FGF17 protects cerebral ischemia reperfusion-induced blood-brain barrier disruption via FGF receptor 3-mediated PI3K/AKT signaling pathway.

Maintaining blood-brain barrier (BBB) integrity is critical components of therapeutic approach for ischemic stroke. Fibroblast growth factor 17 (FGF17), a member of FGF8 superfamily, exhibits the strongest expression throughout the wall of all major arteries during development. However, its molecular action and potential protective role on brain endothelial cells after stroke remains unclear. Here, we observed reduced levels of FGF17 in the serum of patients with ischemic stroke, as well as in the brains of mice subjected to middle cerebral artery occlusion (MCAO) injury and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced brain microvascular endothelial cells (bEnd.3) cells. Moreover, treatment with exogenous recombinant human FGF17 (rhFGF17) decreased infarct volume, improved neurological deficits, reduced Evans Blue leakage and upregulated the expression of tight junctions in MCAO-injured mice. Meanwhile, rhFGF17 increased cell viability, enhanced trans-endothelial electrical resistance, reduced sodium fluorescein leakage, and alleviated reactive oxygen species (ROS) generation in OGD/R-induced bEnd.3 cells. Mechanistically, the treatment with rhFGF17 resulted in nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation and upregulation of heme oxygenase-1 (HO-1) expression. Additionally, based on in-vivo and in-vitro research, rhFGF17 exerted protective effects against ischemia/reperfusion (I/R) -induced BBB disruption and endothelial cell apoptosis through the activation of the FGF receptor 3/PI3K/AKT signaling pathway. Overall, our findings indicated that FGF17 may hold promise as a novel therapeutic strategy for ischemic stroke patients.

Poor-Grade Aneurysmal Subarachnoid Hemorrhage: Risk Factors Affecting Clinical Outcomes in Intracranial Aneurysm Patients in a Multi-Center Study.

Objective: Patients with poor-grade aneurysm subarachnoid hemorrhage (SAH) have commonly been considered to have a poor prognosis. The objective of this study was to investigate the independent risk factors affecting clinical outcomes in intracranial aneurysm patients with poor-grade aneurysm subarachnoid hemorrhage (aSAH) underwent different intervention therapies. Methods: A multicenter observational registry of 324 poor-grade aSAH patients treated at tertiary referral centers from October 2010 to March 2012 were enrolled in this study. The clinical data including patient characteristics on admission and during treatment course, treatment modality, aneurysm size and location, radiologic features, signs of cerebral herniation (dilated pupils), and functional neurologic outcome were collected. Clinical outcomes were assessed via a modified Rankin Scale at 12 months. Multivariate logistic regression models were used to develop prognostic models. The area under the receiver operator characteristic curves (AUC) and Hosmer-Lemeshow tests were used to assess discrimination and calibration. WAP score was developed to predict risk of poor outcome. Results: Older age, female gender, ventilated breathing status, non-reactive pupil response, pupil dilation, lower GCS score, a WFNS grade of V, intraventricular hemorrhage, a higher Fisher grade, a higher modified Fisher grade, and conservative treatment were calculated to be associated with a relatively poor outcome. Multivariate analyses revealed that older age, lower Glasgow coma scale score (GCS), the absence of pupillary reactivity, higher modified Fisher grade, and conservative treatment were independent predictors of poor outcome, showed good discrimination and calibration. Patients with WFNS grade V, older age and non-reactive pupillary reactivity were predicted to have a poor outcome by WAP risk score. Conclusions: A simple WAP risk score had good discrimination and calibration in the prediction of outcome. The risk score can be easily measured and may complement treatment decision-making.

Comparison of Aggressive Surgical Treatment and Palliative Treatment in Elderly Patients with Poor-Grade Intracranial Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: To compare the current treatment approach in elderly patients with poor-grade aneurysmal subarachnoid hemorrhage (SAH) and identify the independent predictors of the outcome after aggressive surgical treatment. METHOD: This prospective, multicenter cohort study included 104 poor-grade aneurysmal SAH elderly patients, 60 years or older, treated in our institution from October 2010 to March 2013. Patients were grouped according to three treatment arms. Neurological outcome was assessed using the Glasgow Outcome Scale (GOS) at baseline and at a 12-month follow-up. Univariate and multivariate analysis were performed using the following factors: sex, age, smoking history, breathing ability, alcohol consumption, cerebral hernia, aneurysm location, aneurysm diameter, WFNS grade, CT Fisher grade, treatment approach, and the timing of the aneurysm surgery. RESULTS: At the 12-month follow-up, patients in the coiling group and clipping group had better prognosis than patients in the palliative treatment group. Univariate analysis confirmed that the treatment approach, WFNS grade, CT Fisher grade, and age are critical factors for neurological outcomes in poor-grade SAH. Multivariate analysis indicated that WFNS grade V, CT Fisher grades 3-5, and palliative treatment were independent predictors of poor prognoses. CONCLUSION: Aggressive surgical treatment improves the prognoses in poor-grade aneurysm elderly patients with SAH. Elderly Patients of WFNS grade IV and CT Fisher grades 1-2 are more likely to have a better outcome.

Alterations of caveolin-1 expression in a mouse model of delayed cerebral vasospasm following subarachnoid hemorrhage.

The aim of the present study was to evaluate the expression levels of caveolin-1 in the basilar artery following delayed cerebral vasospasm (DCVS) in a rat model of subarachnoid hemorrhage (SAH), in order to investigate the association between caveolin-1 and DCVS, and its potential as a treatment for DCVS of SAH. A total of 150 Sprague Dawley rats were randomly allocated into blank, saline and SAH groups. The SAH and saline groups were subdivided into days 3, 5, 7 and 14 following the establishment of the model. The murine model of SAH was established by double injection of autologous arterial blood into the cisterna magana and DCVS was detected using Bederson neurological severity scores. Hematoxylin and eosin (HE) staining was used to observe the inner perimeter of the basilar artery pipe and variations in the thickness of the basilar artery wall. Alterations in the levels of caveolin-1 protein in the basilar artery were measured using immunofluorescence and western blot analysis; whereas alterations in the mRNA expression levels of caveolin-1 were detected by reverse transcription-quantitative polymerase chain reaction. In the present study, 15 mice succumbed to SAH-induced DCVS in the day 3 (n=3), 5 (n=5) and 7 (n=2) groups. No mortality was observed in the blank control and saline groups during the process of observation in the SAH group, All mice in the SAH groups exhibited Bederson neurological severity scores ≥1; whereas no neurological impairment was detected in the blank and normal saline groups, demonstrating the success of the model. HE staining was used to assess vasospasm and the results demonstrated that the inner perimeter of the basal artery pipe decreased at day 3 in the SAH group; whereas values peaked in the day 7 group. The thickness of the basal artery wall significantly increased (P<0.05), as compared with the blank and saline groups, in which no significant alterations in the wall thickness and the inner perimeter of the basal artery pipe were detected. As detected by immunofluorescence and western blot analysis, the expression levels of caveolin-1 protein significantly decreased in the day 7 of SAH group, as compared with the blank and saline groups (P<0.01), in which no significant alterations were detected. Caveolin-1 mRNA expression levels significantly increased at the day 7 in the SAH group, as compared with the blank and the saline groups (P<0.01), as detected by RT-qPCR. Furthermore, significant differences were detected at day 14 in the SAH group, as compared with the blank and the saline groups (P>0.05), in which no significant alterations were detected. Therefore, the results of the present study demonstrated that caveolin-1 protein was downregulated in the basilar artery of a rat modeling SAH, which may be associated with DCVS. This suggested that caveolin-1 may be a potential target for the treatment of DCVS.

[Analysis of prognostic factors on posterior communicating artery aneurysm caused oculomotor nerve palsy].

OBJECTIVE: To study and analyze the factors affecting the recovery of posterior communicating artery aneurysm-induced oculomotor nerve palsy (ONP). METHODS: The clinical and follow-up data of posterior communicating artery aneurysm-induced ONP in 23 patients from May 2005 to May 2009 were retrospectively compared. There were 7 male and 16 female with a mean age of 50.4 years. Among the 23 patients, 13 patients underwent endovascular coiling (endovascular group) and 10 patients underwent surgical clipping (surgical group). RESULTS: Of the patients with 2 year of follow-up, 6 patients recovered completely and 7 patients recovered partially in the endovascular group, compared with 6 patients recovered completely and 4 patients recovered partially in the surgical group (P = 0.407). Compared to the patients with preoperative complete ONP, the rate of complete recovery was higher in the patients with preoperative partial ONP, while the results did not reach the significance (P = 0.095). Patients accepted treatment in 14 days since the onset of symptoms recovered significantly than who accepted treatment after 14 days since the onset of symptoms (P = 0.045). CONCLUSIONS: There is no significant difference in recovery from ONP between endovascular coiling and surgical clipping as treatment for posterior communicating artery aneurysm patients with ONP. Timing of treatment after onset of symptoms is a factor affects the recovery of ONP.

Computed tomography angiography based emergency microsurgery for massive intracranial hematoma arising from arteriovenous malformations.

BACKGROUND: Digital subtraction angiography (DSA) and magnetic resonance angiography are the imaging modalities for the detection of intracranial arteriovenous malformations. However, these modalities are time consuming and cannot be used in emergency conditions. Computed tomography angiography (CTA) has also been shown to reliably detect vascular disorders such as cerebral arteriovenous malformations (AVMs). AIMS: The purpose of this study was to evaluate the usefulness CTA in the surgical treatment of AVMs and the hematoma evacuation. PATIENTS AND METHODS: Case records of 18 patients with massive intracranial hematoma secondary to AVMs were retrospectively reviewed. All patients had emergent brain CT and CTA. Follow-up DSA was performed two to three weeks after surgery. The outcome was assessed using Glasgow Outcome Scale (GOS). Results : Emergent CTA demonstrated AVMs and defined the feeding arteries, abnormal vascular nest, and draining veins in all the patients. Fourteen patients underwent hematoma evacuation and total resection of the AVMs, and four patients had hematoma evacuation and a partial resection. Follow-up DSA demonstrated complete resection of AVM in 14/18 patients and partial resection in 4 patients. There were no deaths and none of the patients had rebleeding in the follow up. A GOS scores during follow-up were: GOS 3 in 12 patients, GOS 4 in 4 patients and GOS 2 in 2 patients. CONCLUSIONS: CTA can be a reliable and rapid diagnostic tool for detecting underlying AVM in patients presenting with intracranial hematoma and for the pretreatment planning of emergency craniotomy.

Expression change of interleukin-8 gene in rabbit basilar artery after subarachnoid hemorrhage.

OBJECTIVE: To study the expression change of interleukin-8 (IL-8) gene in the basilar artery of rabbit and the effect of IL-8 on the development of cerebral vasospasm induced by experimental subarachnoid hemorrhage (SAH). METHODS: Thirty five healthy Japanese White Rabbits were randomly divided into saline-control group and experimental group. The experimental group was subdivided into four groups, representing day 1, 4, 7 and 14 after the first blood injection of SAH. The delayed cerebral vasospasm (DCVS) model was established by double injection of autologous blood into the cisterna magna. The expression change of cytokine IL-8 mRNA in the basilar artery was analyzed by RTPCR. RESULTS: The expression of IL-8 gene increased on day 4-7 after the first blood injection of SAH compared with control (P< 0.001), and decreased to normal on day 14. The expression of IL-8 gene in the SAH groups were positively correlated with the degree of basilar artery stenosis (r = 0.642, P< 0.01). CONCLUSION: The expression level of IL-8 gene in basilar arteries was intimately associated with the degree of cerebral vasospasm, suggesting that IL-8 may play an important role in the DCVS after SAH as an immunological inflammatory factor.

Diagnostic value of CTA and MRA in intracranial traumatic aneurysms.

OBJECTIVE: To investigate the diagnostic value of computerized tomographic angiography (CTA) and magnetic resonance angiography (MRA) for intracranial traumatic aneurysms (TAs). METHODS: CTA and MRA of six patients with intracranial TAs verified by digital subtraction angiography (DSA) and surgery were retrospectively analysed. All patients were examined by nonenhanced computerized tomography (CT) and two by CTA. The source data were reconstructed by volume rendering (VR) and multi-planar reconstruction (MPR) from CTA. Four of them had maximum intensity project (MIP) from MRA. RESULTS: Of the six patients, a total of seven TAs were detected by CTA and MRA examinations. Five cases had only one TA and one case had two TAs. The average diameter was 2.3 cm (1.1-3.3 cm). CTA demonstrated two TAs appeared at the cavernous segment of the internal carotid artery (ICA) and the middle cerebral artery (MCA) respectively. MCA TA was definitely and clearly demonstrated on VR images, whereas VR images failed to depict the cavernous ICA TA, which was detected on MPR images. Two TAs were found irregular saccular shape, irregular margin of parent artery and wide neck on CTA. Four MRA examinations demonstrated five TAs, including the cavernous segment ICA TAs (2 cases), the supraclinoid segment ICA TA (1 case), and the cavernous segment associated with opposite side of the petrosal segment ICA TA (1 case). In a cavernous ICA TA, MRA only revealed aneurysm body, whereas aneurysm neck and distal segment of the parent artery were not revealed. In the remaining cases, MRA clearly depicted aneurysm body and parent artery, whereas the neck was not displayed. ICA TAs showed irregular capsule-like high signal intensity on MRA images. Four TAs exhibited irregular distal segment of the parent artery. TAs at the supraclinoid segment or MCA failed to find fracture signs on nonenhanced CT. CONCLUSIONS: Both CTA and MRA examinations are the effective non-invasive method of imageology for diagnosing intracranial TAs, while CTA is more eligible for diagnosing TAs after nonenhanced CT has demonstrated skull base fractures.