C5a-C5AR1 axis as a potential trigger of the rupture of intracranial aneurysms.

Recent studies have indicated the involvement of neutrophil-mediated inflammatory responses in the process leading to intracranial aneurysm (IA) rupture. Receptors mediating neutrophil recruitment could thus be therapeutic targets of unruptured IAs. In this study, complement C5a receptor 1 (C5AR1) was picked up as a candidate that may cause neutrophil-dependent inflammation in IA lesions from comprehensive gene expression profile data acquired from rat and human samples. The induction of C5AR1 in IA lesions was confirmed by immunohistochemistry; the up-regulations of C5AR1/C5ar1 stemmed from infiltrated neutrophils, which physiologically express C5AR1/C5ar1, and adventitial fibroblasts that induce C5AR1/C5ar1 in human/rat IA lesions. In in vitro experiments using NIH/3T3, a mouse fibroblast-like cell line, induction of C5ar1 was demonstrated by starvation or pharmacological inhibition of mTOR signaling by Torin1. Immunohistochemistry and an experiment in a cell-free system using recombinant C5 protein and recombinant Plasmin indicated that the ligand of C5AR1, C5a, could be produced through the enzymatic digestion by Plasmin in IA lesions. In conclusion, we have identified a potential contribution of the C5a-C5AR1 axis to neutrophil infiltration as well as inflammatory responses in inflammatory cells and fibroblasts of IA lesions. This cascade may become a therapeutic target to prevent the rupture of IAs.

Preoperative Ocular Symptoms Predict Acute Glaucoma After Carotid Revascularization: An Analysis of Combined Single-Center Data and a Systematic Review.

BACKGROUND: Acute glaucoma is a potential complication of carotid revascularization procedures such as endarterectomy or stenting. Although preoperative ocular hypoperfusion may predispose patients to postoperative glaucoma, the details of this complication have not been clarified. METHODS: We retrospectively reviewed the medical records of consecutive patients who underwent carotid revascularization at our institution from January 2019 to December 2022. These patients were divided into glaucoma and nonglaucoma groups. Given the rarity of the event, a systematic literature review was performed to additionally include data from patients who developed acute glaucoma after carotid revascularization. Multivariate logistic regression was performed to identify the risk factors for acute glaucoma. RESULTS: Thirty-five cases, including 2 from our institution, were included in the glaucoma group, and 130 were included in the nonglaucoma group. Most cases (79%) occurred within five days postoperatively. Multivariate analysis revealed that preoperative ocular symptoms were significantly associated with the development of postoperative glaucoma (odds ratio, 361.06; 95% confidence interval, 34.09-3824.27; P < 0.001). Preoperative neovascularization at the iris or anterior chamber angle, indicating severe ocular hypoperfusion, was found in 84% of patients with glaucoma. Permanent visual loss occurred in 41% of patients. The incidence of postoperative glaucoma at our institution was 1.5% (2/132). The positive predictive value of preoperative ocular symptoms for postoperative glaucoma was 0.25 (95% confidence interval, 0.18-0.32). CONCLUSIONS: This study was the first to clarify the risk factors and characteristics of acute glaucoma after carotid revascularization.

Effective Mechanical Thrombectomy for Posterior Circulation Ischemia Using Magnetic Resonance Imaging-based Arterial Structures.

To improve the success of mechanical thrombectomy, three-dimensional turbo spin-echo (3D-TSE) sequences on T2WI can be employed to estimate the vascular structure of the posterior circulation. In addition to the short imaging time of 3D-TSE T2WI (33 sec), it can visualize the outer diameter of the main cerebral artery, including the occluded vessels. However, to date, the efficacy of mechanical thrombectomy in the posterior circulation remains unclear, and safer and more efficient mechanical thrombectomy procedures are required. Assessment of the anatomical variations in the posterior circulation using 3D-TSE T2WI is valuable for access decisions, device selection, and safe device guidance and retrieval techniques to the target vessel. Herein, we present representative cases of basilar artery and posterior cerebral artery occlusions in our institute and describe the utility of preoperative 3D-TSE T2WI in these patients.

Symptomatic atherosclerotic plaque accompanied by carotid web.

Here, we describe a case of a 67-year-old man who was transferred to our hospital with complaints of sudden upper right limb weakness and ataxia. Scattered acute cerebral infarction was found in the watershed zone between the left anterior cerebral artery and the middle cerebral artery territories. A shelf-like structure at the origin of the left carotid artery and a vulnerable plaque distal to the lesion was found. Symptomatic atherosclerotic plaque with concomitant carotid web was diagnosed. Carotid endarterectomy resulted in good revascularization. Hemodynamic changes associated with vascular stenosis are involved in atherosclerosis. The current case is valuable and shows that carotid web can cause not only embolic infarction but also cerebral thrombosis due to atheroma formation in the carotid artery.

Predicting the growth of middle cerebral artery bifurcation aneurysms using differences in the bifurcation angle and inflow coefficient.

OBJECTIVE: Growing intracranial aneurysms (IAs) are prone to rupture. Previous cross-sectional studies using postrupture morphology have shown the morphological or hemodynamic features related to IA rupture. Yet, which morphological or hemodynamic differences of the prerupture status can predict the growth and rupture of smaller IAs remains unknown. The purpose of this longitudinal study was to investigate the effects of morphological features and the hemodynamic environment on the growth of IAs at middle cerebral artery (MCA) bifurcations during the follow-up period. METHODS: One hundred two patients with MCA M1-2 bifurcation saccular IAs who underwent follow-up for more than 2 years at the authors' institutions between 2011 and 2019 were retrospectively identified. During the follow-up period, cases involving growth of MCA IAs were assigned to the event group, and those with MCA IAs unchanged in size were assigned to the control group. The morphological parameters examined were aneurysmal neck length, dome height, aspect ratio and volume, M1 and M2 diameters and their ratio, and angle configurations among M1, M2, and the aneurysm. Hemodynamic parameters were flow rate and wall shear stress in M1, M2, and the aneurysm, including the aneurysmal inflow rate coefficient (AIRC), defined as the ratio of the aneurysmal inflow rate to the M1 flow rate. Those parameters were compared statistically between the two groups. Correlations between morphological and hemodynamic parameters were also examined. RESULTS: Eighty-three of 102 patients were included: 25 with growing MCA IAs (event group) and 58 with stable MCA IAs (control group). The median patient age at initial diagnosis was 66.9 (IQR 59.8-72.3) years. The median follow-up period was 48.5 (IQR 36.5-65.6) months. Both patient age and the AIRC were significant independent predictors of the growth of MCA IAs. Moreover, the AIRC was strongly correlated with sharper bifurcation and inflow angles, as well as wider inclination angles between the M1 and M2 arteries. CONCLUSIONS: The AIRC was a significant independent predictor of the growth of MCA IAs. Sharper bifurcation and inflow angles and wider inclination angles between the M1 and M2 arteries were correlated with the AIRC. MCA IAs with such a bifurcation configuration are more prone to grow and rupture.

Associations Between Drug Treatments and the Risk of Aneurysmal Subarachnoid Hemorrhage: a Systematic Review and Meta-analysis.

There is increasing interest in drug therapy for preventing aneurysmal subarachnoid hemorrhage (aSAH). We aimed to comprehensively evaluate the association between drug use and the risk of aSAH. We searched PubMed and Scopus from the databases' inception until December 2021. Observational studies reporting the association between any drug therapy and aSAH were included. The odds ratios (ORs) for each drug used in aSAH were meta-analyzed with a random-effect model. According to the systematic review, 25 observational studies were eligible for the present study. Four therapeutic purpose-based classes (e.g., lipid-lowering agents) and 14 mechanism-based classes (e.g., statins) were meta-analyzed. Anti-hypertensive agents (OR, 0.50; 95% confidence interval [95% CI], 0.33-0.74), statins (OR, 0.55; 95% CI, 0.35-0.85), biguanides (OR, 0.57; 95% CI, 0.34-0.96), and acetylsalicylic acid (ASA) (OR, 0.62; 95% CI, 0.41-0.94) were inversely associated with the risk of aSAH. Non-ASA non-steroidal anti-inflammatory drugs (OR, 1.73; 95% CI, 1.07-2.79), selective cyclooxygenase-2 inhibitors (OR, 2.04; 95% CI, 1.24-3.35), vitamin K antagonists (OR, 1.50; 95% CI, 1.18-1.91), and dipyridamole (OR, 1.77; 95% CI, 1.23-2.54) were positively associated with the incidence of aSAH. There was also a trend toward a positive association between glucocorticoids (OR, 1.38; 95% CI, 0.97-1.94) and aSAH. The present study suggests that anti-hypertensive agents, statins, biguanides, and ASA are candidate drugs for preventing aSAH. By contrast, several drugs (e.g., anti-thrombotic drugs) may increase the risk of aSAH. Thus, the indications of these drugs in patients with intracranial aneurysms should be carefully determined.

Intramural Hematoma in Vertebrobasilar Dolichoectasia-Related Stroke: A Retrospective Analysis of Six Consecutive Patients.

BACKGROUND: The pathophysiology underlying vertebrobasilar dolichoectasia (VBD) is largely unknown. However, a few reports have demonstrated that acute intramural hematoma (IMH) in VBD is associated with stroke. We aimed to investigate the clinical and radiological features of IMH in VBD and the role of IMH in predicting rupture and patient outcomes. METHODS: We retrospectively reviewed the medical records of patients treated in 2 stroke centers between January 2012 and December 2021. Patients presenting with VBD and stroke were eligible for study inclusion. We excluded patients with stroke caused by arterial dissection or artery-to-artery embolism. IMH was defined as a crescent-shaped area of high signal density in the vessel wall on axial computed tomography in the absence of an intimal flap, double lumen, and pearl-and-string sign. RESULTS: Six patients were analyzed. All presented with symptoms of brainstem/cerebellar infarction without headache. Interobserver agreement for the presence or absence of IMH was excellent (100%). IMH was detected in 5 patients. The positive predictive value of IMH for rupture was 80% (95% confidence interval, 28%-99.5%). The median time from symptom onset to rupture was 2.5 days (range, 1.5-4). Median computed tomography values were significantly higher within the IMH than those in the lumen of the basilar artery (70 vs. 44.5 Hounsfield units; P = 0.008). The modified Rankin scale score on day 30 after onset was 5 in 1 patient and 6 in the remaining 5. CONCLUSIONS: IMH in patients with VBD presenting with brainstem/cerebellar infarction should be regarded as a sign associated with a high risk of rupture.

The bifurcation angle is associated with the progression of saccular aneurysms.

The role of the bifurcation angle in progression of saccular intracranial aneurysms (sIAs) has been undetermined. We, therefore, assessed the association of bifurcation angles with aneurysm progression using a bifurcation-type aneurysm model in rats and anterior communicating artery aneurysms in a multicenter case-control study. Aneurysm progression was defined as growth by ≥ 1 mm or rupture during observation, and controls as progression-free for 30 days in rats and ≥ 36 months in humans. In the rat model, baseline bifurcation angles were significantly wider in progressive aneurysms than in stable ones. In the case-control study, 27 and 65 patients were enrolled in the progression and control groups. Inter-observer agreement for the presence or absence of the growth was excellent (κ coefficient, 0.82; 95% CI, 0.61-1.0). Multivariate logistic regression analysis showed that wider baseline bifurcation angles were significantly associated with subsequent progressions. The odds ratio for the progression of the second (145°-179°) or third (180°-274°) tertiles compared to the first tertile (46°-143°) were 5.5 (95% CI, 1.3-35). Besides, the bifurcation angle was positively correlated with the size of aneurysms (Spearman's rho, 0.39; P = 0.00014). The present study suggests the usefulness of the bifurcation angle for predicting the progression of sIAs.

True superficial temporal artery aneurysm: A case after extracranial-intracranial bypass surgery and a systematic review.

Background: Nontraumatic true superficial temporal artery aneurysm (STAA) is rare, and its characteristics and pathogenesis are unclear. Methods: We report a case of STAA and performed a systematic review of PubMed, Scopus, and Web of Science using the keyword "superficial temporal artery aneurysm" to include studies on STAA reported through July 2022. We excluded studies on STAA associated with trauma, arterial dissection, infection, or vasculitis. Results: A 63-year-old woman who underwent left superficial temporal artery (STA)-middle cerebral artery bypass surgery 8 years previously was diagnosed with an aneurysm located at the left STA. The blood flow volume estimated by ultrasonography was higher in the left STA than in the contralateral counterpart (114 mL/min vs. 32 mL/min). She underwent clipping surgery to prevent aneurysmal rupture without sequela. The lesion was diagnosed as a true aneurysm by histology. The systematic review identified 63 cases (including the present case) of nontraumatic true STAA. The median age of the patients was 57 (interquartile range [IQR]: 41-70) years. Most (90.5%) cases were detected as a palpable mass. Aneurysmal rupture occurred in only 1 (1.6%) case, despite the large size of aneurysms (median size: 13 [IQR: 8-20] mm) and the high frequency (33.3%) of aneurysmal growth during observation. Most (93.7%) patients underwent surgical resection of STAA without sequela. Conclusion: Our findings suggest that the pathogenesis of true STAA is promoted by hemodynamic stress. The systematic review clarified patients' and aneurysmal characteristics and treatment outcomes, providing further insight into the pathogenesis of nontraumatic true STAA.

3D Turbo Spin-echo MRI-based Mechanical Thrombectomy at Middle Cerebral Artery Bifurcations.

We describe three cases with acute middle cerebral artery (MCA) occlusion. From the pre-operative MRI, including three-dimensional turbo spin-echo sequences using T1WI and T2WI, we assessed both thrombus configuration and arterial anatomy at the MCA bifurcations. For efficient endovascular thrombectomy, we identified the applied MCA segment 2 (M2) branch, in which the main thrombus was buried. Sufficient recanalization after a single pass was achieved and the patients made a marked recovery. Although mechanical thrombectomy for M2 occlusion has not been of proven benefit, the endovascular procedure based on three-dimensional turbo spin-echo imaging is useful for more complete thrombus removal at MCA bifurcations.

Induction of CCN1 in Growing Saccular Aneurysms: A Potential Marker Predicting Unstable Lesions.

Growing evidence has suggested that inflammatory responses promote the progression of saccular intracranial aneurysms (IAs). However, a biomarker predicting the progression has yet to be established. This study aimed to identify novel molecules upregulated during the progression using a previously established rat aneurysm model. In this model, aneurysms are induced at the surgically created common carotid artery (CCA) bifurcation. Based on sequential morphological data, the observation periods after the surgical manipulations were defined as the growing phase (on the 10th day) or the stable phase (on the 30th day). Total cell lysates from the CCA with or without an aneurysm lesion were prepared to perform protein array analysis. The protein array analysis revealed that the matricellular protein cellular communication network factor 1 (CCN1) is induced in lesions during the growing phase. Immunohistochemistry corroborated the significant upregulation of CCN1 in the growing phase compared with the stable phase. Simultaneously with the induction of CCN1, significant increases in the number of CD68-positive macrophages, myeloperoxidase-positive cells, and proliferating smooth muscle cells in lesions were observed. Immunohistochemistry of human IA specimens reproduced the induction of CCN1 in some lesions. These findings imply a potential role of CCN1 as a marker predicting the progression of saccular aneurysms.

Candidate drugs for preventive treatment of unruptured intracranial aneurysms: A cross-sectional study.

BACKGROUND AND PURPOSE: Establishment of drug therapy to prevent rupture of unruptured intracranial aneurysms (IAs) is needed. Previous human and animal studies have gradually clarified candidate drugs for preventive treatment of IA rupture. However, because most of these candidates belong to classes of drugs frequently co-administered to prevent cardiovascular diseases, epidemiological studies evaluating these drugs simultaneously should be performed. Furthermore, because drugs included in the same class may have different effects in terms of disease prevention, drug-by-drug assessments are important for planning intervention trials. MATERIALS AND METHODS: We performed a cross-sectional study enrolling patients diagnosed with IAs between July 2011 and June 2019 at our institution. Patients were divided into ruptured or unruptured groups. The drugs investigated were selected according to evidence suggested by either human or animal studies. Univariate and multivariate logistic regression analyses were performed to assess the association of drug treatment with rupture status. We also performed drug-by-drug assessments of the association, including dose-response relationships, with rupture status. RESULTS: In total, 310 patients with ruptured and 887 patients with unruptured IAs were included. Multivariate analysis revealed an inverse association of statins (odds ratio (OR), 0.54; 95% confidence interval (CI) 0.38-0.77), calcium channel blockers (OR, 0.41; 95% CI 0.30-0.58), and angiotensin II receptor blockers (ARBs) (OR, 0.67; 95% CI 0.48-0.93) with ruptured IAs. Moreover, inverse dose-response relationships with rupture status were observed for pitavastatin and rosuvastatin among statins, benidipine, cilnidipine, and amlodipine among calcium channel blockers, and valsartan, azilsartan, candesartan, and olmesartan among ARBs. Only non-aspirin non-steroidal anti-inflammatory drugs were positively associated with ruptured IAs (OR, 3.24; 95% CI 1.71-6.13). CONCLUSIONS: The present analysis suggests that several types of statins, calcium channel blockers, and ARBs are candidate drugs for preventive treatment of unruptured IAs.

Hemodynamic Force as a Potential Regulator of Inflammation-Mediated Focal Growth of Saccular Aneurysms in a Rat Model.

Past studies have elucidated the crucial role of macrophage-mediated inflammation in the growth of intracranial aneurysms (IAs), but the contributions of hemodynamics are unclear. Considering the size of the arteries, we induced de novo aneurysms at the bifurcations created by end-to-side anastomoses with the bilateral common carotid arteries in rats. Sequential morphological data of induced aneurysms were acquired by magnetic resonance angiography. Computational fluid dynamics analyses and macrophage imaging by ferumoxytol were performed. Using this model, we found that de novo saccular aneurysms with a median size of 3.2 mm were induced in 20/45 (44%) of animals. These aneurysms mimicked human IAs both in morphology and pathology. We detected the focal growth of induced aneurysms between the 10th and 17th day after the anastomosis. The regional maps of hemodynamic parameters demonstrated the area exposed to low wall shear stress (WSS) and high oscillatory shear index (OSI) colocalized with the regions of growth. WSS values were significantly lower in the growing regions than in ones without growth. Macrophage imaging showed colocalization of macrophage infiltration with the growing regions. This experimental model demonstrates the potential contribution of low WSS and high OSI to the macrophage-mediated growth of saccular aneurysms.

Involvement of neutrophils in machineries underlying the rupture of intracranial aneurysms in rats.

Subarachnoid hemorrhage due to rupture of an intracranial aneurysm has a quite poor prognosis after the onset of symptoms, despite the modern technical advances. Thus, the mechanisms underlying the rupture of lesions should be clarified. To this end, we obtained gene expression profile data and identified the neutrophil-related enriched terms in rupture-prone lesions using Gene Ontology analysis. Next, to validate the role of neutrophils in the rupture of lesions, granulocyte-colony stimulating factor (G-CSF) was administered to a rat model, in which more than half of induced lesions spontaneously ruptured, leading to subarachnoid hemorrhage. As a result, G-CSF treatment not only increased the number of infiltrating neutrophils, but also significantly facilitated the rupture of lesions. To clarify the mechanisms of how neutrophils facilitate this rupture, we used HL-60 cell line and found an enhanced collagenolytic activity, corresponding to matrix metalloproteinase 9 (MMP9), upon inflammatory stimuli. The immunohistochemical analyses revealed the accumulation of neutrophils around the site of rupture and the production of MMP9 from these cells in situ. Consistently, the collagenolytic activity of MMP9 could be detected in the lysate of ruptured lesions. These results suggest the crucial role of neutrophils to the rupture of intracranial aneurysms; implying neutrophils as a therapeutic or diagnostic target candidate.

The Bilateral Ovariectomy in a Female Animal Exacerbates the Pathogenesis of an Intracranial Aneurysm.

Considering the poor outcome of subarachnoid hemorrhage (SAH) due to the rupture of intracranial aneurysms (IA), mechanisms underlying the pathogenesis of IAs, especially the rupture of lesions, should be clarified. In the present study, a rat model of IAs in which induced lesions spontaneously ruptured resulting in SAH was used. In this model, the combination of the female sex and the bilateral ovariectomy increased the incidence of SAH, similar to epidemiological evidence in human cases. Importantly, unruptured IA lesions induced in female animals with bilateral ovariectomy were histopathologically similar to ruptured ones in the presence of vasa vasorum and the accumulation of abundant inflammatory cells, suggesting the exacerbation of the disease. The post-stenotic dilatation of the carotid artery was disturbed by the bilateral ovariectomy in female rats, which was restored by hormone replacement therapy. The in vivo study thus suggested the protective effect of estrogen from the ovary on endothelial cells loaded by wall shear stress. -estradiol or dihydrotestosterone also suppressed the lipopolysaccharide-induced expression of pro-inflammatory genes in cultured macrophages and neutrophils. The results of the present study have thus provided new insights about the process regulating the progression of the disease.

Dedifferentiation of smooth muscle cells in intracranial aneurysms and its potential contribution to the pathogenesis.

Smooth muscle cells (SMCs) are the major type of cells constituting arterial walls and play a role to maintain stiffness via producing extracellular matrix. Here, the loss and degenerative changes of SMCs become the major histopathological features of an intracranial aneurysm (IA), a major cause of subarachnoid hemorrhage. Considering the important role of SMCs and the loss of this type of cells in IA lesions, we in the present study subjected rats to IA models and examined how SMCs behave during disease progression. We found that, at the neck portion of IAs, SMCs accumulated underneath the internal elastic lamina according to disease progression and formed the intimal hyperplasia. As these SMCs were positive for a dedifferentiation marker, myosin heavy chain 10, and contained abundant mitochondria and rough endoplasmic reticulum, SMCs at the intimal hyperplasia were dedifferentiated and activated. Furthermore, dedifferentiated SMCs expressed some pro-inflammatory factors, suggesting the role in the formation of inflammatory microenvironment to promote the disease. Intriguingly, some SMCs at the intimal hyperplasia were positive for CD68 and contained lipid depositions, indicating similarity with atherosclerosis. We next examined a potential factor mediating dedifferentiation and recruitment of SMCs. Platelet derived growth factor (PDGF)-BB was expressed in endothelial cells at the neck portion of lesions where high wall shear stress (WSS) was loaded. PDGF-BB facilitated migration of SMCs across matrigel-coated pores in a transwell system, promoted dedifferentiation of SMCs and induced expression of pro-inflammatory genes in these cells in vitro. Because, in a stenosis model of rats, PDGF-BB expression was expressed in endothelial cells loaded in high WSS regions, and SMCs present nearby were dedifferentiated, hence a correlation existed between high WSS, PDGFB and dedifferentiation in vivo. In conclusion, dedifferentiated SMCs presumably by PDGF-BB produced from high WSS-loaded endothelial cells accumulate in the intimal hyperplasia to form inflammatory microenvironment leading to the progression of the disease.

Eicosapentaenoic acid prevents the progression of intracranial aneurysms in rats.

BACKGROUND: As subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor outcome despite of an intensive medical care, development of a novel treatment targeting unruptured IAs based on the correct understanding of pathogenesis is mandatory for social health. METHODS: Using previously obtained gene expression profile data from surgically resected unruptured human IA lesions, we selected G-protein coupled receptor 120 (GPR120) as a gene whose expression is significantly higher in lesions than that in control arterial walls. To corroborate a contribution of GPR120 signaling to the pathophysiology, we used an animal model of IAs and examine the effect of a GPR120 agonist on the progression of the disease. IA lesion was induced in rats through an increase of hemodynamic stress achieved by a one-sided carotid ligation and induced hypervolemia. Eicosapentaenoic acid (EPA) was used as an agonist for GPR120 in this study and its effect on the size of IAs, the thinning of media, and infiltration of macrophages in lesions were examined. RESULT: EPA administered significantly suppressed the size of IAs and the degenerative changes in the media in rats. EPA treatment also inhibited infiltration of macrophages, a hallmark of inflammatory responses in lesions. In in vitro experiments using RAW264.7 cells, pre-treatment of EPA partially suppressed lipopolysaccharide-induced activation of nuclear factor-kappa B and also the transcriptional induction of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant for macrophages to accumulate in lesions. As a selective agonist of GPR120, TUG-891, could reproduce the effect of EPA in RAW264.7 cells, EPA presumably acted on this receptor to suppress inflammatory responses. Consistently, EPA remarkably suppressed MCP-1 expression in lesions, suggesting the in vivo relevance of in vitro studies. CONCLUSIONS: These results combined together suggest the potential of the medical therapy targeting GPR120 or using EPA to prevent the progression of IAs.

Association of zinc administration with growth suppression of intracranial aneurysms via induction of A20.

OBJECTIVE: Zinc is an essential micronutrient with multiple biological effects, including antiinflammation. Previously, the authors demonstrated that the pathogenesis of intracranial aneurysms (IAs) is strongly related to chronic inflammation. In this study, the authors investigated whether administration of zinc inhibits the growth of IAs in a rat model. METHODS: The authors analyzed surgically induced IAs in Sprague-Dawley male rats, which were subsequently treated with intraperitoneal injections of zinc sulfate heptahydrate (ZnSO4; 3 mg/kg/day) or vehicle for 4 weeks. RESULTS: Size and wall thickness ratios of experimentally induced IAs were assessed in both treatment groups after induction and in a control group. The effects of zinc administration in IAs were examined by immunohistochemistry and Western blotting. Zinc administration significantly suppressed aneurysm size and also preserved the internal elastic lumen. Administration of zinc significantly attenuated infiltration of macrophages into IAs. CONCLUSIONS: Zinc treatment significantly increased expression of the antiinflammatory signaling protein A20, an inhibitor of the nuclear factor κB (NF-κB) pathway, in rat IAs. Zinc administration may prevent the growth of rat IAs by inducing A20-attributed inactivation of NF-κB signaling.

Rat Model of Intracranial Aneurysm: Variations, Usefulness, and Limitations of the Hashimoto Model.

Given the poor outcome of subarachnoid hemorrhage due to rupture of intracranial aneurysms (IAs) and high prevalence of IAs in general public, elucidation of mechanisms underlying the pathogenesis of the disease and development of effective treatment are mandatory for social health. Recent experimental findings have revealed the crucial contribution of macrophage-mediated chronic inflammation to and greatly promoted our understanding of the pathogenesis. Also a series of studies have proposed the potential of anti-inflammatory drugs as therapeutic ones. In this process, a rodent model of IAs plays an indispensable role. Basic concept of IA induction in such kind of models is that IA formation is triggered by hemodynamic stress loaded on damaged arterial walls. To be more precise, although detailed procedures are different among researchers, animals are subjected to a ligation of a unilateral carotid artery and systemic hypertension achieved by a salt overloading, and IAs are induced at the contralateral bifurcation site. Importantly, trigger of IA formation in the model mimics human one, and IA lesions induced share similarity in histology with human ones such as degenerative changes of media. For further elucidating the pathogenesis, we need to well understand variations, usefulness, and also limits of this model.

Vasa vasorum formation is associated with rupture of intracranial aneurysms.

OBJECTIVE: Subarachnoid hemorrhage (SAH) has a poor outcome despite modern advancements in medical care. The development of a novel therapeutic strategy to prevent rupture of intracranial aneurysms (IAs) or a novel diagnostic marker to predict rupture-prone lesions is thus mandatory. Therefore, in the present study, the authors established a rat model in which IAs spontaneously rupture and examined this model to clarify histopathological features associated with rupture of lesions. METHODS: Female Sprague Dawley rats were subjected to bilateral ovariectomy; the ligation of the left common carotid, the right external carotid, and the right pterygopalatine arteries; induced systemic hypertension; and the administration of a lysyl oxidase inhibitor. RESULTS: Aneurysmal SAH occurred in one-third of manipulated animals and the locations of ruptured IAs were exclusively at a posterior or anterior communicating artery (PCoA/ACoA). Histopathological examination using ruptured IAs, rupture-prone IAs induced at a PCoA or ACoA, and IAs induced at an anterior cerebral artery-olfactory artery bifurcation that never ruptured revealed the formation of vasa vasorum as an event associated with rupture of IAs. CONCLUSIONS: The authors propose the contribution of a structural change in an adventitia, i.e., vasa vasorum formation, to the rupture of IAs. Findings from this study provide important insights about the pathogenesis of IAs.