{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:58:49Z","timestamp":1792205929874,"version":"4.4.0"},"reference-count":133,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T00:00:00Z","timestamp":1623715200000},"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":["18K06695"],"award-info":[{"award-number":["18K06695"]}],"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":["20K16016"],"award-info":[{"award-number":["20K16016"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Traumatic brain injury (TBI) is immediate damage caused by a blow to the head resulting from traffic accidents, falls, and sporting activity, which causes death or serious disabilities in survivors. TBI induces multiple secondary injuries, including neuroinflammation, disruption of the blood\u2013brain barrier (BBB), and brain edema. Despite these emergent conditions, current therapies for TBI are limited or insufficient in some cases. Although several candidate drugs exerted beneficial effects in TBI animal models, most of them failed to show significant effects in clinical trials. Multiple studies have suggested that astrocytes play a key role in the pathogenesis of TBI. Increased reactive astrocytes and astrocyte-derived factors are commonly observed in both TBI patients and experimental animal models. Astrocytes have beneficial and detrimental effects on TBI, including promotion and restriction of neurogenesis and synaptogenesis, acceleration and suppression of neuroinflammation, and disruption and repair of the BBB via multiple bioactive factors. Additionally, astrocytic aquaporin-4 is involved in the formation of cytotoxic edema. Thus, astrocytes are attractive targets for novel therapeutic drugs for TBI, although astrocyte-targeting drugs have not yet been developed. This article reviews recent observations of the roles of astrocytes and expected astrocyte-targeting drugs in TBI.<\/jats:p>","DOI":"10.3390\/ijms22126418","type":"journal-article","created":{"date-parts":[[2021,6,15]],"date-time":"2021-06-15T11:00:33Z","timestamp":1623754833000},"page":"6418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":142,"title":["Pathophysiological Responses and Roles of Astrocytes in Traumatic Brain Injury"],"prefix":"10.3390","volume":"22","author":[{"given":"Shotaro","family":"Michinaga","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6508-0094","authenticated-orcid":false,"given":"Yutaka","family":"Koyama","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyama-Kita Higashinada, Kobe 668-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nrn3174","article-title":"Neuroprotective mechanisms of hypothermia in brain ischemia","volume":"13","author":"Yenari","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.neuropharm.2018.08.004","article-title":"Pathophysiology and treatment of cerebral edema in traumatic brain injury","volume":"145","author":"Jha","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.nurt.2009.10.022","article-title":"Clinical trials in traumatic brain injury: Past experience and current developments","volume":"7","author":"Maas","year":"2010","journal-title":"Neurotherapeutics"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/fcp.12656","article-title":"Neuropharmacology in traumatic brain injury: From preclinical to clinical neuroprotection?","volume":"35","author":"Lerouet","year":"2021","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/s41586-020-2388-4","article-title":"Reversing a model of Parkinson\u2019s disease with in situ converted nigral neurons","volume":"582","author":"Qian","year":"2020","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1080\/026990598122539","article-title":"Morphological astrocytic changes in complicated human brain trauma. A light and electron microscopic study","volume":"12","year":"1998","journal-title":"Brain Inj."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3359","DOI":"10.1096\/fj.201902842R","article-title":"Traumatic brain injury increases plasma astrocyte-derived exosome levels of neurotoxic complement proteins","volume":"34","author":"Goetzl","year":"2020","journal-title":"FASEB J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.pneurobio.2016.03.010","article-title":"Astrocytes as a target for neuroprotection: Modulation by progesterone and dehydroepiandrosterone","volume":"144","author":"Arbo","year":"2016","journal-title":"Prog. Neurobiol."},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12964-020-00549-2","article-title":"Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury","volume":"18","author":"Zhou","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_11","first-page":"S7","article-title":"Targeting the Ischemic Penumbra","volume":"42","author":"Campos","year":"2011","journal-title":"Stroke"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.3760\/cma.j.issn.0366-6999.20120638","article-title":"Research progress in traumatic brain penumbra","volume":"127","author":"Wang","year":"2014","journal-title":"Chin. Med. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/B978-0-444-52892-6.00022-2","article-title":"Neuroprotection for traumatic brain injury","volume":"127","author":"Loane","year":"2015","journal-title":"Handb. Clin. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7231","DOI":"10.1523\/JNEUROSCI.1709-08.2008","article-title":"STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury","volume":"28","author":"Herrmann","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"5016","DOI":"10.1523\/JNEUROSCI.0820-04.2004","article-title":"Absence of Glial Fibrillary Acidic Protein and Vimentin Prevents Hypertrophy of Astrocytic Processes and Improves Post-Traumatic Regeneration","volume":"24","author":"Wilhelmsson","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1002\/glia.22723","article-title":"Beneficial effects of gfap\/vimentin re-active astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke","volume":"62","author":"Liu","year":"2014","journal-title":"Glia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e1385","DOI":"10.1212\/WNL.0000000000006321","article-title":"Glial fibrillary acidic protein elevations relate to neuroimaging abnormalities after mild TBI","volume":"91","author":"Gill","year":"2018","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1089\/neu.2018.5986","article-title":"Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2: Role in Hemorrhagic Progression of Contusion","volume":"36","author":"Gerzanich","year":"2019","journal-title":"J. Neurotrauma"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11771","DOI":"10.1038\/s41598-019-48145-w","article-title":"Survival-time dependent increase in neuronal IL-6 and astroglial GFAP expression in fatally injured human brain tissue","volume":"9","author":"Trautz","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1097\/01.shk.0000131193.80038.f1","article-title":"Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury","volume":"22","author":"Hayakata","year":"2004","journal-title":"Shock"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1089\/neu.2004.21.1553","article-title":"GFAP versus S100B in serum after traumatic brain injury: Relationship to brain damage and outcome","volume":"21","author":"Pelinka","year":"2004","journal-title":"J. Neurotrauma"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.expneurol.2015.07.016","article-title":"Longitudinal changes in the DTI measures, anti-GFAP ex-pression and levels of serum inflammatory cytokines following mild traumatic brain injury","volume":"275","author":"Singh","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1944","DOI":"10.1523\/JNEUROSCI.1067-18.2018","article-title":"Repetitive diffuse mild traumatic brain injury causes an atypical astrocyte response and spontaneous recurrent seizures","volume":"39","author":"Shandra","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"134335","DOI":"10.1016\/j.neulet.2019.134335","article-title":"Glial response in early stages of traumatic brain injury","volume":"708","author":"Zhao","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"13369","DOI":"10.1038\/s41598-020-70266-w","article-title":"Circulating GFAP and Iba-1 levels are associated with pathophysiological sequelae in the thalamus in a pig model of mild TBI","volume":"10","author":"Lafrenaye","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_27","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 pilocar-pine-induced seizures in traumatic brain injury model mice","volume":"145","author":"Sakai","year":"2021","journal-title":"J. Pharmacol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"82","DOI":"10.3389\/fneur.2014.00082","article-title":"Temporal dynamics of cerebral blood flow, cortical damage, apoptosis, astrocyte-vasculature interaction and astrogliosis in the pericontusional region after traumatic brain injury","volume":"5","author":"Villapol","year":"2014","journal-title":"Front. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1042\/AN20130034","article-title":"Temporal patterns of cortical proliferation of glial cell populations after traumatic brain injury in mice","volume":"6","author":"Susarla","year":"2014","journal-title":"ASN Neuro"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1089\/neu.2017.5421","article-title":"Delayed administration of BQ788, an ETB antagonist, after experimental traumatic brain injury promotes recovery of blood-brain barrier function and a reduction of cerebral edema in mice","volume":"35","author":"Michinaga","year":"2018","journal-title":"J. Neurotrauma"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1093\/brain\/awl165","article-title":"Essential protective roles of reactive astrocytes in traumatic brain injury","volume":"129","author":"Myer","year":"2006","journal-title":"Brain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8999","DOI":"10.1073\/pnas.1533187100","article-title":"Axonal plasticity and functional recovery after spinal cord injury in mice deficient in both glial fibrillary acidic protein and vimentin genes","volume":"100","author":"Menet","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1097\/shk.0b013e31802f9eaf","article-title":"Biphasic elevation in cerebrospinal fluid and plasma concentrations of endothelin 1 after traumatic brain injury in human patients","volume":"27","author":"Maier","year":"2007","journal-title":"Shock"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108182","DOI":"10.1016\/j.neuropharm.2020.108182","article-title":"Endothelin receptor antagonists alleviate blood-brain barrier disruption and cerebral edema in a mouse model of traumatic brain injury: A comparison between bosentan and ambrisentan","volume":"175","author":"Michinaga","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"13988","DOI":"10.1038\/s41598-017-13174-w","article-title":"Transcriptome Analysis Reveals neuroprotective aspects of Human Reactive Astrocytes induced by interleukin 1beta","volume":"7","author":"The","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gayen, M., Bhomia, M., Balakathiresan, N., and Knollmann-Ritschel, B. (2020). Exosomal MicroRNAs Released by Activated Astrocytes as Potential Neuroinflammatory Biomarkers. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072312"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7864","DOI":"10.1523\/JNEUROSCI.0982-17.2017","article-title":"Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain","volume":"37","author":"Semple","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/2051-5960-1-21","article-title":"MCP-1\/CCR2 signaling-mediated astrocytosis is accelerated in a transgenic mouse model of SOD1-mutated familial ALS","volume":"1","author":"Yamamoto","year":"2013","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.cell.2019.01.044","article-title":"CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury","volume":"176","author":"Joy","year":"2019","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Liraz-Zaltsman, S., Friedman-Levi, Y., Shabashov-Stone, D., Gincberg, M.G., Atrakchi-Baranes, D., Joy, M.T., Carmichael, S.T., Silva, A.J., and Shohami, E. (2021). Chemokine Receptors CC Chemokine Receptor 5 and C-X-C Motif Chemokine Receptor 4 Are New Therapeutic Targets for Brain Recovery after Traumatic Brain Injury. J. Neurotrauma.","DOI":"10.1089\/neu.2020.7015"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.brainres.2015.04.035","article-title":"VEGI attenuates the inflammatory injury and disruption of blood-brain barrier partly by suppressing the TLR4\/NF-\u03baB signaling pathway in experimental traumatic brain injury","volume":"1622","author":"Gao","year":"2015","journal-title":"Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1111\/j.1471-4159.2011.07610.x","article-title":"STAT3 signaling after traumatic brain injury","volume":"120","author":"Oliva","year":"2012","journal-title":"J. Neurochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3920","DOI":"10.1074\/jbc.RA118.005614","article-title":"Endothelin-1 stimulates expression of cyclin D1 and S-phase kinase-associated protein 2 by activating the transcription factor STAT3 in cultured rat astrocytes","volume":"294","author":"Koyama","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.neuint.2013.04.004","article-title":"Endothelin-1 stimulates cyclin D1 expression in rat cultured astrocytes via activation of Sp1","volume":"63","author":"Michinaga","year":"2013","journal-title":"Neurochem. Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1089\/neu.1999.16.1023","article-title":"Prolonged activation of NF-kappaB following traumatic brain injury in rats","volume":"16","author":"Nonaka","year":"1999","journal-title":"J. Neurotrauma"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1002\/jnr.10140","article-title":"NF-kappaB and IkappaBalpha expression following traumatic brain injury to the immature rat brain","volume":"67","author":"Sanz","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1111\/jnc.13423","article-title":"SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-\u03baB p65 acetylation and activation","volume":"136","author":"Yuan","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s40478-016-0350-3","article-title":"Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia","volume":"4","author":"Saggu","year":"2016","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1089\/neu.2013.3169","article-title":"Activation of NF-\u03baB mediates astrocyte swelling and brain edema in traumatic brain injury","volume":"31","author":"Jayakumar","year":"2014","journal-title":"J. Neurotrauma"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.neuroscience.2013.07.061","article-title":"IL-1\u03b2 induces GFAP expression in vitro and in vivo and protects neurons from traumatic injury-associated apoptosis in rat brain striatum via NF\u03baB\/Ca2+-calmodulin\/ERK mitogen-activated protein kinase signaling pathway","volume":"252","author":"Sticozzi","year":"2013","journal-title":"Neuroscience"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/4582135","article-title":"Loss of Sigma-1 Receptor Chaperone Promotes Astrocytosis and Enhances the Nrf2 Antioxidant Defense","volume":"2017","author":"Weng","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.phrs.2019.04.026","article-title":"Neuroprotection in non-transgenic and transgenic mouse models of Alzheimer\u2019s disease by positive modulation of sigma(1) receptors","volume":"144","author":"Maurice","year":"2019","journal-title":"Pharmacol Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.expneurol.2012.08.015","article-title":"Effects of heat shock protein 72 (Hsp72) on evolution of astrocyte activation following stroke in the mouse","volume":"238","author":"Barreto","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.bbrc.2019.08.100","article-title":"PDIA3-regulted inflammation and oxidative stress contribute to the traumatic brain injury (TBI) in mice","volume":"518","author":"Wang","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1089\/neu.2005.22.645","article-title":"Enhanced Hippocampal Neurogenesis by Intraventricular S100B Infusion Is Associated with Improved Cognitive Recovery after Traumatic Brain Injury","volume":"22","author":"Kleindienst","year":"2005","journal-title":"J. Neurotrauma"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/s00401-007-0208-7","article-title":"Cellular localization of pituitary adenylate cyclase-activating peptide (PACAP) following traumatic brain injury in humans","volume":"113","author":"Weiss","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41419-020-03329-5","article-title":"Downregulation of microRNA-9-5p promotes synaptic remodeling in the chronic phase after traumatic brain injury","volume":"12","author":"Wu","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/1759091416630220","article-title":"Astrocytic Ephrin-B1 Regulates Synapse Remodeling Following Traumatic Brain Injury","volume":"8","author":"Nikolakopoulou","year":"2016","journal-title":"ASN Neuro"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3114","DOI":"10.1172\/JCI92300","article-title":"Enhanced astrocytic d-serine underlies synaptic damage after traumatic brain injury","volume":"127","author":"Perez","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"105042","DOI":"10.1016\/j.neuint.2021.105042","article-title":"Down-regulation of astrocytic sonic hedgehog by acti-vation of endothelin ETB receptors: Involvement in traumatic brain injury-induced disruption of blood brain barrier in a mouse model","volume":"146","author":"Michinaga","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e117","DOI":"10.1016\/j.wneu.2018.05.202","article-title":"Mesencephalic Astrocyte-Derived Neurotrophic Factor Prevents Traumatic Brain Injury in Rats by Inhibiting Inflammatory Activation and Protecting the Blood-Brain Barrier","volume":"117","author":"Li","year":"2018","journal-title":"World Neurosurg."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"113044","DOI":"10.1016\/j.expneurol.2019.113044","article-title":"Astrocyte-derived fatty acid-binding protein 7 protects blood-brain barrier integrity through a caveolin-1\/MMP signaling pathway following traumatic brain injury","volume":"322","author":"Rui","year":"2019","journal-title":"Exp. Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"17584","DOI":"10.1002\/jcb.29025","article-title":"Overexpression of long noncoding RNA Malat1 ameliorates traumatic brain injury induced brain edema by inhibiting AQP4 and the NF-\u03baB\/IL-6 pathway","volume":"120","author":"Zhang","year":"2019","journal-title":"J. Cell. Biochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jocn.2020.09.015","article-title":"AQP4-siRNA alleviates traumatic brain edema by altering post-traumatic AQP4 polarity reversal in TBI rats","volume":"81","author":"Lu","year":"2020","journal-title":"J. Clin. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"17398","DOI":"10.1523\/JNEUROSCI.2756-13.2013","article-title":"Foxo3a Transcriptionally Upregulates AQP4 and Induces Cerebral Edema Following Traumatic Brain Injury","volume":"33","author":"Kapoor","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1111\/j.1471-4159.2011.07211.x","article-title":"Na-K-Cl cotransporter-1 in the mechanism of cell swelling in cultured astrocytes after fluid percussion injury","volume":"117","author":"Jayakumar","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.neuroscience.2014.04.040","article-title":"Glibenclamide reduces secondary brain damage after experimental traumatic brain injury","volume":"272","author":"Zweckberger","year":"2014","journal-title":"Neuroscience"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1016\/j.neuron.2017.07.010","article-title":"Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift","volume":"95","author":"Jassam","year":"2017","journal-title":"Neuron"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1089\/neu.2018.6226","article-title":"Therapeutic Effect of a Novel Fatty Acid Amide Hydrolase Inhibitor PF04457845 in the Repetitive Closed Head Injury Mouse Model","volume":"36","author":"Selvaraj","year":"2019","journal-title":"J. Neurotrauma"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1111\/bpa.12865","article-title":"Increased expression of miR142 and miR155 in glial and immune cells after traumatic brain injury may contribute to neuroinflammation via astrocyte activation","volume":"30","author":"Korotkov","year":"2020","journal-title":"Brain Pathol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3173","DOI":"10.1089\/neu.2016.4900","article-title":"Interleukin-33 Promotes Recruitment of Microglia\/Macrophages in Response to Traumatic Brain Injury","volume":"34","author":"Wicher","year":"2017","journal-title":"J. Neurotrauma"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1038\/jcbfm.2015.165","article-title":"S100B inhibition reduces be-havioral and pathologic changes in experimental traumatic brain injury","volume":"35","author":"Kabadi","year":"2015","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s12974-020-01761-0","article-title":"Astrocyte-derived exosomes enriched with miR-873a-5p inhibit neuroinflammation via microglia phenotype modulation after traumatic brain injury","volume":"17","author":"Long","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.nec.2006.10.007","article-title":"Neurogenesis After Traumatic Brain Injury","volume":"18","author":"Richardson","year":"2007","journal-title":"Neurosurg. Clin. N. Am."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.neuron.2019.11.029","article-title":"Communication, Cross Talk, and Signal Integration in the Adult Hippocampal Neurogenic Niche","volume":"105","author":"Vicidomini","year":"2020","journal-title":"Neuron"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"674","DOI":"10.3171\/2014.6.JNS132838","article-title":"Prognostic significance of blood-brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy","volume":"121","author":"Ho","year":"2014","journal-title":"J. Neurosurg."},{"key":"ref_77","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."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/jnc.14957","article-title":"Angiopoietin-1\/Tie-2 signal after focal traumatic brain injury is potentiated by BQ788, an ET B receptor antagonist, in the mouse cerebrum: Involvement in recovery of blood-brain barrier function","volume":"154","author":"Michinaga","year":"2020","journal-title":"J. Neurochem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"105080","DOI":"10.1016\/j.nbd.2020.105080","article-title":"Long-lasting blood-brain barrier dysfunction and neuroinflammation after traumatic brain injury","volume":"145","author":"Lehto","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"386","DOI":"10.3389\/fncel.2017.00386","article-title":"Transcriptome Analysis of Gene Expression Provides New Insights into the Effect of Mild Therapeutic Hypothermia on Primary Human Cortical Astrocytes Cultured under Hypoxia","volume":"11","author":"Salman","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13024-018-0249-5","article-title":"Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury","volume":"13","author":"Main","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41586-020-2247-3","article-title":"APOE4 leads to blood\u2013brain barrier dysfunction predicting cognitive decline","volume":"581","author":"Montagne","year":"2020","journal-title":"Nature"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12987-018-0108-3","article-title":"A perfused human blood-brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport","volume":"15","author":"Wevers","year":"2018","journal-title":"Fluids Barriers CNS"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"573775","DOI":"10.3389\/fbioe.2020.573775","article-title":"Design and Validation of a Human Brain Endothelial Microvessel-on-a-Chip Open Microfluidic Model Enabling Advanced Optical Imaging","volume":"8","author":"Salman","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1016\/j.cell.2020.03.037","article-title":"Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema","volume":"181","author":"Kitchen","year":"2020","journal-title":"Cell"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"16873","DOI":"10.1074\/jbc.M115.646034","article-title":"Identification and Molecular Mechanisms of the Rapid Tonicity-induced Relocalization of the Aquaporin 4 Channel","volume":"290","author":"Kitchen","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2317","DOI":"10.1089\/neu.2017.5593","article-title":"Neuroin-flammation after traumatic brain injury is enhanced in activating transcription factor 3 mutant mice","volume":"35","author":"Rehman","year":"2018","journal-title":"J. Neurotrauma"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1089\/neu.2020.7177","article-title":"High-Sensitivity C-Reactive Protein Is a Prognostic Biomarker of Six-Month Disability after Traumatic Brain Injury: Results from the TRACK-TBI Study","volume":"38","author":"Xu","year":"2020","journal-title":"J. Neurotrauma"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1089\/neu.2019.6979","article-title":"Early versus Late Profiles of Inflammatory Cytokines after Mild Traumatic Brain Injury and Their Association with Neuropsychological Outcomes","volume":"38","author":"Vedantam","year":"2021","journal-title":"J. Neurotrauma"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.lfs.2007.05.023","article-title":"Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury","volume":"81","author":"Chen","year":"2007","journal-title":"Life Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.expneurol.2007.03.031","article-title":"Simvastatin and atorvastatin improve behavioral outcome, reduce hippocampal degeneration, and improve cerebral blood flow after experimental traumatic brain injury","volume":"206","author":"Wang","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jocn.2017.06.010","article-title":"Effects of atorvastatin on brain contusion volume and functional outcome of patients with moderate and severe traumatic brain injury; a randomized double-blind placebo-controlled clinical trial","volume":"44","author":"Farzanegan","year":"2017","journal-title":"J. Clin. Neurosci."},{"key":"ref_93","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_94","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1007\/s12975-014-0362-x","article-title":"Recombinant Human Erythropoietin Improves the Neurofunctional Recovery of Rats Following Traumatic Brain Injury via an Increase in Circulating Endothelial Progenitor Cells","volume":"6","author":"Wang","year":"2015","journal-title":"Transl. Stroke Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1001\/jama.2014.6490","article-title":"Rivera, L.; Saucedo-Crespo, H.; et al. 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_96","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1016\/S0140-6736(15)00386-4","article-title":"Erythropoietin in traumatic brain injury (EPO-TBI): A double-blind randomised controlled trial","volume":"386","author":"Nichol","year":"2015","journal-title":"Lancet"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e1202","DOI":"10.1212\/WNL.0000000000011450","article-title":"Cell therapy for chronic TBI: Interim analysis of the randomized controlled STEMTRA trial","volume":"96","author":"Kawabori","year":"2021","journal-title":"Neurology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1111\/jnc.13920","article-title":"Transient receptor potential vanilloid type 4 channels mediate Na-K-Cl-co-transporter-induced brain edema after traumatic brain injury","volume":"140","author":"Lu","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.neuint.2017.05.020","article-title":"Inhibition of Na+-K+-2Cl\u2212 cotransporter attenuates blood-brain-barrier disruption in a mouse model of traumatic brain injury","volume":"111","author":"Zhang","year":"2017","journal-title":"Neurochem. Int."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1089\/neu.2016.4491","article-title":"Glibenclamide Attenuates Blood-Brain Barrier Disruption in Adult Mice after Traumatic Brain Injury","volume":"34","author":"Xu","year":"2017","journal-title":"J. Neurotrauma"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1089\/neu.2016.4696","article-title":"Glibenclamide Produces Region-Dependent Effects on Cerebral Edema in a Combined Injury Model of Traumatic Brain Injury and Hemorrhagic Shock in Mice","volume":"35","author":"Jha","year":"2018","journal-title":"J. Neurotrauma"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"25113","DOI":"10.5812\/traumamon.25113","article-title":"Evaluation of the Effect of Glibenclamide in Patients with Diffuse Axonal Injury Due to Moderate to Severe Head Trauma","volume":"21","author":"Zafardoost","year":"2016","journal-title":"Trauma Mon."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.wneu.2017.01.103","article-title":"Effects of Oral Glibenclamide on Brain Contusion Volume and Functional Outcome of Patients with Moderate and Severe Traumatic Brain Injuries: A Randomized Double-Blind Placebo-Controlled Clinical Trial","volume":"101","author":"Khalili","year":"2017","journal-title":"World Neurosurg."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1089\/neu.2013.2854","article-title":"17\u03b2-Estradiol Confers Protection after Traumatic Brain Injury in the Rat and Involves Activation of G Protein-Coupled Estrogen Receptor 1","volume":"30","author":"Day","year":"2013","journal-title":"J. Neurotrauma"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1007\/s12035-020-02171-2","article-title":"Estrogen Attenuates Traumatic Brain Injury by Inhibiting the Activation of Microglia and Astrocyte-Mediated Neuroinflammatory Responses","volume":"58","author":"Wang","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.yfrne.2018.03.006","article-title":"Sex-related responses after traumatic brain injury: Considerations for preclinical modeling","volume":"50","author":"Braun","year":"2018","journal-title":"Front. Neuroendocr."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2467","DOI":"10.1056\/NEJMoa1411090","article-title":"A Clinical Trial of Progesterone for Severe Traumatic Brain Injury","volume":"371","author":"Skolnick","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"13442","DOI":"10.1038\/srep13442","article-title":"Efficacy of progesterone for moderate to severe traumatic brain injury: A meta-analysis of randomized clinical trials","volume":"5","author":"Lin","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s12975-017-0588-5","article-title":"Effects of Female Sex Steroids Administration on Pathophysiologic Mechanisms in Traumatic Brain Injury","volume":"9","author":"Khaksari","year":"2018","journal-title":"Transl. Stroke Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1097\/01.ccm.0000473851.20338.3b","article-title":"Effect of the novel aquaporin-4 antagonist AER-271 in combined TBI plus hemorrhagic shock in mice","volume":"43","author":"Wallisch","year":"2015","journal-title":"Crit. Care Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"183573","DOI":"10.1016\/j.bbamem.2021.183573","article-title":"The effects of trifluoperazine on brain edema, aquaporin-4 expression and metabolic markers during the acute phase of stroke using photothrombotic mouse model","volume":"1863","author":"Sylvain","year":"2021","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.neulet.2005.06.019","article-title":"Fenofibrate, a peroxisome proliferator-activated receptor \u03b1 agonist, exerts neuroprotective effects in traumatic brain injury","volume":"388","author":"Besson","year":"2005","journal-title":"Neurosci. Lett."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1089\/neu.2006.0216","article-title":"Neurological Recovery-Promoting, Anti-Inflammatory, and Anti-Oxidative Effects Afforded by Fenofibrate, a PPAR Alpha Agonist, in Traumatic Brain Injury","volume":"24","author":"Chen","year":"2007","journal-title":"J. Neurotrauma"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.brainres.2008.09.074","article-title":"PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms","volume":"1244","author":"Yi","year":"2008","journal-title":"Brain Res."},{"key":"ref_115","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_116","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1089\/neu.2010.1685","article-title":"Pioglitazone reduces secondary brain damage after experimental brain trauma by PPAR-gamma-independent mechanisms","volume":"28","author":"Thal","year":"2011","journal-title":"J. Neurotrauma."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Hadass, O., Tomlinson, B.N., Gooyit, M., Chen, S., Purdy, J.J., Walker, J.M., Zhang, C., Giritharan, A.B., Purnell, W., and Robinson, C.R. (2013). Selective Inhibition of Matrix Metalloproteinase-9 Attenuates Secondary Damage Resulting from Severe Traumatic Brain Injury. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076904"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1089\/neu.2013.3230","article-title":"MMP-9 Inhibitor SB-3CT Attenuates Behavioral Impairments and Hippocampal Loss after Traumatic Brain Injury in Rat","volume":"31","author":"Jia","year":"2014","journal-title":"J. Neurotrauma"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1002\/cne.1129","article-title":"Reactive astrocytes express estrogen receptors in the injured primate brain","volume":"433","author":"Tuszynski","year":"2001","journal-title":"J. Comp. Neurol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"8867","DOI":"10.1073\/pnas.1103833108","article-title":"Neuroprotection mediated through estrogen receptor-alpha in astrocytes","volume":"108","author":"Spence","year":"2011","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1016\/j.expneurol.2004.06.008","article-title":"Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury","volume":"189","author":"He","year":"2004","journal-title":"Exp. Neurol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1002\/jcp.26083","article-title":"17\u03b2-estradiol rescues damages following traumatic brain injury from molecule to behavior in mice","volume":"233","author":"Lu","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_123","first-page":"142","article-title":"Gait\u00e1n-Vaca, D.M.; Areiza, N.; Echeverria, V.; Ashraf, G.M.; Gonz\u00e1lez, J.; Sahebkar, A.; Garcia-Segura, L.M.; Barreto, G.E. Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury","volume":"108","year":"2018","journal-title":"Neuroendocrinology"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"27618","DOI":"10.1038\/srep27618","article-title":"Localization of PPAR isotypes in the adult mouse and human brain","volume":"6","author":"Warden","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1210\/js.2017-00242","article-title":"Astrocyte-specific deletion of peroxisome-proliferator activated receptor-\u03b3 impairs glucose metabolism and estrous cy-clinG in female mice","volume":"1","author":"Fernandez","year":"2017","journal-title":"J. Endocr. Soc."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/nm1387","article-title":"Role of matrix metalloproteinases in delayed cortical responses after stroke","volume":"12","author":"Zhao","year":"2006","journal-title":"Nat. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1007\/s12975-011-0125-x","article-title":"Blood-Brain Barrier Pathophysiology in Traumatic Brain Injury","volume":"2","author":"Chodobski","year":"2011","journal-title":"Transl. Stroke Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"565","DOI":"10.3171\/jns.2003.98.3.0565","article-title":"Regulation of aquaporin-4 in a traumatic brain injury model in rats","volume":"98","author":"Sun","year":"2003","journal-title":"J. Neurosurg."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/978-3-540-79885-9_7","article-title":"Role of Aquaporin-4 in Cerebral Edema and Stroke","volume":"190","author":"Zador","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1111\/ejn.13723","article-title":"Hypothermia increases aquaporin 4 (AQP4) plasma membrane abundance in human primary cortical astrocytes via a calcium\/transient receptor potential vanilloid 4 (TRPV4)- and calmodulin-mediated mechanism","volume":"46","author":"Salman","year":"2017","journal-title":"Eur. J. Neurosci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"3860","DOI":"10.1016\/j.celrep.2019.05.097","article-title":"Aquaporin-4 Surface Trafficking Regulates Astrocytic Process Motility and Synaptic Activity in Health and Autoimmune Disease","volume":"27","author":"Ciappelloni","year":"2019","journal-title":"Cell Rep."},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Aldewachi, H., Al-Zidan, R.N., Conner, M.T., and Salman, M.M. (2021). High-Throughput Screening Platforms in the Discovery of Novel Drugs for Neurodegenerative Diseases. Bioengineering, 8.","DOI":"10.3390\/bioengineering8020030"},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Salman, M.M., Al-Obaidi, Z., Kitchen, P., Loreto, A., Bill, R., and Wade-Martins, R. (2021). Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22094688"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6418\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:16:32Z","timestamp":1760163392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/12\/6418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,15]]},"references-count":133,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22126418"],"URL":"https:\/\/doi.org\/10.3390\/ijms22126418","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,15]]}}}