Background and Purpose: The incidences of intracranial aneurysm and aneurysmal subarachnoid hemorrhage are high in postmenopausal women. Although population-based studies suggest that hormone replacement therapy is beneficial for postmenopausal women with intracranial aneurysms, estrogen replacement may no longer be recommended for the prevention of chronic diseases given its association with adverse outcomes, such as cancer and ischemic stroke. The isoflavone daidzein and its intestinal metabolite equol are bioactive phytoestrogens and potent agonists of estrogen receptors. Given their estrogenic properties, we investigated whether the isoflavones daidzein and equol are protective against the formation and rupture of intracranial aneurysms in a mouse model of the postmenopausal state. Methods: We induced intracranial aneurysms in ovariectomized adult female mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. We fed the mice with an isoflavone-free diet with/without daidzein supplementation, or in a combination of intraperitoneal equol, or oral vancomycin treatment. We also used estrogen receptor beta knockout mice. Results: Both dietary daidzein and supplementation with its metabolite, equol, were protective against aneurysm formation in ovariectomized mice. The protective effects of daidzein and equol required estrogen receptor-β. The disruption of the intestinal microbial conversion of daidzein to equol abolished daidzein’s protective effect against aneurysm formation. Mice treated with equol had lower inflammatory cytokines in the cerebral arteries, suggesting that phytoestrogens modulate inflammatory processes important to intracranial aneurysm pathogenesis. Conclusions: Our study establishes that both dietary daidzein and its metabolite, equol, protect against aneurysm formation in ovariectomized female mice through the activation of estrogen receptor-β and subsequent suppression of inflammation. Dietary daidzein’s protective effect required the intestinal conversion to equol. Our results indicate the potential therapeutic value of dietary daidzein and its metabolite, equol, for the prevention of the formation of intracranial aneurysms and related subarachnoid hemorrhage.

Background: This study aimed to identify easily available prognostic factors in severe traumatic brain injury (TBI) patients undergoing craniotomy. Methods: We retrospectively analyzed the clinical characteristics (age, sex, Glasgow coma scale score, cause of TBI, and oral antithrombotic drug use), laboratory parameters (hemoglobin, sodium, C-reactive protein, D-dimer, activated partial thromboplastin time, prothrombin time-international normalized ratio, and glucose-potassium [GP] ratio), and neuroradiological findings of 132 patients who underwent craniotomy for severe TBI in our hospital between January 2015 and December 2021. The patients were divided into two groups: Those with fatal clinical outcomes and those with non-fatal clinical outcomes, and compared between the two groups. Results: The patients comprised 79 (59.8%) male and 53 (40.2%) female patients. Their mean age was 67 ± 17 years (range, 16–94 years). Computed tomography revealed acute subdural hematoma in 108 (81.8%) patients, acute epidural hematoma in 31 (23.5%), traumatic brain contusion in 39 (29.5%), and traumatic subarachnoid hemorrhage in 62 (47.0%). All 132 patients underwent craniotomy, and 41 eventually died. There were significant differences in the D-dimer, GP ratio, and optic nerve sheath diameter between the groups (all P < 0.01). Multivariate logistic regression analysis showed elevated GP ratio and D-dimer were associated with the death group (P < 0.01, P < 0.01, respectively). A GP ratio of >42 was the optimal cutoff value for the prediction of a fatal outcome of TBI (sensitivity, 85.4%; specificity, 51.1%). Conclusion: The GP ratio and D-dimer were significantly associated with poor outcomes of TBI. A GP ratio of >42 could be a predictor of a fatal outcome of TBI.

Background and Objectives: Nutritional management in patients with subarachnoid hemorrhage (SAH) during the acute phase is important; however, there is no proper evidence or recommendations on the appropriate nutrients for early enteral nutrition. This study compared the influence the two different tube-feeding liquid diets for early enteral nutrition might have on the prognosis of patients with SAH. Materials and Methods: In a seven-year period, this single-center retrospective study included 245 patients with aneurysmal SAH who underwent craniotomy and aneurysm neck clipping and received enteral nutrition. The patients were divided into two groups according to the nutrient received: (1) high-protein whey peptide oligomeric formula diet (oligomeric group, 109 patients); and (2) high eicosapentaenoic acid-containing polymeric formula diet (polymeric group, 136 patients). The modified Rankin Scale (mRS) score at discharge was evaluated as the primary outcome. The presence or absence of diarrhea (watery stool and mushy stool) during the period from initiation of enteral nutrition to discharge from the stroke unit was also evaluated. Results: There were no significant differences in patient characteristics between groups. The time until initiation of enteral feeding in the oligomeric and polymeric groups was 2.8 ± 2.3 and 2.9 ± 2.2 days, respectively. The proportion of patients with mRS scores of 0–1 was significantly higher in the oligomeric group (25.7%) than in the polymeric group (14.7%) (p = 0.036), while the incidence of watery stool was significantly lower in the oligomeric group (15.8% to 34.3% in the polymeric group) (p = 0.003). Multivariate analyses confirmed that the oligomeric diet and the presence or absence of diarrhea significantly affected the mRS scores. Conclusions: The adoption of early enteral nutrition with high-protein whey peptide digestive nutrients might be associated with superior mRS scores at discharge and decreased diarrhea in patients with SA, indicating that the choice of nutrients might affect the outcome and prognosis.

BACKGROUND: Multiple pathways and factors are involved in the rupture of intracranial aneurysms. The EGFR (epidermal growth factor receptor) has been shown to mediate inflammatory vascular diseases, including atherosclerosis and aortic aneurysm. However, the role of EGFR in mediating intracranial aneurysm rupture and its underlying mechanisms have yet to be determined. Emerging evidence indicates that endoplasmic reticulum (ER) stress might be the link between EGFR activation and the resultant inflammation. ER stress is strongly implicated in inflammation and apoptosis of vascular smooth muscle cells, both of which are key components of the pathophysiology of aneurysm rupture. Therefore, we hypothesized that EGFR activation promotes aneurysmal rupture by inducing ER stress. METHODS: Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture. RESULTS: Pharmacological inhibition of EGFR markedly decreased the rupture rate of intracranial aneurysms without altering the formation rate. EGFR inhibition also significantly reduced the mRNA (messenger RNA) expression levels of ER-stress markers and inflammatory cytokines in cerebral arteries. Similarly, ER-stress inhibition also significantly decreased the rupture rate. In contrast, ER-stress induction nullified the protective effect of EGFR inhibition on aneurysm rupture. CONCLUSIONS: Our data suggest that EGFR activation is an upstream event that contributes to aneurysm rupture via the induction of ER stress. Pharmacological inhibition of EGFR or downstream ER stress may be a promising therapeutic strategy for preventing aneurysm rupture and subarachnoid hemorrhage.