title: S100B inhibition reduces behavioral and pathologic changes in experimental traumatic brain injury.
abstract: Neuroinflammation following traumatic brain injury (TBI) is increasingly recognized to contribute to chronic tissue loss and neurologic dysfunction. Circulating levels of S100B increase after TBI and have been used as a biomarker. S100B is produced by activated astrocytes and can promote microglial activation; signaling by S100B through interaction with the multiligand advanced glycation end product-specific receptor (AGER) has been implicated in brain injury and microglial activation during chronic neurodegeneration. We examined the effects of S100B inhibition in a controlled cortical impact model, using S100B knockout mice or administration of neutralizing S100B antibody. Both interventions significantly reduced TBI-induced lesion volume, improved retention memory function, and attenuated microglial activation. The neutralizing antibody also significantly reduced sensorimotor deficits and improved neuronal survival in the cortex. However, S100B did not alter microglial activation in BV2 cells or primary microglial cultures stimulated by lipopolysaccharide or interferon gamma. Further, proximity ligation assays did not support direct interaction in the brain between S100B and AGER following TBI. Future studies are needed to elucidate specific pathways underlying S100B-mediated neuroinflammatory actions after TBI. Our results strongly implicate S100B in TBI-induced neuroinflammation, cell loss, and neurologic dysfunction, thereby indicating that it is a potential therapeutic target for TBI.
authors.affiliation: Center for Shock, Trauma and Anesthesiology Research (STAR) and Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Shruti V
authors.initials: SV
authors.lastname: Kabadi
authors.affiliation: Center for Shock, Trauma and Anesthesiology Research (STAR) and Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Stoica
authors.affiliation: Center for Biomolecular Therapeutics and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Danna B
authors.initials: DB
authors.lastname: Zimmer
authors.affiliation: Center for Biomolecular Therapeutics and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Lauriaselle
authors.initials: L
authors.lastname: Afanador
authors.affiliation: Center for Biomolecular Therapeutics and Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kara B
authors.initials: KB
authors.lastname: Duffy
authors.affiliation: Center for Shock, Trauma and Anesthesiology Research (STAR) and Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Loane
authors.affiliation: Center for Shock, Trauma and Anesthesiology Research (STAR) and Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology*; D001930:Brain Injuries / Q000473:pathology* / Q000523:psychology*; D002460:Cell Line; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008297:Male; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia; D004856:Postural Balance; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D021641:Recognition, Psychology; D064568:S100 Calcium Binding Protein beta Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics*
chemical_list: C000593873:Ager protein, mouse; D057134:Antibodies, Neutralizing; D008070:Lipopolysaccharides; D000067759:Receptor for Advanced Glycation End Products; D064568:S100 Calcium Binding Protein beta Subunit; C579159:S100b protein, mouse; D007371:Interferon-gamma