Canagliflozin Inhibits Glioblastoma Growth and Proliferation by Activating AMPK.

Sodium-glucose transporter 2 (SGLT2) inhibitors are antidiabetic drugs affecting SGLT2. Recent studies have shown various cancers expressing SGLT2, and SGLT2 inhibitors attenuating tumor proliferation. We evaluated the antitumor activities of canagliflozin, a SGLT2 inhibitor, on glioblastoma (GBM). Three GBM cell lines, U251MG (human), U87MG (human), and GL261 (murine), were used. We assessed the expression of SGLT2 of GBM through immunoblotting, specimen-use, cell viability assays, and glucose uptake assay with canagliflozin. Then, we assessed phosphorylation of AMP-activated protein kinase (AMPK), p70 S6 kinase, and S6 ribosomal protein by immunoblotting. Concentrations of 5, 10, 20, and 40 µM canagliflozin were used in these tests. We also evaluated cell viability and immunoblotting using U251MG with siRNA knockdown of SGLT2. Furthermore, we divided the mice into vehicle group and canagliflozin group. The canagliflozin group was administrated with 100 mg/kg of canagliflozin orally for 10 days starting from the third days post-GBM transplant. The brains were removed and the tumor volume was evaluated using sections. SGLT2 was expressed in GBM cell and GBM allograft mouse. Canagliflozin administration at 40 µM significantly inhibited cell proliferation and glucose uptake into the cell. Additionally, canagliflozin at 40 µM significantly increased the phosphorylation of AMPK and suppressed that of p70 S6 kinase and S6 ribosomal protein. Similar results of cell viability assays and immunoblotting were obtained using siRNA SGLT2. Furthermore, although less effective than in vitro, the canagliflozin group significantly suppressed tumor growth in GBM-transplanted mice. This suggests that canagliflozin can be used as a potential treatment for GBM.

How I do it: combined bypass for adult moyamoya disease with maximal consideration of cosmetic aspects.

BACKGROUND: Combined bypass, including direct and indirect procedures, has been recognized as the maximal revascularization to prevent further hemorrhagic or ischemic stroke in adult moyamoya disease (MMD). It is also important to consider cosmetic aspects when planning combined bypass for MMD. However, there are few reports that have described the cosmetic considerations in bypass surgery for MMD. METHODS: We demonstrate our surgical techniques aimed at achieving extended revascularization as well as excellent cosmetic outcomes with figures and video. CONCLUSION: Our combined bypass procedures which focus on achieving maximal cosmetic results are effective methods that require no special instruments or techniques.

Nafamostat protects against early brain injury after subarachnoid hemorrhage in mice.

This study aimed to evaluate the effects of nafamostat, a serin protease inhibitor, in the management of subarachnoid hemorrhage (SAH). SAH was induced by endovascular perforation in male mice. Nafamostat was administered intraperitoneally four times immediately after SAH induction. Cerebral blood flow, neurological behavior tests, SAH grade and protein expression were evaluated at 24 h after SAH induction. In the in vitro model, human brain microvascular endothelial cells (HBMVECs), HBVECs were exposed to thrombin and hypoxia for 24 h; nafamostat was administered and the protein expression was evaluated. Eighty-eight mice were included in the in vivo study. Fifteen mice (17%) were excluded because of death or procedure failure. Nafamostat exerted no significant effect on the SAH grade or cerebral blood flow; however, it improved the neurological behavior and suppressed the thrombin and MMP-9 expression. In addition, nafamostat suppressed the ICAM-1 expression and p38 phosphorylation in the in vitro study. Nafamostat has a protective effect against HBMVEC after exposure to thrombin and hypoxia, suggesting its role in improving the neurological outcomes after SAH. These findings indicate that nafamostat has the potential to be a novel therapeutic drug in the management of SAH.

What's happening in carotid stent? A case report of prominent plaque protrusion after carotid artery stenting observed on angioscopy.

Thromboembolic complications after carotid artery stenting (CAS) remain an unsolved problem, and several intravascular imaging tools have been proposed to clarify the mechanism of these complications. We report a case of intraprocedural plaque protrusion revealed by angioscopy. A 64-year-old woman underwent CAS for left carotid artery stenosis. After stent placement, optical frequency domain imaging demonstrated some plaque protrusion, and angioscopy showed prominent mobile plaque fragments protruding into the vessel between stent struts and confirmed the coverage of the protruded plaque after the overlapping stent was placed. Compared with other tools, angioscopy more clearly revealed plaque protrusion in the vessel after CAS.

Impact of Procedure Time on Clinical Outcomes of Patients Who Underwent Endovascular Therapy for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: The time from onset to reperfusion is associated with clinical outcomes in acute ischemic stroke due to large vessel occlusion (LVO); nevertheless, the time limit of the continuing procedure remains unclear. We analyzed the relationship between procedure time and clinical outcomes in patients with LVO who underwent endovascular treatment (EVT). METHODS: We assessed 1,247 patients who underwent EVT for LVO. Data were obtained from our multicenter registry, and patients were included if data on procedure time were available. Multivariate analysis was performed to assess the impact of procedure time on clinical outcomes using the following parameters: favorable outcome (the modified Rankin score of 0-2 at 90 days), mortality within 90 days, symptomatic intracranial hemorrhage within 72 h after stroke onset, and procedure-related complications. RESULTS: The rate of favorable outcomes linearly decreased with increasing procedure time, but there was no linear relationship between procedure time and other outcomes. The adjusted odds ratio for 30-minute delay in procedure time was 0.76 (95% confidence interval, 0.68-0.84) for favorable outcome, 1.15 (0.97-1.36) for mortality, 1.08 (0.87-1.33) for symptomatic intracranial hemorrhage, and 0.92 (0.75-1.16) for complications. Significant interactions in the effect of procedure time on favorable outcome were observed between the subgroups stratified by age (≥75 or <75 years). Younger patients had a greater deleterious effect of delayed reperfusion. CONCLUSIONS: Increasing procedure time was associated with less favorable outcomes, but not with the rate of mortality, symptomatic intracerebral hemorrhage, or complications in our cohort.

Long-term complications after stent assist coiling dependent on clopidogrel response.

BACKGROUND: Dual antiplatelet therapy (DAPT) is necessary for stent assisted coiling. However, long term use of DAPT has a potential risk of hemorrhagic events. We aimed to examine the relationship between clopidogrel reactivity and complications. METHODS: Patients who underwent stent assisted coiling for unruptured aneurysms or previously treated aneurysms and received periprocedural DAPT in our institution between August 2011 to March 2020 were included. Platelet reactivity for clopidogrel was measured by VerifyNow assay system, and we defined the cut off value of P2Y12 Reaction Units (PRU) at 208 and classified patients as hypo-responders (PRU≧208) or responders (PRU<208). The rates of hemorrhagic and thrombotic events within 30 days (acute phase) and 30 days after the procedure (delayed phase) were compared between the two groups. Furthermore, changes in hemoglobin levels were measured before and after the procedure and at chronic stages (1 to 6 months thereafter). RESULTS: From 61 patients included in this study, 36 patients were hypo-responders and 25 patients were responders. Hemorrhagic events occurred 8.0% only in responders in the acute phase (p = 0.16), and 2.78% in hypo-responders and 20.0% in responders in the delayed phase (p = 0.037). Changes in hemoglobin levels before and after the procedure were 1.22 g/dl in hypo-responders and 1.74 g/dl in responders (p = 0.032) while before the procedure and chronic stages they were 0.39 g/dl in hypo-responders and 1.39 g/dl in responders (p <  0.01). Thrombotic events were not significantly different between the two groups. CONCLUSION: Long term use of DAPT after stent assisted coiling is related to hemorrhagic events in the delayed phase. Preventing for hemorrhagic events, the duration of DAPT should be carefully considered in clopidogrel responders.

Real-world treatment results for ruptured blood-blister aneurysm of the internal carotid artery: analysis of a Japanese nationwide multicenter study.

Ruptured blood-blister aneurysm (BBA) of the internal carotid artery (ICA) remains a challenging lesion, even in the age of modern neurosurgery and endovascular treatment. This retrospective multicenter study aimed to investigate the real-world treatment choice and treatment results. We included 182 ruptured BBAs of the ICA treated at 51 neurosurgical centers in Japan between 2013 and 2017. The baseline patient characteristics, radiological features of the aneurysm, treatment modality, details of treatment, complications of treatment, and treatment results were retrospectively collected. The treatment strategy was divided into deconstructive and reconstructive procedures. Primary clinical outcomes were evaluated using the modified Rankin scale (mRS) at final follow-up. Direct surgery was performed in 144 (79%) cases, and the remaining 38 (21%) cases received endovascular treatment. The majority of treatment selections were deconstructive and reconstructive procedures in the direct surgery group and endovascular treatment group, respectively. Overall, favorable clinical outcomes (mRS 0 to 2) were achieved in 66% of cases, and the mortality rate was 15% at the final follow-up (mean 23 months). There was no significant difference in clinical outcome between direct and endovascular treatment groups. Our large nationwide study compared the real-world treatment options for ruptured BBAs and their results. Our findings may offer beneficial information for treatment decision and for future studies investigating ruptured BBAs.

Involvement of Cerebral Blood Flow on Neurological and Behavioral Functions after Subarachnoid Hemorrhage in Mice.

OBJECTIVE: Cerebral Blood Flow (CBF) change after Subarachnoid Hemorrhage (SAH) is strongly associated with brain injuries such as early brain injury and delayed cerebral ischemia. We evaluated the correlation between CBF using Laser Speckle Flow Imaging (LSFI) after SAH and neurological findings in the sub-acute phase. METHOD: An SAH was induced by endovascular perforation in male mice. CBF was quantitatively measured by using LSFI at six time points, immediately to 14 days after SAH induction. Behavior tests and survival rate were evaluated. The mice were divided into recovery and hypo-perfusion groups according to their CBF at 1 day after the procedure. RESULT: Forty mice were included in this study. Five mice (20%) were included in the hypo-perfusion group, and the remaining 20 (80%) mice were classified as the recovery group. The decrease of CBF in the recovery group was observed until 1 day after the procedure. However, the decrease of CBF in the hypo-perfusion group was prolonged until 7 days after the procedure. Neurological findings and survival rates in the hypo-perfusion group were significantly worse than those in the recovery group. The low alternation cases (≤ 50%) in the Y-maze test in the recovery group (n = 5) had significantly lower CBF at 1 day after the procedure. CONCLUSION: Low blood flow at 1 day after SAH was associated with worse survival rate, neurological findings, and memory disturbance. Early improvement in CBF may be associated with an improved prognosis after SAH.

Tissue Protrusion With Attenuation Is Associated With Ischemic Brain Lesions After Carotid Artery Stenting.

Background and Purpose- Tissue protrusion between stent struts is frequently observed on optical frequency domain imaging evaluation after carotid artery stenting, but its clinical relevance is unclear. We aimed to investigate the association between the characteristics of tissue protrusion assessed by optical frequency domain imaging and brain lesions identified by diffusion-weighted imaging after carotid artery stenting. Methods- Sixty-five consecutive patients who underwent optical frequency domain imaging after protected carotid artery stenting were enrolled in the study. Cross-sectional optical frequency domain images within the stented segments were evaluated at 0.125-mm intervals. Magnetic resonance imaging was performed 1 to 10 days after treatment. The characteristics of tissue protrusion were compared between patients with and without new ipsilateral brain lesions on posttreatment magnetic resonance imaging. Results- Tissue protrusion was observed in 62 patients (95%). New brain lesions were observed in 24 patients (37%). In the multivariate analysis, the presence of protrusion with attenuation (odds ratio, 2.94 [95% CI, 1.05-8.68] P=0.04) was associated with new brain lesions after carotid artery stenting. Conclusions- The presence of protrusion with attenuation assessed by optical frequency domain imaging was associated with ipsilateral brain lesions after carotid artery stenting. Prevention or treatment of protrusions with attenuation may reduce ischemic brain lesions after carotid artery stenting.

A Case of Delayed Intraparenchymal Hemorrhage Due to Hyperperfusion After Flow Diverter Treatment.

Delayed intraparenchymal hemorrhage (DIPH) is one of the complications of flow diverter (FD) treatment, however, the mechanism is unclear. We present the case of a 54-year-old woman with a partially thrombosed large internal carotid artery aneurysm. She presented intraparenchymal hemorrhage in the right parietal lobe three days after the successful FD treatment. We performed endoscopic hematoma removal, and then her consciousness disturbance was fully recovered. IMP single-photon emission computed tomography showed significant increase of cerebral blood flow in the right hemisphere. We diagnosed DIPH associated with hyperperfusion after FD treatment. It is necessary to consider that DIPH due to hyperperfusion may occur after FD treatment.

Importance of CBF measurement to exclude concomitant cerebral infarction in the murine endovascular perforation SAH model.

OBJECTIVE: Concomitant cerebral infarction (CI) is could be a potential concern in experimental subarachnoid hemorrhage (SAH) induced by endovascular perforation. We propose a noninvasive method for excluding CI in a murine SAH model by using Laser speckle flow imaging (LSFI). METHODS: An SAH was induced with endovascular perforation (EVP) in male ddY mice. The cerebral blood flow (CBF) was quantitatively measured in the bilateral cerebral cortex was performed by using LSFI at five timepoints (preprocedure, immediately after, and 3 hours, 6 hours, and 24 hours after the procedure). The mice were then euthanized, and the SAH grade and volume of the CI were evaluated. The mice were divided into the SAH group and the SAH + CI group. Differences between the groups were assessed. RESULTS: Forty-eight mice were used in this study. Six were the sham control group. Five SAH mice died within 24 hours after the procedure. A large CI on the ipsilateral side occurred in 15 (40.5%) mice (i.e., SAH + CI group). The remaining 22 (59.5%) mice were classified as the SAH group. The SAH grading score was not significantly different between the groups. The neurological score and CBF of the ipsilateral hemisphere were significantly higher in the SAH group than in the SAH + CI group (neurological score: 12.3 vs. 8, p < 0.01; CBF: 343.1 vs. 205.5; p < 0.01). The cut-off modified neurological score for excluding CI was 8 (area under the curve [AUC]: 0.77) and CBF at 24 hours after the procedure was 279.2 (AUC:0.856). CONCLUSIONS: Using LSFI is less invasive and effectively excludes concomitant CI in experimental SAH. This methodological protocol may ad in improving the quality of the EVP-SAH model.

A Rare Case of Symptomatic Carotid Stenosis Caused by Mechanical Stimulation by Thyroid Cartilage and Frequent Swimming.

BACKGROUND: Bony structures around the carotid artery such as the styloid process and hyoid bone can cause dissection, compression, plaque formation, and plaque rupture of the carotid artery. To the best of our knowledge, this case is the first finding of thyroid cartilage being the cause of a lesion corresponding to adjacent common carotid artery (CCA) atherosclerosis. CASE DESCRIPTION: A 51-year-old man with a history of hypertension and dyslipidemia suddenly experienced right facial numbness and dysphasia while front crawl swimming, which he usually did 3 times weekly. Diffusion-weighted magnetic resonance imaging showed high intensity areas in the left frontal and parietal lobes. He was diagnosed with acute cerebral infarction and was administered with tissue plasminogen activator. Angiography of the left CCA revealed mild stenosis with an intravascular filling defect, and carotid duplex ultrasonography of the CCA on the second day after symptom onset showed plaque and intraluminal thrombus at the stenotic site. Plain and contrast-enhanced computed tomography showed that thyroid cartilage contacted the left CCA at the stenotic site, and the left CCA moved backward and forward with the thyroid cartilage during neck rotation. We determined that mechanical stimulation by the thyroid cartilage had induced the plaque during the frequent neck rotation that is a feature of front crawl swimming. CONCLUSIONS: Evaluation of anatomical interactions between the carotid artery and bony structures including the thyroid cartilage is important to ensure that appropriate treatment is selected to prevent further ischemia.

[Acute Thrombectomy for Atherothrombotic Major Vessel Occlusion].

Although the most common cause of major vessel occlusion is cardiogenic embolism(CE), atherothrombotic(AT)major vessel occlusion sometimes occur and recognize it during endovascular therapy. We evaluated the characteristics of patients with atherothrombotic major vessel occlusion who underwent endovascular therapy by comparing with them with those with cardiogenic embolism. We retrospectively evaluated 64 consecutive patients with major vessel occlusion who underwent endovascular thrombectomy between July 2014 and March 2018 in our institution. Eleven(17%)of the 64 patients were classified into the atherothombotic group based on the Trial of Org 10172 in Acute Stroke Treatment(TOAST)classification except for artery to artery embolism. In the AT group, the proportions of patients with younger age(67±13 years old vs. 77±11 years old, p=0.048)and posterior circulation(55% vs. 8%, p=0.001)were significantly higher than in the CE group. The mean times from onset to hospital arrival and from onset to revascularization were significantly longer in the AT group than in the CE group(313±325min vs. 129±67min, p=0.008 and 468±359min vs. 280±93min, p=0.018). No significant differences in the rate of successful revascularization and favorable outcome were found between the 2 groups. More patients in the AT group than in the CE group tended to maintain their previous modified Ranking Scale score(54% vs. 24%, p=0.058). Our study shows that the patients with atherothrombotic major vessel occlusion had lower activities-of-daily living scores but attained high successful rates of revascularization and similar neurological outcome as that of multimodal endovascular therapy, as compared with the patients with cardiogenic embolism.

Tailored Strategies in Carotid Artery Stenting to Avoid Periprocedural Complications.

Carotid artery stenting (CAS) has been widely accepted as a valuable therapeutic alternative to carotid endarterectomy (CEA) for high-grade carotid stenosis. Because carotid revascularization including CAS is usually performed in patients with minimal or no neurological deficits, utmost care should be taken to avoid periprocedural complications. The major concerns associated with CAS are embolic stroke, hyperperfusion syndrome (HPS), and perioperative myocardial infarction.Plaque characteristics, cerebral blood flow (CBF) in the affected cerebral hemisphere, and concomitant coronary artery disease prior to CAS are all important to assess the risks of these complications and are routinely evaluated.Tailored CAS is planned based on findings of preoperative evaluation, as follows. (1) If the plaque component is thought vulnerable, proximal embolic protection methods, use of a closed-cell-type stent, or referral to CEA should be considered to avoid embolic complications. (2) If patients have severe CBF impairment, staged angioplasty is an effective strategy to prevent postoperative HPS. (3) If concomitant cardiac diseases are present, the optimal treatment sequence should be discussed between cardiologists and neurointerventionalists.These tailored strategies based on preoperative risk evaluations may lead to safer procedures and better clinical outcome in CAS patients.

Intravenous tissue plasminogen activator before endovascular treatment increases symptomatic intracranial hemorrhage in patients with occlusion of the middle cerebral artery second division: subanalysis of the RESCUE-Japan Registry.

INTRODUCTION: No previous study has investigated the relationship between intravenous tissue plasminogen activator (IV t-PA) and intracranial hemorrhage (ICH) according to the location of vessel occlusion. The aim of the present study was to investigate the relationship between preprocedural IV t-PA and endovascular treatment (EVT) and ICH according to the location of occlusion using data from the nationwide prospective registry of acute cerebral large vessel occlusion (LVO), the RESCUE-Japan Registry. METHODS: Among 1442 patients with acute LVO enrolled in the registry, we examined 410 patients who received EVT. Patients were divided into the following four groups according to the location of occlusion: the internal carotid artery (ICA), middle cerebral artery first division (M1), middle cerebral artery second division (M2), and vertebral artery (VA)/basilar artery (BA) groups. RESULTS: A total of 399 patients in whom the occlusion was located in these vessels were finally included. Any ICH (aICH) was identified in 127 (30.9%) patients, and symptomatic ICH (sICH) was identified in 20 (4.9%). Preprocedural IV t-PA did not increase the incidence of aICH in any group and tended to increase the incidence of sICH in only the M2 group. In multivariate analysis of the M2 group, IV t-PA was an independent risk factor for sICH. CONCLUSION: Preprocedural IV t-PA did not increase the incidence of ICH in total, but could increase the incidence of sICH in those with M2 occlusion. IV t-PA before EVT may be an independent risk factor for sICH in patients with M2 occlusion.

Lipocalin 2 and Blood-Brain Barrier Disruption in White Matter after Experimental Subarachnoid Hemorrhage.

We reported previously that subarachnoid hemorrhage (SAH) causes acute white matter injury in mice. In this study, we investigated lipocalin 2 (LCN2) mediated blood-brain barrier (BBB) disruption in white matter, which may lead to subsequent injury. SAH was induced by endovascular perforation in wild-type (WT) and LCN2-knockout (LCN2(-/-)) mice. Sham mice underwent the same procedure without perforation. Mice underwent magnetic resonance imaging (MRI) 24 h after SAH to confirm the development of T2-hyperintensity in white matter. Western blotting and immunohistochemistry were performed to elucidate the mechanisms of LCN2-mediated white matter injury and BBB disruption. It was confirmed that LCN2 expression was significantly increased in white matter of WT mice after SAH by Western blotting (versus sham; p < 0.05). Immunohistochemistry showed that LCN2 receptor 24p3R was expressed in oligodendrocytes, astrocytes, endothelial cells, and pericytes in the white matter. In WT mice with SAH, albumin leakage along the white matter was prominently observed and was consistent with T2-hyperintensity on MRI. As with our previous report, LCN2(-/-) mice scarcely developed T2-hyperintensity on MRI or albumin leakage in white matter. Our results suggest that BBB leakage occurs in white matter after SAH and that LCN2 contributes to SAH-induced BBB disruption.

The Risk of Intracranial Hemorrhage in Japanese Patients with Acute Large Vessel Occlusion; subanalysis of the RESCUE-Japan registry.

BACKGROUND: Recanalization therapies such as intravenous thrombolysis (IVT) or endovascular treatment (EVT) improve acute ischemic stroke outcomes; however, they carry the risk of intracranial hemorrhage (ICH). The present study assessed the frequency and predictive factor of ICH in Japanese patients with acute large vessel occlusion. METHODS: The Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism-Japan Registry prospectively registered 1442 stroke patients with major vessel occlusion who were admitted to 84 Japanese stroke centers within 24 hours after onset, from July 2010 to June 2011. Among these 1442 patients, 1357 were included to evaluate the incidence rate and predictive factors of ICH within 24 hours after onset. RESULTS: ICH was observed in 284 (20.9%) patients. Among these patients, 46 (3.4%) had symptomatic ICH, and its incidence was higher in the recanalization therapy (IVT and/or EVT) group than in the conservative therapy group (4.5% versus 2.1%, P = .013). On multivariate analyses, symptomatic ICH was related to pretreatment antiplatelet agent use and systemic heparinization, and was related to neither IVT nor EVT. CONCLUSIONS: Symptomatic ICH was not affected by recanalization therapy or EVT itself in Japanese patients with acute large vessel occlusion.

New grading system based on magnetic resonance imaging in a mouse model of subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: A grading system for experimental subarachnoid hemorrhage (SAH) that does not require animal euthanasia is currently unavailable. We proposed a new grading system based on MRI and evaluated the feasibility of this method in a mouse model of SAH. METHODS: SAH was induced by endovascular perforation in adult male C57BL/6 mice. Mice underwent MRI 24 hours after SAH and were categorized into the following 5 grades based on T2*-weighted imaging: Grade 0, no visible SAH or intraventricular hemorrhage (IVH); Grade 1, minimal/localized SAH without IVH; Grade 2, minimal/localized SAH with IVH; Grade 3, thick/diffuse SAH without IVH; and Grade 4, thick/diffuse SAH with IVH. Neurological deficits were then assessed and the mice euthanized for conventional SAH grading. RESULTS: Among a total of 47 mice, 4% were scored as grade 0, 30% as grade 1, 11% as grade 2, 30% as grade 3, and 26% as grade 4. This MRI grading had excellent interobserver reliability (weighted κ value =0.94), and there were strong correlations between the MRI grading and the conventional grading (r=0.85; P<0.001) or between MRI grade and neurological scores (r=-0.46; P<0.01). CONCLUSIONS: The new MRI grading correlated well with conventional grading and enabled in vivo evaluation of SAH severity. This grading system may offer advantages in future studies of experimental SAH.

White Matter Injury After Subarachnoid Hemorrhage: Role of Blood-Brain Barrier Disruption and Matrix Metalloproteinase-9.

BACKGROUND AND PURPOSE: We recently observed early white matter injury after experimental subarachnoid hemorrhage (SAH), but the underlying mechanisms are uncertain. This study investigated the potential role of matrix metalloproteinase (MMP)-9 in blood-brain barrier (BBB) disruption and consequent white matter injury. METHODS: SAH was induced by endovascular perforation in adult male mice. The following 3 experiments were devised: (1) mice underwent magnetic resonance imaging at 24 h after SAH and were euthanized to determine BBB disruption and MMP-9 activation in white matter; (2) to investigate the role of MMP-9 in BBB disruption, lesion volumes on magnetic resonance imaging were compared between wild-type (WT) and MMP-9 knockout (MMP-9-/-) mice at 24 h after SAH; (3) WT and MMP-9-/- mice underwent magnetic resonance imaging at 1 and 8 days after SAH to detect time-dependent changes in brain injury. Brains were used to investigate myelin integrity in white matter. RESULTS: In WT mice with SAH, white matter showed BBB disruption (albumin leakage) and T2 hyperintensity on magnetic resonance imaging. MMP-9 activity was elevated at 24 h after SAH. MMP-9-/- mice had less white matter T2 hyperintensity after SAH than WT mice. At 8 days after SAH, WT mice had decreased myelin integrity and MMP-9-/- mice developed less white matter injury. CONCLUSIONS: SAH causes BBB disruption and consequent injury in white matter. MMP-9 plays an important role in those pathologies and could be a therapeutic target for SAH-induced white matter injury.