Deficiency of tenascin-C and attenuation of blood-brain barrier disruption following experimental subarachnoid hemorrhage in mice

Abstract

A neurysmAl subarachnoid hemorrhage (SAH) is one of the most life-threatening cerebrovascular disorders, with high mortality and morbidity rates. 26,33 Delayed cerebral ischemia (DCI) remains the most important cause of morbidity and mortality in those patients who survive the initial bleeding. 20 Recent studies have reported that early brain injury (EBI), as well as cerebral vasospasm, is a major cause of DCI following SAH. 20EBI occurs before the onset of cerebral vasospasm and may cause DCI with no significant vasospasm. 3 Brain edema, which results mainly from blood-brain barrier (BBB) disruption, 18 plays an important role in the pathological abbreviatioNs 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 = plateletderived growth factor; SAH = subarachnoid hemorrhage; TNC = tenascin-C; TNKO = TNC knockout; WT = wild-type; ZO = zona occludens. obJective 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.

Cross‐talk between monocyte invasion and astrocyte proliferation regulates scarring in brain injury

“…This suggests that the reduction in the GFAP + area at later stages (28 dpi) is not due to an initially reduced upregulation of this protein. We further noted much higher levels (more than 100×) of tenascin‐C (Tn‐C) in WT compared to CCR2 −/− , an intriguing observation given the adverse effects Tn‐C has on the lesion size and scar formation . Reduced Tn‐C levels surrounding the injury site in CCR2 −/− mice at 5 dpi was confirmed by immunostaining (Fig EV5).…”

“…noted much higher levels (more than 100×) of tenascin-C (Tn-C) in WT compared to CCR2 À/À , an intriguing observation given the adverse effects Tn-C has on the lesion size and scar formation [41].…”

Plasma Periostin and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

“…In experimental SAH, POSTN caused EBI or BBB disruption via the activation of mitogen-activated protein kinases (MAPKs) and matrix metalloproteinase (MMP)-9, interacting with another matricellular protein tenascin-C [13]. MAPKs and MMP-9 are well known to cause the degradation of cerebral microvessel basal lamina and tight junction protein zona occludens-1, resulting in BBB disruption and brain edema formation after SAH [31,32]. A more recent study also showed the possible involvement of POSTN in the development of EBI or BBB disruption after experimental SAH [28].…”

Preventive effects of cilostazol against the development of shunt-dependent hydrocephalus after subarachnoid hemorrhage

“…30,32 TNC also caused brain injuries after experimental SAH. 12,29 Cilostazol-a selective inhibitor of phosphodiesterase Type III and a cyclic adenosine monophosphate (cAMP)elevating agent-is a clinically available antiplatelet agent and has pleiotropic actions, including vasodilatory and antiinflammatory effects. 25 It has been suggested that cilostazol reduces symptomatic vasospasm and is relatively widely administered to SAH patients in Japan.…”