Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats.

BackgroundEstrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women. Estrogen replacement therapy appears to reduce this risk but is associated with significant side effects. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor (ER) modulator with fewer estrogenic side effects, reduces cerebral aneurysm rupture in a new model of ovariectomized rats.MethodsTen-week-old female Sprague-Dawley rats were subjected to ovariectomy, hemodynamic changes, and hypertension to induce aneurysms (ovariectomized aneurysm rats) and treated with vehicle or with 0.3 or 1.0 mg/kg/day bazedoxifene. They were compared with sham-ovariectomized rats subjected to hypertension and hemodynamic changes (HT rats). The vasoprotective effects of bazedoxifene and the mechanisms underlying its efficacy were analyzed.ResultsDuring 12 weeks of observation, the incidence of aneurysm rupture was 52% in ovariectomized rats. With no effect on the blood pressure, treatment with 0.3 or 1.0 mg/kg/day bazedoxifene lowered this rate to 11 and 17%, almost the same as in HT rats (17%). In ovariectomized rats, the mRNA level of ERα, ERβ, and the tissue inhibitor of metalloproteinase-2 was downregulated in the cerebral artery prone to rupture at 5 weeks after aneurysm induction; the mRNA level of interleukin-1β and the matrix metalloproteinase-9 was upregulated. In HT rats, bazedoxifene restored the mRNA level of ERα and ERβ and decreased the level of interleukin-1β and matrix metalloproteinase-9. These findings suggest that bazedoxifene was protective against aneurysmal rupture by alleviating the vascular inflammation and degradation exacerbated by the decrease in ERα and ERβ.ConclusionsOur observation that bazedoxifene decreased the incidence of aneurysmal rupture in ovariectomized rats warrants further studies to validate this response in humans

Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats.

BackgroundHyperhomocysteinemia (HHcy) is associated with inflammation and a rise in the expression of matrix metalloproteinase-9 (MMP-9) in the vascular wall. However, the role of HHcy in the growth and rupture of cerebral aneurysms remains unclear.MethodsThirteen-week-old female Sprague-Dawley rats were subject to bilateral ovariectomy and ligation of the right common carotid artery and fed an 8 % high-salt diet to induce cerebral aneurysms. Two weeks later, they underwent ligation of the bilateral posterior renal arteries. They were divided into two groups and methionine (MET) was or was not added to their drinking water. In another set of experiments, the role of folic acid (FA) against cerebral aneurysms was assessed.ResultsDuring a 12-week observation period, subarachnoid hemorrhage due to aneurysm rupture was observed at the anterior communicating artery (AcomA) or the posterior half of the circle of Willis. HHcy induced by excessive MET intake significantly increased the incidence of ruptured aneurysms at 6-8 weeks. At the AcomA of rats treated with MET, we observed the promotion of aneurysmal growth and infiltration by M1 macrophages. Furthermore, the mRNA level of MMP-9, the ratio of MMP-9 to the tissue inhibitor of metalloproteinase-2, and the level of interleukin-6 were higher in these rats. Treatment with FA abolished the effect of MET, suggesting that the inflammatory response and vascular degradation at the AcomA is attributable to HHcy due to excessive MET intake.ConclusionsWe first demonstrate that in hypertensive ovariectomized rats, HHcy induced by excessive MET intake may be associated with the propensity of the aneurysm wall to rupture

Successful Emergency Carotid Endarterectomy after Thrombolysis with Intravenous Recombinant Tissue-Type Plasminogen Activator

Acute internal carotid artery (ICA) occlusion may result in severe disability or death. Revascularization by carotid artery stenting after treatment with intravenous (iv) recombinant tissue-type plasminogen activator (rt-PA) has been documented. However, there are few reports on emergency carotid endarterectomy (CEA) within 24 hours after the iv administration of rt-PA. We treated a 58-year-old man with right ICA occlusion with iv rt-PA. Although partial recanalization of the ICA was obtained, severe stenosis at the origin of the ICA persisted and he developed fluctuating neurological deficits. To prevent progressive stroke he underwent CEA 10.5 hours after rt-PA treatment. Thereafter his blood pressure was strictly controlled under sedation. During and after CEA there were no hemorrhagic complications. Our findings suggest that emergency CEA may be an option to address symptomatic severe residual ICA stenosis even after iv rt-PA therapy delivered in the acute stage

Treatment with the PPARγ Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats

Neurogenesis is essential for a good post-stroke outcome. Exogenous stem cells are currently being tested to promote neurogenesis after stroke. Elsewhere, we demonstrated that treatment with the PPARγ agonist pioglitazone (PGZ) before cerebral ischemia induction reduced brain damage and activated survival-related genes in ovariectomized (OVX) rats. Here, we tested our hypothesis that post-ischemia treatment with PGZ inhibits brain damage and contributes to neurogenesis via activated stem cells. Bone marrow (BM) cells of 7-week-old Wistar female rats were replaced with BM cells from green fluorescent protein-transgenic (GFP+BM) rats. Three weeks later, they were ovariectomized (OVX/GFP+BM rats). We subjected 7-week-old Wistar male and 13-week-old OVX/GFP+BM rats to 90-min cerebral ischemia. Male and OVX/GFP+BM rats were divided into two groups, one was treated with PGZ (2.5 mg/kg/day) and the other served as the vehicle control (VC). In both male and OVX/GFP+BM rats, post-ischemia treatment with PGZ reduced neurological deficits and the infarct volume. In male rats, PGZ decreased the mRNA level of IL-6 and M1-like macrophages after 24 h. In OVX/GFP+BM rats, PGZ augmented the proliferation of resident stem cells in the subventricular zone (SVZ) and the recruitment of GFP+BM stem cells on days 7–14. Both types of proliferated stem cells migrated from the SVZ into the peri-infarct area. There, they differentiated into mature neurons, glia, and blood vessels in association with activated Akt, MAP2, and VEGF. Post-ischemia treatment with PGZ may offer a new avenue for stroke treatment through contribution to neuroprotection and neurogenesis

INVOLVEMENT OF NETS IN CEREBRAL AVM

BACKGROUND: Cerebral arteriovenous malformations (cAVMs) represent tangles of abnormal vasculature without intervening capillaries. High-pressure vascular channels due to abnormal arterial and venous shunts can lead to rupture. Multiple pathways are involved in the pathobiology of cAVMs including inflammation and genetic factors such as KRAS mutations. Neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs), plays a multifunctional role in infection, inflammation, thrombosis, intracranial aneurysms, and tumor progression. However, the relationship between NETs and the pathobiology of cAVMs remains unknown. We tested whether NETs play a role in the pathobiology of cAVMs. METHODS: We analyzed samples from patients who had undergone surgery for cAVM and immunohistochemically investigated expression of citrullinated histone H3 (CitH3) as a marker of NETs. CitH3 expression was compared among samples from cAVM patients, epilepsy patients, and normal human brain tissue. Expressions of thrombotic and inflammatory markers were also examined immunohistochemically in samples from cAVM patients. RESULTS: Expression of CitH3 derived from neutrophils was observed intravascularly in all cAVM samples but not other samples. Nidi of AVMs showed migration of many Iba-I-positive cells adjacent to the endothelium and endothelial COX2 expression, accompanied by expression of IL-6 and IL-8 in the endothelium and intravascular neutrophils. Unexpectedly, expression of CitH3 was not necessarily localized to the vascular wall and thrombus. CONCLUSIONS: Our results offer the first evidence of intravascular expression of NETs, which might be associated with vascular inflammation in cAVMs

Research and surgery for brain AVMs

Arteriovenous malformations (AVMs) are hemorrhagic vascular diseases in which arteries and veins are directly connected with no capillary bed between the two. We herein introduce the results of basic research of this disease and surgical techniques based on our data and experiences. The results obtained from our research show that cell death- and inflammation-related molecules changed or became activated compared with control specimens. These findings indicate that chronic inflammation occurs in and around the nidus of AVMs. Various molecules are involved in the mechanisms of cell death and angiogenesis during this process. Confirmation of blood flow in the nidus is very important to avoid hemorrhagic complications during surgical removal of the nidus. The risk of hemorrhage increases when the blood flow in the nidus is not reduced. We reported the advantages of serial indocyanine green videoangiography, which is used to assess the blood flow during AVM nidus removal. Since publication of the ARUBA trial and Scottish Audit, treatments with high morbidity have not been allowed. It is especially important for neurosurgeons to treat low Spetzler–Martin grade AVMs with low morbidity

Could clazosentan, first approved in Japan, improve neurological prognosis after subarachnoid hemorrhage in combination with modified water-electrolyte management?

An aneurysmal subarachnoid hemorrhage (aSAH) is a devastating event associated with a high mortality and morbidity rate. Though numerous medications are used to prevent cerebral vasospasm and vasospasm-related cerebral infarction after aSAH, no effective pharmacological treatment has been established. Clazosentan, a highly selective endothelin receptor type A antagonist, was approved for use in Japan in April 2022 based on results of two pivotal randomized, placebo-controlled phase 3 studies (JapicCTI-163369, JapicCTI-163368). These studies indicated that clazosentan significantly reduced the incidence of vasospasm-related morbidity and all-cause mortality after aneurysm coiling and clipping. Clazosentan is thus expected to become a “game changer” for improving the neurological prognosis after aSAH. However, other reports indicate that even when clazosentan or nimodipine are administered for prophylaxis against delayed neurological decline, patients treated with increased colloid administration or hypertonic saline (3% sodium chloride) load exhibit poor functional outcome and higher mortality, suggesting that extra fluid and sodium derived from prophylactic colloid administration contribute to negative outcomes after aSAH. Pharmacological treatments such as clazosentan in addition to perioperative management involving delivery of less water and sodium might be crucial for achieving better outcomes than conventional therapy. Based on a literature review, we present here the future perspectives regarding clazosentan and the necessity for modifying management of the water-electrolyte balance by focusing on endothelin-1 and blood–brain barrier disruption

Time-dependent and site-dependent morphological changes in rupture-prone arteries : ovariectomized rat intracranial aneurysm model

OBJECTIVE The pathogenesis of intracranial aneurysm rupture remains unclear. Because it is difficult to study the time course of human aneurysms and most unruptured aneurysms are stable, animal models are used to investigate the characteristics of intracranial aneurysms. The authors have newly established a rat intracranial aneurysm rupture model that features site-specific ruptured and unruptured aneurysms. In the present study the authors examined the time course of changes in the vascular morphology to clarify the mechanisms leading to rupture. METHODS Ten-week-old female Sprague-Dawley rats were subjected to hemodynamic changes, hypertension, and ovariectomy. Morphological changes in rupture-prone intracranial arteries were examined under a scanning electron microscope and the association with vascular degradation molecules was investigated. RESULTS At 2–6 weeks after aneurysm induction, morphological changes and rupture were mainly observed at the posterior cerebral artery; at 7–12 weeks they were seen at the anterior Willis circle including the anterior communicating artery. No aneurysms at the anterior cerebral artery–olfactory artery bifurcation ruptured, suggesting that the inception of morphological changes is site dependent. On week 6, the messenger RNA level of matrix metalloproteinase–9, interleukin-1β, and the ratio of matrix metalloproteinase–9 to the tissue inhibitor of metalloproteinase–2 was significantly higher at the posterior cerebral artery, but not at the anterior communicating artery, of rats with aneurysms than in sham-operated rats. These findings suggest that aneurysm rupture is attributable to significant morphological changes and an increase in degradation molecules. CONCLUSIONS Time-dependent and site-dependent morphological changes and the level of degradation molecules may be indicative of the vulnerability of aneurysms to rupture

脳動脈瘤破裂におけるERα/Sirt1低下とNLRP3活性化

Objective : Subarachnoid hemorrhage （SAH） due to rupture of intracranial aneurysm is often a devastating event. Since the incidence of SAH increases, especially in menopause, it is crucial to clarify the detailed pathogenesis of these events. We tested our hypothesis that, under estrogen-deficient conditions, activation of vascular nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 （NLRP3） inflammasomes via down-regulation of estrogen receptor （ER） and sirtuin1 （Sirt1） facilitates the ruptured intracranial aneurysms. Methods : Ten-week-old female Sprague-Dawley rats with and without oophorectomy （OVX+ and OVX- rats, respectively） were subjected to hemodynamic changes and hypertension and fed a high-salt diet. Using human brain endothelial cells （HBECs） and smooth muscle cells （HBSMCs）, we tested the effect of estradiol, ER agonists. Results : In OVX+ rats, the frequency of intracranial aneurysm rupture was significantly higher than in OVX- rats （p=0.03）. In the left posterior cerebral artery prone to rupture in OVX+ rats, the levels of the mRNAs encoding ERα and Sirt1, but not of that encoding ERβ, were decreased and the levels of the mRNAs encoding NLRP3, interleukin-1β （IL-1β）, and matrix metalloproteinase 9 （MMP-9） were elevated. Immunohistochemistry, the expression profiles of these proteins were correlated with their mRNA levels. Treatment with an ER modulator, bazedoxifene, normalized the expression profiles of these proteins and improved SAH-free survival. In HBECs and HBSMCs grown under estrogen-free conditions, the elevation of NLRP3, IL-1β, MMP-9, and the depletion of ERα and Sirt1, were counteracted by exposure to an ERα agonist, but not an ERβ agonist. Conclusions : The down-regulation of ERα and Sirt1 by estrogen deficiency may contribute to the activation of the NLRP3/IL-1β/MMP-9 pathway, facilitating the rupture of intracranial aneurysms

トクシマ ダイガク ビョウイン ノウソッチュウ センター ニオケル インナイ ハッショウ ノウソッチュウ ノ ケントウ

We assessed the current status of patients with acute in-hospital stroke. 63 patients with acute in-hospital stroke were enrolled. The most prevalent subtype of stroke was embolism（n＝24）. The main cause of hospitalization were malignant neoplasms in15. Only 5 patients were treated with rt-PA, 8 patients received endovascular interventions. In-hospital stroke is a sever complication of in-patients and is associated with an unfavorable prognosis, but endovascular interventions offer safe and feasible therapeutic treatment options