Introduction:
Tenascin-C (TNC) is one of pleiotropic matricellular proteins, which are non-structural and secreted extracellular matrix proteins that exert diverse functions. Recently we showed that TNC is involved in the mechanisms of cerebral vasospasm and early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the role of TNC has not been sufficiently investigated in SAH.
Materials and Methods:
First, TNC knockout (TNKO) mice SAH models were produced by endovascular perforation method, and examined the direct evidence that TNC is induced after SAH and causes cerebral vasospasm and EBI. Second, TNC was measured in serum from 156 aneurysmal SAH patients, and cilostazol (0-300 mg/day) was administered postoperatively, and investigated as to the dose-dependent effect of cilostazol on cerebral vasospasm, delayed cerebral ischemia and infarction.
Results:
In experimental SAH, TNKO prevented blood-brain barrier disruption and brain edema formation by inhibiting mitogen-activated protein kinase (MAPK)-mediated matrix metalloproteinase-9 activation. TNKO also suppressed post-SAH induction of another matricellular protein, periostin, which aggravates post-SAH EBI. TNKO also prevented neuroinflammation and neuronal apoptosis via inhibiting upregulation of Toll-like receptor 4, phosphorylation of nuclear factor-κB, and induction of proinflammatory cytokines in neurons. TNKO suppressed post-SAH cerebral vasospasm via inhibiting the activation of MAPKs. In the clinical study, cilostazol treatment suppressed plasma TNC levels from days 1-3 to days 10-12 post-SAH, and showed dose-dependent effects against delayed cerebral infarction, leading to improved outcome. Multivariate analyses revealed that 300 mg/day cilostazol treatment was an independent determinant against poor outcomes post-SAH.
Conclusions:
TNKO exerted protective effects against neuroinflammation, blood-brain barrier disruption, neuronal apoptosis, and cerebral vasospasm. The 300 mg/day cilostazol may improve post-SAH outcomes by reducing plasma TNC levels and delayed cerebral infarction. Further investigations may provide a novel therapeutic approach targeting TNC.
Treatment with sodium orthovanadate reduces blood-brain barrier disruption via phosphatase and tensin homolog deleted on chromosome 10 (PTEN) phosphorylation in experimental subarachnoid hemorrhage
