sb-3ct-compound and Subarachnoid-Hemorrhage

Our previous study determined that prominent cerebral vasospasm (CVS) may occur in an in vivo model of subarachnoid hemorrhage (SAH) in rats. Matrix metalloproteinase 9 (MMP‑9) expression levels in basilar arteries were upregulated in a similar manner to the development of CVS following SAH. To identify the changes that occur in the contractility of cerebrovascular smooth muscle cells and the expression levels of MMP‑9 in an in vitro model of SAH, rat cerebrovascular smooth muscle cells were isolated, cultured, and then stimulated with hemolysate. Additionally, 2-[(4-phenoxyphenylsulfonyl)methyl]thiirane (SB-3CT), a selective MMP-9 inhibitor, was used to determine the effect of MMP‑9 on the contractility of cerebrovascular smooth muscle cells. Cerebrovascular smooth muscle cells were successfully isolated and cultured in vitro, and hemolysate stimulation enhanced their contractility and increased MMP‑9 expression levels. The present study also revealed that pretreatment with SB‑3CT decreased MMP‑9 expression levels in cerebrovascular smooth muscle cells, and reduced their contractility upon hemolysate treatment. Therefore, the current study confirmed that MMP‑9 is important for the enhancement of the contractility of cerebrovascular smooth muscle cells in an in vitro rat model of SAH.

Topics: Animals; Basilar Artery; Cells, Cultured; Disease Models, Animal; Heterocyclic Compounds, 1-Ring; Humans; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Muscle Contraction; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Rats; Subarachnoid Hemorrhage; Sulfones

This study investigated the possible involvement of matrix metalloproteinase 9 (MMP-9) in cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in rats. The CVS model was established by injection of fresh autologous nonheparinized arterial blood into the cisterna magna. Experiment 1 aimed to investigate the timecourse of the MMP-9 expression in the basilar artery after SAH. In Experiment 2, we chose the maximum time point of vasospasm (Day 3) and assessed the effect of SB-3CT (a selective MMP- 9 inhibitor) on the regulation of cerebral vasospasm. The cross-sectional area of basilar artery was measured by H&E staining and the MMP-9 expression was assessed by immunohistochemistry analysis. The elevated expression of MMP-9 was detected in the basilar artery after SAH and peaked on day 3. After intracisternal administration of SB-3CT, the vasospasm was markedly attenuated after blood injection on day 3. Our results suggest that MMP-9 is increasingly expressed in a parallel time course to the development of cerebral vasospasm in this rat experimental model of SAH and that the administration of the specific MMP-9 inhibitor could prevent or reduce cerebral vasospasm caused by SAH.

Topics: Animals; Basilar Artery; Heterocyclic Compounds, 1-Ring; Immunohistochemistry; Male; Matrix Metalloproteinase 9; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Sulfones; Vasospasm, Intracranial

An increasing number of unruptured intracranial aneurysms are being detected, partly due to the increased use of brain imaging techniques. Pharmacological stabilization of aneurysms for the prevention of aneurysmal rupture could potentially be an attractive alternative approach to clipping or coiling in patients with unruptured intracranial aneurysms. We have developed a mouse model of intracranial aneurysm that recapitulates key features of intracranial aneurysms. In this model, subarachnoid hemorrhage from aneurysmal rupture causes neurological symptoms that can be easily detected by a simple neurological examination. Using this model, we tested whether anti-inflammatory agents such as tetracycline derivatives, or a selective inhibitor of matrix metalloproteinases-2 and -9 (SB-3CT), can prevent the rupture of intracranial aneurysms.. Aneurysms were induced by a combination of induced hypertension and a single injection of elastase into the cerebrospinal fluid in mice. Treatment with minocycline, doxycycline, or SB-3CT was started 6 days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysms with subarachnoid hemorrhage.. Minocycline and doxycycline significantly reduced rupture rates (vehicle versus doxycycline=80% versus 35%, P<0.05; vehicle versus minocycline=73% versus 24%, P<0.05) without affecting the overall incidence of aneurysms. However, SB-3CT did not affect the rupture rate (62% versus 55%, P=0.53).. Our data established the feasibility of using a mouse model of intracranial aneurysm to test pharmacological stabilization of aneurysms. Tetracycline derivatives could be potentially effective in preventing aneurysmal rupture.

Topics: Aneurysm, Ruptured; Animals; Blood Pressure; Disease Models, Animal; Doxycycline; Feasibility Studies; Gelatinases; Heterocyclic Compounds, 1-Ring; Intracranial Aneurysm; Male; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Minocycline; Neurologic Examination; Protease Inhibitors; Subarachnoid Hemorrhage; Sulfones; Survival Analysis; Tetracyclines

This study investigated the role of matrix metalloproteinase-9 (MMP-9) in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Sprague-Dawley male rats (n=30) between 250 and 300 g were used. SAH was produced by injecting autologous arterial blood into the prechiasmatic cistern. SB-3CT, a selective MMP-9 inhibitor, was injected intraperitoneally after SAH induction. MMP-9 protein expression was measured by western blot; laminin expression and neuronal cells in the cerebral cortex were studied by immunohistochemistry and TUNEL staining at 24h after SAH. MMP-9 expression was increased after SAH and decreased by SB-3CT inhibition at 24h after SAH (P<0.01). Laminin, the substrate of MMP-9, was decreased at 24h after SAH, and SB-3CT prevented laminin degradation. The number of TUNEL-positive neurons in cerebral cortex was increased after SAH and decreased by SB-3CT (P<0.01). MMP-9 may be involved in EBI after SAH and inhibition of MMP-9 may reduce EBI in cerebral cortex.

Topics: Analysis of Variance; Animals; Brain Injuries; Cerebral Cortex; Disease Models, Animal; Down-Regulation; Enzyme Inhibitors; Heterocyclic Compounds, 1-Ring; In Situ Nick-End Labeling; Laminin; Male; Matrix Metalloproteinase 9; Neurons; Rats; Rats, Sprague-Dawley; Subarachnoid Hemorrhage; Sulfones