title: Deficiency of tenascin-C and attenuation of blood-brain barrier disruption following experimental subarachnoid hemorrhage in mice.
abstract: OBJECT Tenascin-C (TNC), a matricellular protein, is induced in the brain following subarachnoid hemorrhage (SAH). The authors investigated if TNC causes brain edema and blood-brain barrier (BBB) disruption following experimental SAH. METHODS C57BL/6 wild-type (WT) or TNC knockout (TNKO) mice were subjected to SAH by endovascular puncture. Ninety-seven mice were randomly allocated to WT sham-operated (n = 16), TNKO sham-operated (n = 16), WT SAH (n = 34), and TNKO SAH (n = 31) groups. Mice were examined by means of neuroscore and brain water content 24-48 hours post-SAH; and Evans blue dye extravasation and Western blotting of TNC, matrix metalloproteinase (MMP)-9, and zona occludens (ZO)-1 at 24 hours post-SAH. As a separate study, 16 mice were randomized to WT sham-operated, TNKO sham-operated, WT SAH, and TNKO SAH groups (n = 4 in each group), and activation of mitogen-activated protein kinases (MAPKs) was immunohistochemically evaluated at 24 hours post-SAH. Moreover, 40 TNKO mice randomly received an intracerebroventricular injection of TNC or phosphate-buffered saline, and effects of exogenous TNC on brain edema and BBB disruption following SAH were studied. RESULTS Deficiency of endogenous TNC prevented neurological impairments, brain edema formation, and BBB disruption following SAH; it was also associated with the inhibition of both MMP-9 induction and ZO-1 degradation. Endogenous TNC deficiency also inhibited post-SAH MAPK activation in brain capillary endothelial cells. Exogenous TNC treatment abolished the neuroprotective effects shown in TNKO mice with SAH. CONCLUSIONS Tenascin-C may be an important mediator in the development of brain edema and BBB disruption following SAH, mechanisms for which may involve MAPK-mediated MMP-9 induction and ZO-1 degradation. TNC could be a molecular target against which to develop new therapies for SAH-induced brain injuries.
authors.affiliation: Departments of 1 Neurosurgery and.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Departments of 1 Neurosurgery and.
authors.forename: Masato
authors.initials: M
authors.lastname: Shiba
authors.affiliation: Departments of 1 Neurosurgery and.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Kawakita
authors.affiliation: Departments of 1 Neurosurgery and.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Pathology and Matrix Biology.|Research Center for Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Shimojo
authors.affiliation: Pathology and Matrix Biology.|Research Center for Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
authors.affiliation: Pathology and Matrix Biology.|Research Center for Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Departments of 1 Neurosurgery and.|Research Center for Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D015153:Blotting, Western; D001929:Brain Edema / Q000503:physiopathology; D002199:Capillary Permeability / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011897:Random Allocation; D013345:Subarachnoid Hemorrhage / Q000503:physiopathology*; D019063:Tenascin / Q000172:deficiency* / Q000235:genetics; D062826:Zonula Occludens-1 Protein / Q000378:metabolism
chemical_list: D019063:Tenascin; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: BBB = blood-brain barrier; DCI = delayed cerebral ischemia; EBI = early brain injury; ERK = extracellular signal-regulated kinase; ICA = internal carotid artery; JNK = c-Jun N-terminal kinase; MAPK = mitogen-activated protein kinase; MMP = matrix metalloproteinase; PBS = phosphate-buffered saline; PDGF = platelet-derived growth factor; SAH = subarachnoid hemorrhage; TNC = tenascin-C; TNKO = TNC knockout; WT = wild-type; ZO = zona occludens; blood-brain barrier disruption; brain edema; early brain injury; knockout mice; subarachnoid hemorrhage; tenascin-C; vascular disorders