{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T16:07:24Z","timestamp":1768320444581,"version":"3.49.0"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,25]],"date-time":"2025-03-25T00:00:00Z","timestamp":1742860800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JAPAN SOCIETY FOR THE PROMOTION OF SCIENCE","doi-asserted-by":"publisher","award":["JP21K06813"],"award-info":[{"award-number":["JP21K06813"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JAPAN SOCIETY FOR THE PROMOTION OF SCIENCE","doi-asserted-by":"publisher","award":["JP20K16065"],"award-info":[{"award-number":["JP20K16065"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JAPAN SOCIETY FOR THE PROMOTION OF SCIENCE","doi-asserted-by":"publisher","award":["JP23K14401"],"award-info":[{"award-number":["JP23K14401"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JAPAN SOCIETY FOR THE PROMOTION OF SCIENCE","doi-asserted-by":"publisher","award":["JP21H04863"],"award-info":[{"award-number":["JP21H04863"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JAPAN SOCIETY FOR THE PROMOTION OF SCIENCE","doi-asserted-by":"publisher","award":["JP23K18205"],"award-info":[{"award-number":["JP23K18205"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JAPAN SOCIETY FOR THE PROMOTION OF SCIENCE","doi-asserted-by":"publisher","award":["GW2411"],"award-info":[{"award-number":["GW2411"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005738","name":"CENTRAL RESEARCH INSTITUTE OF FUKUOKA UNIVERSITY","doi-asserted-by":"publisher","award":["JP21K06813"],"award-info":[{"award-number":["JP21K06813"]}],"id":[{"id":"10.13039\/501100005738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005738","name":"CENTRAL RESEARCH INSTITUTE OF FUKUOKA UNIVERSITY","doi-asserted-by":"publisher","award":["JP20K16065"],"award-info":[{"award-number":["JP20K16065"]}],"id":[{"id":"10.13039\/501100005738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005738","name":"CENTRAL RESEARCH INSTITUTE OF FUKUOKA UNIVERSITY","doi-asserted-by":"publisher","award":["JP23K14401"],"award-info":[{"award-number":["JP23K14401"]}],"id":[{"id":"10.13039\/501100005738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005738","name":"CENTRAL RESEARCH INSTITUTE OF FUKUOKA UNIVERSITY","doi-asserted-by":"publisher","award":["JP21H04863"],"award-info":[{"award-number":["JP21H04863"]}],"id":[{"id":"10.13039\/501100005738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005738","name":"CENTRAL RESEARCH INSTITUTE OF FUKUOKA UNIVERSITY","doi-asserted-by":"publisher","award":["JP23K18205"],"award-info":[{"award-number":["JP23K18205"]}],"id":[{"id":"10.13039\/501100005738","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005738","name":"CENTRAL RESEARCH INSTITUTE OF FUKUOKA UNIVERSITY","doi-asserted-by":"publisher","award":["GW2411"],"award-info":[{"award-number":["GW2411"]}],"id":[{"id":"10.13039\/501100005738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Traumatic brain injury (TBI) causes neurovascular unit (NVU) dysfunction, including hyperpermeability of the blood\u2013brain barrier to fibrinogen, glial activation, and neuronal damage, possibly leading to secondary brain damage. However, no known substance can inhibit its pathogenesis. In this study, we investigated noggin, a bone morphogenetic protein (BMP) 4 inhibitor, as a TBI pathogenesis-inhibiting substance. We induced acute TBI in C57BL\/6J mice through a controlled cortical impact (CCI) and evaluated the effects of noggin on fibrinogen leakage into the brain and NVU-constituting cells, including pericytes, microglia, astrocytes, and neurons. CCI mice showed increased BMP4 levels and extravascular fibrinogen in the hippocampus. Noggin treatment significantly suppressed fibrinogen leakage four days post-CCI in a dose-dependent manner. Immunofluorescence staining revealed that noggin administration did not inhibit the activation of NVU cells such as pericytes, microglia, and astrocytes, which were characterized by increased PDGFR\u03b2, Iba1, and GFAP expression levels, respectively. On postoperative day 4, CCI mice showed neuronal cell and myelinated neuronal fiber loss, which were not significantly affected by noggin administration. In conclusion, noggin administration suppresses fibrinogen leakage into the brain in the acute phase after TBI. However, the suppression of fibrinogen leakage through noggin administration did not alleviate neuronal damage and activation of NVU cells during the acute phase of TBI.<\/jats:p>","DOI":"10.3390\/ijms26073002","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T04:17:14Z","timestamp":1742962634000},"page":"3002","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Administration of Noggin Suppresses Fibrinogen Leakage into the Brain in the Acute Phase After Traumatic Brain Injury in Mice"],"prefix":"10.3390","volume":"26","author":[{"given":"Miho","family":"Yasunaga","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8752-7272","authenticated-orcid":false,"given":"Fuyuko","family":"Takata","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9510-5928","authenticated-orcid":false,"given":"Takuro","family":"Iwao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junko","family":"Mizoguchi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nanako","family":"Tajima","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8036-0510","authenticated-orcid":false,"given":"Shinya","family":"Dohgu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"153943","DOI":"10.1016\/j.metabol.2019.07.007","article-title":"Traumatic brain injury (TBI) in collision sports: Possible mechanisms of transformation into chronic traumatic encephalopathy (CTE)","volume":"100s","author":"VanItallie","year":"2019","journal-title":"Metab. Clin. Exp."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.mcn.2015.03.012","article-title":"Neurological consequences of traumatic brain injuries in sports","volume":"66","author":"Ling","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_3","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_4","doi-asserted-by":"crossref","unstructured":"Jochems, D., van Rein, E., Niemeijer, M., van Heijl, M., van Es, M.A., Nijboer, T., Leenen, L.P.H., Houwert, R.M., and van Wessem, K.J.P. (2021). Incidence, causes and consequences of moderate and severe traumatic brain injury as determined by Abbreviated Injury Score in the Netherlands. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-99484-6"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.biopsych.2021.05.025","article-title":"Traumatic Brain Injury and Risk of Neurodegenerative Disorder","volume":"91","author":"Brett","year":"2022","journal-title":"Biol. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.expneurol.2012.01.013","article-title":"Axonal pathology in traumatic brain injury","volume":"246","author":"Johnson","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3171\/2015.2.JNS14503","article-title":"Association of traumatic brain injury with subsequent neurological and psychiatric disease: A meta-analysis","volume":"124","author":"Perry","year":"2016","journal-title":"J. Neurosurg."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sulimai, N., Brown, J., and Lominadze, D. (2024). The Effect of Reduced Fibrinogen on Cerebrovascular Permeability during Traumatic Brain Injury in Fibrinogen Gene Heterozygous Knockout Mice. Biomolecules, 14.","DOI":"10.3390\/biom14040385"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jphs.2020.11.008","article-title":"Reactive pericytes in early phase are involved in glial activation and late-onset hypersusceptibility to pilocarpine-induced seizures in traumatic brain injury model mice","volume":"145","author":"Sakai","year":"2021","journal-title":"J. Pharmacol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1186\/s12974-024-03092-w","article-title":"Fibrin promotes oxidative stress and neuronal loss in traumatic brain injury via innate immune activation","volume":"21","author":"Dean","year":"2024","journal-title":"J. Neuroinflammation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.expneurol.2015.08.018","article-title":"Microglia in the TBI brain: The good, the bad, and the dysregulated","volume":"275","author":"Loane","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e34009","DOI":"10.1097\/MD.0000000000034009","article-title":"Research progress of neuroinflammation-related cells in traumatic brain injury: A review","volume":"102","author":"Zhao","year":"2023","journal-title":"Medicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/nrn.2018.13","article-title":"Fibrinogen in neurological diseases: Mechanisms, imaging and therapeutics","volume":"19","author":"Petersen","year":"2018","journal-title":"Nat. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"fcz028","DOI":"10.1093\/braincomms\/fcz028","article-title":"Activation of both transforming growth factor-\u03b2 and bone morphogenetic protein signalling pathways upon traumatic brain injury restrains pro-inflammatory and boosts tissue reparatory responses of reactive astrocytes and microglia","volume":"1","author":"Divolis","year":"2019","journal-title":"Brain Commun."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Logan, T.T., Villapol, S., and Symes, A.J. (2013). TGF-\u03b2 superfamily gene expression and induction of the Runx1 transcription factor in adult neurogenic regions after brain injury. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0059250"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1007\/s10753-017-0627-0","article-title":"Endothelial BMP4 Regulates Leukocyte Diapedesis and Promotes Inflammation","volume":"40","author":"Helbing","year":"2017","journal-title":"Inflammation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.arr.2012.05.002","article-title":"The function of BMP4 during neurogenesis in the adult hippocampus in Alzheimer\u2019s disease","volume":"12","author":"Xu","year":"2013","journal-title":"Ageing Res. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/S0012-1606(02)00037-4","article-title":"Transgenic overexpression of BMP4 increases astroglial and decreases oligodendroglial lineage commitment","volume":"255","author":"Gomes","year":"2003","journal-title":"Dev. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1161\/STROKEAHA.109.565523","article-title":"Noggin protects against ischemic brain injury in rodents","volume":"41","author":"Samanta","year":"2010","journal-title":"Stroke"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11625","DOI":"10.1073\/pnas.1813205115","article-title":"Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology","volume":"115","author":"Armenteros","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"492","DOI":"10.4103\/1673-5374.350190","article-title":"Neuroprotective role of Noggin in spinal cord injury","volume":"18","author":"Mahmood","year":"2023","journal-title":"Neural Regen. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"164","DOI":"10.3171\/2009.2.JNS081199","article-title":"Intranasal delivery of erythropoietin plus insulin-like growth factor-I for acute neuroprotection in stroke. Laboratory investigation","volume":"111","author":"Fletcher","year":"2009","journal-title":"J. Neurosurg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.jocn.2012.03.028","article-title":"Transplantation of mesenchymal stem cells to the brain by topical application in an experimental traumatic brain injury model","volume":"20","author":"Lam","year":"2013","journal-title":"J. Clin. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1093\/brain\/awab205","article-title":"Human platelet lysate biotherapy for traumatic brain injury: Preclinical assessment","volume":"144","author":"Nebie","year":"2021","journal-title":"Brain J. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.bbi.2014.03.013","article-title":"Noggin improves ischemic brain tissue repair and promotes alternative activation of microglia in mice","volume":"40","author":"Shin","year":"2014","journal-title":"Brain Behav. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/S0896-6273(00)00148-3","article-title":"Noggin antagonizes BMP signaling to create a niche for adult neurogenesis","volume":"28","author":"Lim","year":"2000","journal-title":"Neuron"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"154837","DOI":"10.1016\/j.metabol.2021.154837","article-title":"Bone morphogenetic proteins (BMPs) in the central regulation of energy balance and adult neural plasticity","volume":"123","author":"Jensen","year":"2021","journal-title":"Metab. Clin. Exp."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1179\/016164107X204693","article-title":"Neovascularization following traumatic brain injury: Possible evidence for both angiogenesis and vasculogenesis","volume":"29","author":"Morgan","year":"2007","journal-title":"Neurol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1093\/brain\/awm118","article-title":"Angiogenesis is associated with blood-brain barrier permeability in temporal lobe epilepsy","volume":"130","author":"Rigau","year":"2007","journal-title":"Brain J. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1111\/epi.13245","article-title":"Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II: Potential mechanisms","volume":"57","author":"Otte","year":"2016","journal-title":"Epilepsia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.biocel.2011.01.007","article-title":"Noggin","volume":"43","author":"Krause","year":"2011","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1016\/j.neuron.2019.01.014","article-title":"Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer\u2019s Disease Model","volume":"101","author":"Merlini","year":"2019","journal-title":"Neuron"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/j.1538-7836.2009.03438.x","article-title":"Fibrinogen signal transduction in the nervous system","volume":"7","author":"Ryu","year":"2009","journal-title":"J. Thromb. Haemost. JTH"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/glia.24166","article-title":"Fibrinogen regulates lesion border-forming reactive astrocyte properties after vascular damage","volume":"70","author":"Conforti","year":"2022","journal-title":"Glia"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sulimai, N., Brown, J., and Lominadze, D. (2021). Fibrinogen Interaction with Astrocyte ICAM-1 and PrP(C) Results in the Generation of ROS and Neuronal Death. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052391"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1038\/s41590-023-01522-0","article-title":"Defining blood-induced microglia functions in neurodegeneration through multiomic profiling","volume":"24","author":"Mendiola","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.expneurol.2015.03.020","article-title":"Astrocyte roles in traumatic brain injury","volume":"275","author":"Burda","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1089\/neu.2011.1841","article-title":"Trauma-induced plasmalemma disruptions in three-dimensional neural cultures are dependent on strain modality and rate","volume":"28","author":"Cullen","year":"2011","journal-title":"J. Neurotrauma"},{"key":"ref_39","first-page":"1147","article-title":"Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans","volume":"74","author":"Hay","year":"2015","journal-title":"J. Neuropathol. Exp. Neurol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3002\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:00:11Z","timestamp":1760029211000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/3002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,25]]},"references-count":39,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26073002"],"URL":"https:\/\/doi.org\/10.3390\/ijms26073002","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,25]]}}}