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

Five case of tardive dystonia treatment with pallidal deep brain stimulation

We assessed the efficiency of pallidal deep brain stimulation for tardive dystonia. This search was carried out in Electronic chart of Tokushima University Hospital. ５ patients with tardive dystonia were enrolled. GPi（internal segment of globus pallidus）was the target in all patients. The motor part of Burke-Fahn-Marsden Dystonia Rating Scale（BFMDRS）was improved by ７８．４％ on average when compared to preoperative BFMDRS scores. The performed analysis indicates that GPi-DBS is an effective and safe treatment for tardive dystonia

選択的エストロゲン受容体モジュレーターのバゼドキシフェンは卵巣摘除ラットにおいて脳動脈瘤破裂を抑制する

Background: Estrogen 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. Methods: Ten-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. Results: During 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. Conclusions: Our observation that bazedoxifene decreased the incidence of aneurysmal rupture in ovariectomized rats warrants further studies to validate this response in humans

RUPTURED CEREBRAL ANEURYSMS AND SEVERE PD

BACKGROUND: The pathophysiology of subarachnoid hemorrhages (SAHs) due to ruptured intracranial aneurysms (IAs) remains unclear.Although a relationship between SAHs and periodontal disease (PD) has been suggested, the mechanism requires clarification. OBJECTIVE: To evaluate the relationship between PD and SAHs and to identify periodontal pathogens associated with SAHs. METHODS: This prospective study included consecutive patients with ruptured (n = 11) and unruptured (n = 14) IAs and healthy controls (n = 8). The plasma and plaque subgingival bacterial deoxyribonucleic acid (DNA) levels in PD were evaluated by a dentist using the Community Periodontal Index of Treatment Needs (CPITN). Plasma levels of matrix metalloproteinase (MMP-9), tissue inhibitors of matrix metalloproteinase (TIMP2), and procollagen I were analyzed. RESULTS: Patients with ruptured IAs, had significantly higher CPITN scores than the controls, suggesting that ruptured IAs were associated with severe PD. Although no rupture-specific bacteria were identified, the positive rate of plaque subgingival bacterial DNA was significantly higher in patients with severe PD than in those without severe PD. Multivariate logistic regression analysis indicated that bleeding on probing (BOP)was associated with ruptured IAs (odds ratio, 1.10; 95% confidence interval 1.04–1.20; P = .0001). BOP was positively associated with plasma MMP-9 levels and a disequilibrium in the MMP-9/TIMP2 ratio. BOP was negatively correlated with plasma procollagen I levels (P < .05, for each). This suggested that local inflammation with severe PD might have systemic effects and lead to ruptured IAs. CONCLUSION: Disequilibrium of plasma protease/anti-protease associated with a high BOP rate in severe PD may be attributable to IA rupture

MEDICAL TREATMENT OF UNRUPTURED CEREBRAL ANEURYSMS

Background: Currently there are no pharmacological therapies for patients with unruptured cerebral aneurysms. Elsewhere we showed that the mineralocorticoid receptor antagonist eplerenone prevented the formation of cerebral aneurysms in our ovariectomized hypertensive aneurysm rat model. The current pilot study evaluated whether it can be used to prevent the growth and rupture of cerebral aneurysms in hypertensive patients. Methods: Between August 2011 and May 2014, we enrolled 82 patients with 90 aneurysms in an open-label uncontrolled clinical trial. All provided prior informed consent for inclusion in this study, and all were treated with eplerenone (25-100 mg/d). The primary end points of our study were the rupture and enlargement of the cerebral aneurysms. Results: Of the 82 patients, 80 (88 unruptured aneurysms) were followed for a mean of 21.3 months (153.4 aneurysm-years); 12 patients (15.0%) permanently discontinued taking the drug. One month after the start of eplerenone administration and throughout the follow-up period, eplerenone kept the blood pressure within the normal range. Most notably, no aneurysms smaller than 9 mm ruptured or enlarged. However, of 2 large thrombosed aneurysms, 1 enlarged and the other ruptured. The overall annual rupture rate was .65%; it was 13.16% for aneurysms larger than 10 mm; the overall annual rate for reaching the primary end points was 1.30%. Conclusion: Our observations suggest that eplerenone may help to prevent the growth and rupture of unruptured cerebral aneurysms smaller than 9 mm. To assess its potential long-term clinical benefits, large clinical trials are needed

Rupture related to site-specific MMP-9 elevation

The pathogenesis of subarachnoid hemorrhage (SAH)remains unclear. No models of cerebral aneurysms elicited solely by surgical procedures and diet have been established.Elsewhere we reported that only few rats in our original rat aneurysm model manifested rupture at the anterior-and posterior Willis circle (AW, PW) and thatmany harbored unruptured aneurysms at the anterior cerebral artery-olfactory artery bifurcation (ACA-OA). This suggests that rupture was site-specific. To test our hypothesis that a site-specific responseto hemodynamic changes is associated with aneurysmal rupture, we modified our original aneurysm model by altering the hemodynamics. During 90-day observation, the incidenceof ruptured aneurysms at the AW and PWwas significantly increasedand the high incidence of unruptured aneurysms at the ACA-OA persisted. This phenomenon was associatedwith an increase in the blood flow volume (BFVo). Notably, the level of matrix metalloproteinase(MMP)-9 associated with interleukin (IL)-1βwas augmented by the increase in the BFVo, suggesting that these molecules exacerbated the vulnerability of the aneurysmal wall. The current study first demonstrates that a site-specificincrease in IL-1β and MMP-9 elicited by hemodynamic changes is associated with rupture. Our novel rat model of rupture may help to developpharmaceutical approaches to prevent rupture

Bone Response to Titanium Implants Coated with Double- or Single-Stranded DNA

We aimed to evaluate in vivo bone response and in vitro apatite formation to titanium (Ti) implants, coated with double-stranded DNA (DNA-d) or single-stranded DNA (DNA-s), and to compare the influence in different structure of DNA, double strand and single strand on bone response and apatite formation. The bone responses to multilayered DNA-d/protamine or DNA-s/protamine coating implants were evaluated after implantation into the extracted sockets of rat maxillary molars. Apatite formation on either coating surface after immersion in simulated body fluid (SBF) was evaluated using the quartz crystal microbalance (QCM) method. DNA-d/protamine and DNA-s/protamine coatings produced more roughened and hydrophilic surfaces than untreated Ti. Animal experiments showed that higher bone-to-implant ratios were achieved 3 and 6 weeks after implantation using DNA-d/protamine and DNA-s/protamine coatings compared with Ti. QCM measurements revealed that each coating contributed to significant earlier apatite formation in SBF. We conclude that both DNA-d/protamine and DNA-s/protamine coatings enhanced early bone formation. We suggest that a DNA-multilayer coating is useful for the surface modification of a Ti implant