller, J., and Hoffer, B.J. (2014). Efficacy of N-Acetyl Cysteine in Traumatic Brain Injury. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0090617"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1089\/neu.2017.5348","article-title":"Minocycline Plus N-Acetylcysteine Reduce Behavioral Deficits and Improve Histology with a Clinically Useful Time Window","volume":"35","author":"Sangobowale","year":"2018","journal-title":"J. Neurotrauma"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0006-8993(03)02244-3","article-title":"N-Acetyl Cysteine Protects Against Injury in a Rat Model of Focal Cerebral Ischemia","volume":"971","author":"Sekhon","year":"2003","journal-title":"Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/jnr.20087","article-title":"Administration of N-Acetylcysteine After Focal Cerebral Ischemia Protects Brain and Reduces Inflammation in a Rat Model of Experimental Stroke","volume":"76","author":"Khan","year":"2004","journal-title":"J. Neurosci. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Abdel Baki, S.G., Schwab, B., Haber, M., Fenton, A.A., and Bergold, P.J. (2010). Minocycline Synergizes with N-Acetylcysteine and Improves Cognition and Memory Following Traumatic Brain Injury in Rats. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012490"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.expneurol.2013.09.002","article-title":"Minocycline Plus N-Acetylcysteine Synergize to Modulate Inflammation and Prevent Cognitive and Memory Deficits in a Rat Model of Mild Traumatic Brain Injury","volume":"249","author":"Haber","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.expneurol.2014.04.020","article-title":"N-Acetylcysteine Amide Confers Neuroprotection, Improves Bioenergetics and Behavioral Outcome Following TBI","volume":"257","author":"Pandya","year":"2014","journal-title":"Exp. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s00134-005-2845-4","article-title":"The Effect of N-Acetylcysteine on Posttraumatic Changes After Controlled Cortical Impact in Rats","volume":"32","author":"Thomale","year":"2006","journal-title":"Intensive Care Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1002\/jnr.20649","article-title":"Sulforaphane Enhances Aquaporin-4 Expression and Decreases Cerebral Edema Following Traumatic Brain Injury","volume":"82","author":"Zhao","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10240","DOI":"10.1523\/JNEUROSCI.1683-07.2007","article-title":"Enhancing Expression of Nrf2-Driven Genes Protects the Blood Brain Barrier After Brain Injury","volume":"27","author":"Zhao","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.neulet.2009.04.028","article-title":"Sulforaphane Improves Cognitive Function Administered Following Traumatic Brain Injury","volume":"460","author":"Dash","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.neulet.2005.09.065","article-title":"Sulforaphane Reduces Infarct Volume Following Focal Cerebral Ischemia in Rodents","volume":"393","author":"Zhao","year":"2006","journal-title":"Neurosci. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Porritt, M.J., Andersson, H.C., Hou, L., Nilsson, \u00c5., Pekna, M., Pekny, M., and Nilsson, M. (2012). Photothrombosis-Induced Infarction of the Mouse Cerebral Cortex is Not Affected by the Nrf2-Activator Sulforaphane. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041090"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4117","DOI":"10.1016\/j.bbagen.2013.04.016","article-title":"The Chemistry and Biological Activities of N-Acetylcysteine","volume":"1830","author":"Samuni","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1046\/j.1471-4159.2003.01580.x","article-title":"The Antioxidants Alpha-Lipoic Acid and N-Acetylcysteine Reverse Memory Impairment and Brain Oxidative Stress in Aged SAMP8 Mice","volume":"84","author":"Farr","year":"2003","journal-title":"J. Neurochem."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Clark, R.S.B., Empey, P.E., Bay\u0131r, 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_54","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.neulet.2007.11.060","article-title":"Activation of Nrf2-ARE Pathway in Brain After Traumatic Brain Injury","volume":"431","author":"Yan","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1097\/WNR.0000000000001205","article-title":"Expression of Nuclear Factor Erythroid 2-Related Factor 2 Following Traumatic Brain Injury in the Human Brain","volume":"30","author":"He","year":"2019","journal-title":"Neuroreport"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3280","DOI":"10.1161\/STROKEAHA.107.486506","article-title":"Transcription Factor Nrf2 Protects the Brain from Damage Produced by Intracerebral Hemorrhage","volume":"38","author":"Zhao","year":"2007","journal-title":"Stroke"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1089\/neu.2013.3218","article-title":"Temporal and Spatial Dynamics of nrf2-Antioxidant Response Elements Mediated Gene Targets in Cortex and Hippocampus After Controlled Cortical Impact Traumatic Brain Injury in Mice","volume":"31","author":"Miller","year":"2014","journal-title":"J. Neurotrauma"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1126\/science.1203165","article-title":"A Pericyte Origin of Spinal Cord Scar Tissue","volume":"333","author":"Dias","year":"2011","journal-title":"Science"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1097\/SHK.0b013e3181997173","article-title":"HMGB1 is Markedly Elevated within 6 Hours of Mechanical Trauma in Humans","volume":"32","author":"Peltz","year":"2009","journal-title":"Shock"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"R174","DOI":"10.1186\/cc8152","article-title":"Early Release of High Mobility Group Box Nuclear Protein 1 After Severe Trauma in Humans: Role of Injury Severity and Tissue Hypoperfusion","volume":"13","author":"Cohen","year":"2009","journal-title":"Crit. Care"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1089\/neu.2011.2171","article-title":"Cerebrospinal Fluid Levels of High-Mobility Group Box 1 and Cytochrome C Predict Outcome After Pediatric Traumatic Brain Injury","volume":"29","author":"Au","year":"2012","journal-title":"J. Neurotrauma"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"112979","DOI":"10.1016\/j.expneurol.2019.112979","article-title":"Targeting High-Mobility Group Box Protein 1 (HMGB1) in Pediatric Traumatic Brain Injury: Chronic Neuroinflammatory, Behavioral, and Epileptogenic Consequences","volume":"320","author":"Webster","year":"2019","journal-title":"Exp. Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1089\/neu.2004.21.1431","article-title":"The Effects of Traumatic Brain Injury on Cerebral Blood Flow and Brain Tissue Nitric Oxide Levels and Cytokine Expression","volume":"21","author":"Ahn","year":"2004","journal-title":"J. Neurotrauma"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1097\/01.ta.0000196345.81169.a1","article-title":"The Effect of Traumatic Brain Injury upon the Concentration and Expression of Interleukin-1beta and Interleukin-10 in the Rat","volume":"60","author":"Kamm","year":"2006","journal-title":"J. Trauma"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1097\/HTR.0000000000000067","article-title":"Chronic Inflammation After Severe Traumatic Brain Injury: Characterization and Associations with Outcome at 6 and 12 Months Postinjury","volume":"30","author":"Kumar","year":"2015","journal-title":"J. Head Trauma Rehabil."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1111\/j.1748-1716.1987.tb08112.x","article-title":"Leakiness of Rat Brain Microvessels to Fluorescent Probes Following Craniotomy","volume":"130","author":"Olesen","year":"1987","journal-title":"Acta Physiol. Scand."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1089\/neu.2010.1427","article-title":"Craniotomy: True Sham for Traumatic Brain Injury, Or a Sham of a Sham?","volume":"28","author":"Cole","year":"2011","journal-title":"J. Neurotrauma"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"155","DOI":"10.3389\/fneur.2012.00155","article-title":"Controlled Cortical Impact and Craniotomy Induce Strikingly Similar Profiles of Inflammatory Gene Expression, but with Distinct Kinetics","volume":"3","author":"Lagraoui","year":"2012","journal-title":"Front. Neurol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0014-5793(00)01464-2","article-title":"N-Acetylcysteine Suppresses TNF-Induced NF-kappaB Activation through Inhibition of IkappaB Kinases","volume":"472","author":"Oka","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4486","DOI":"10.1038\/sj.onc.1208656","article-title":"Suppression of NF-kappaB and NF-kappaB-Regulated Gene Expression by Sulforaphane and PEITC through IkappaBalpha, IKK Pathway in Human Prostate Cancer PC-3 Cells","volume":"24","author":"Xu","year":"2005","journal-title":"Oncogene"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.jff.2015.08.030","article-title":"Sulforaphane, a Naturally Occurring Isothiocyanate, Exhibits Anti-Inflammatory Effects by Targeting GSK3\u03b2\/Nrf-2 and NF-\u03baB Pathways in T Cells","volume":"19","author":"Checker","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Lipponen, A., Natunen, T., Hujo, M., Ciszek, R., H\u00e4m\u00e4l\u00e4inen, E., Tohka, J., Hiltunen, M., Paananen, J., Poulsen, D., and Kansanen, E. (2019). In Vitro and in Vivo Pipeline for Validation of Disease-Modifying Effects of Systems Biology-Derived Network Treatments for Traumatic Brain Injury-Lessons Learned. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215395"},{"key":"ref_73","first-page":"853","article-title":"The Impact of Social Isolation on Immunological Parameters in Rats","volume":"88","author":"Fischer","year":"2014","journal-title":"Arch. Toxicol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"112191","DOI":"10.1016\/j.bbr.2019.112191","article-title":"Analysis of the Molecular and Behavioral Effects of Acute Social Isolation on Rats","volume":"377","author":"Alshammari","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/S1474-4422(10)70310-0","article-title":"Mechanisms of Epileptogenesis and Potential Treatment Targets","volume":"10","author":"Lukasiuk","year":"2011","journal-title":"Lancet Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"107907","DOI":"10.1016\/j.neuropharm.2019.107907","article-title":"Modulating Neuroinflammation and Oxidative Stress to Prevent Epilepsy and Improve Outcomes After Traumatic Brain Injury","volume":"172","author":"Eastman","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1528-1167.2010.02602.x","article-title":"Therapeutic Approaches to Epileptogenesis--Hope on the Horizon","volume":"51","year":"2010","journal-title":"Epilepsia"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Gresa-Arribas, N., Vi\u00e9itez, C., Dentesano, G., Serratosa, J., Saura, J., and Sol\u00e0, C. (2012). Modelling Neuroinflammation in Vitro: A Tool to Test the Potential Neuroprotective Effect of Anti-Inflammatory Agents. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0045227"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-017-0991-6","article-title":"DHCR24 Exerts Neuroprotection upon Inflammation-Induced Neuronal Death","volume":"14","author":"Martiskainen","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/bcpt.13094","article-title":"Extracellular Prolyl Oligopeptidase Derived from Activated Microglia is a Potential Neuroprotection Target","volume":"124","author":"Natunen","year":"2019","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1248\/bpb.33.1477","article-title":"Protective Effect of Combination of Sulforaphane and Riluzole on Glutamate-Mediated Excitotoxicity","volume":"33","author":"Chang","year":"2010","journal-title":"Biol. Pharm. Bull."},{"key":"ref_82","first-page":"6647","article-title":"Neuroprotective Effects of N-Acetyl Cysteine on Primary Hippocampus Neurons Against Hydrogen Peroxide-Induced Injury are Mediated Via Inhibition of Mitogen-Activated Protein Kinases Signal Transduction and Antioxidative Action","volume":"17","author":"Wu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1093\/chrsci\/49.10.801","article-title":"Development and Validation of an LC-MS-MS Method for the Simultaneous Determination of Sulforaphane and its Metabolites in Rat Plasma and its Application in Pharmacokinetic Studies","volume":"49","author":"Wang","year":"2011","journal-title":"J. Chromatogr. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0306-4522(89)90247-9","article-title":"Traumatic Brain Injury in the Rat: Characterization of a Lateral Fluid-Percussion Model","volume":"28","author":"McIntosh","year":"1989","journal-title":"Neuroscience"},{"key":"ref_85","unstructured":"Paxinos, G., and Watson, C. (2007). The Rat Brain in Stereotaxic Coordinates, Elsevier. [6th ed.]."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.eplepsyres.2017.07.005","article-title":"Disease-Modifying Effect of Atipamezole in a Model of Post-Traumatic Epilepsy","volume":"136","author":"Nissinen","year":"2017","journal-title":"Epilepsy Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1161\/01.STR.26.4.644","article-title":"Environment Influences Functional Outcome of Cerebral Infarction in Rats","volume":"26","author":"Ohlsson","year":"1995","journal-title":"Stroke"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1111\/epi.13915","article-title":"Standardization Procedure for Plasma Biomarker Analysis in Rat Models of Epileptogenesis: Focus on Circulating microRNAs","volume":"58","author":"Puhakka","year":"2017","journal-title":"Epilepsia"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Schwochow, D., Serieys, L.E., Wayne, R.K., and Thalmann, O. (2012). Efficient Recovery of Whole Blood RNA\u2014A Comparison of Commercial RNA Extraction Protocols for High-Throughput Applications in Wildlife Species. BMC Biotechnol., 12.","DOI":"10.1186\/1472-6750-12-33"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data using Real-Time Quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1089\/neu.2016.4404","article-title":"Unfolded Maps for Quantitative Analysis of Cortical Lesion Location and Extent After Traumatic Brain Injury","volume":"34","author":"Kharatishvili","year":"2017","journal-title":"J. Neurotrauma"},{"key":"ref_92","unstructured":"(2021, August 26). Web Application for Creating Two Dimentional Unfolded Maps. Available online: https:\/\/unfoldedmap.org\/."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1152\/physrev.1999.79.4.1283","article-title":"Mechanism of Action and in Vivo Role of Platelet-Derived Growth Factor","volume":"79","author":"Heldin","year":"1999","journal-title":"Physiol. Rev."},{"key":"ref_94","unstructured":"(2021, August 26). The R Project for Statistical Computing Website. Available online: https:\/\/www.r-project.org\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10555\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:07:34Z","timestamp":1760166454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10555"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,29]]},"references-count":94,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910555"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910555","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,29]]}}}