Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflammation of the arterial wall due to macrophage infiltration triggered by monocyte chemoattractant protein-1 (MCP-1), macrophage activation mediated by the transcription factor nuclear factor κB (NF-κB), and inflammatory signaling involving prostaglandin E (PGE) and prostaglandin E receptor subtype 2 (EP2). We correlated EP2 and cyclooxygenase-2 (COX-2) with macrophage infiltration in human intracranial aneurysm lesions. Monitoring the spatiotemporal pattern of NF-κB activation during intracranial aneurysm development in mice showed that NF-κB was first activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Mice with a macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an IκBα mutant that restricts NF-κB activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-κB activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-α (TNF-α) to activate NF-κB and synergistically induce the expression of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized Ccl2 (encoding MCP-1) by activating the RNA-stabilizing protein HuR. Rats administered an EP2 antagonist had reduced macrophage infiltration and intracranial aneurysm formation and progression. This signaling pathway in macrophages thus facilitates intracranial aneurysm development by amplifying inflammation in intracranial arteries. These results indicate that EP2 antagonists may therefore be a therapeutic alternative to surgery.

Background and PurposeIntracranial aneurysm (IA), common in the general public, causes lethal subarachnoid haemorrhage on rupture. It is, therefore, of utmost importance to prevent the IA from rupturing. However, there is currently no medical treatment. Recent studies suggest that IA is the result of chronic inflammation in the arterial wall caused by endothelial dysfunction and infiltrating macrophages. The sphingosine‐1‐phosphate receptor type 1 (S1P1 receptor) is present on the endothelium and promotes its barrier function. Here we have tested the potential of an S1P1 agonist, ASP4058, to prevent IA in an animal model.Experimental ApproachThe effects of a selective S1P1 agonist, ASP4058, on endothelial permeability and migration of macrophages across an endothelial cell monolayer were tested in vitro using a Transwell system, and its effects on the size of IAs were evaluated in a rat model of IA.Key ResultsS1P1 receptor was expressed in endothelial cells of human IA lesions and control arterial walls. ASP4058 significantly reduced FITC‐dextran leakage through an endothelial monolayer and suppressed the migration of macrophages across the monolayer in vitro. Oral administration of ASP4058 reduced the vascular permeability, macrophage infiltration and size of the IAs by acting as an S1P1 agonist in the rat model. This effect was mimicked by another two structurally‐unrelated S1P1 agonists.Conclusion and ImplicationsA selective S1P1 agonist is a strong drug candidate for IA treatment as it promotes the endothelial cell barrier and suppresses the trans‐endothelial migration of macrophages in IA lesions.

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Background: Recent studies reported that cerebral microbleeds (CMBs), i.e. small areas of signal loss on T₂*-weighted gradient-echo (GE) imaging, could develop rapidly after acute ischemic stroke. We hypothesized that CMBs rapidly emerge after carotid artery stenting (CAS). Objective: We investigated the frequency of and predisposing factors for CMBs after CAS. Methods: We retrospectively examined MRI before and after CAS in 88 consecutive patients (average age: 71.7 ± 7.2 years, average rates of carotid stenosis: 72.6 ± 12.8%) who underwent CAS for carotid artery stenosis between March 1, 2009, and September 30, 2010. We defined new CMBs as signal losses that newly appeared on the follow-up GE. We examined the association of new CMBs with demographics, risk factors, and baseline MBs. Results: Among 88 patients, 18 (20.5%) had CMBs initially, and 7 (8.0%) developed new CMBs right after CAS. New CMBs appeared on the same side of CAS in all of the 7 patients. New CMBs appeared significantly more frequently in the CMB-positive group than in the CMB-negative one (22% vs. 4%, p = 0.03) on the pre-CAS MRI. Multivariate analysis also revealed that the presence of CMBs before CAS was an independent predictor of new development of CMBs after CAS (odds ratio: 8.09, 95% confidence interval: 1.39–47.1). Conclusion: CMBs can develop rapidly after CAS, especially in patients with pre-existing CMBs. Since the existence of CMBs prior to CAS suggests a latent vascular damage which is vulnerable to hemodynamic stress following CAS, particular attention should be paid to the prevention of intracerebral hemorrhage due to hyperperfusion after CAS.

[Purpose] The present study aimed to determine changes in muscle activity while moving on a treadmill at various speeds. [Subjects] The activities of the left vastus lateralis, vastus medialis, hip adductors, lateral head of gastrocnemius, medial head gastrocnemius, soleus, and tibialis anterior of 10 healthy male university students were analyzed. [Methods] University students walked, jogged, and ran for 10 minutes each in random order, and then myogenic potentials were measured 10 minutes later for 30 seconds. The flexion angle of the lower limb upon initial contact, mid stance, and toe off were measured. [Results] The average walking, jogging, and running speeds were 3.6 ± 0.4, 6.7 ± 0.6, and 10.4 ± 1.3 km/h, respectively. The average electromyographic activities of the vastus medial, tibialis anterior, medial head of gastrocnemius, and lateral head of gastrocnemius significantly differed. All muscles were more active during jogging and running than walking. Only the soleus was more active during running than walking, and the activities of the hip adductors and vastus lateralis did not significantly differ. [Conclusion] Velocity is faster and the angles of the lower limbs and ground reaction force (GRF) are larger during running than walking. The vastus medialis and soleus worked more easily according to the angle of the knee joint, whereas the tibialis anterior worked more easily at faster velocities and the medial and lateral heads of the gastrocnemius worked more easily with an increased GRF.