PEDF-34 attenuates neurological deficit and suppresses astrocyte-dependent neuroinflammation by modulating astrocyte polarization via 67LR/JNK/STAT1 signaling pathway after subarachnoid hemorrhage in rats.

BACKGROUND: Reactive astrocytes participate in various pathophysiology after subarachnoid hemorrhage (SAH), including neuroinflammation, glymphatic-lymphatic system dysfunction, brain edema, BBB disruption, and cell death. Astrocytes transform into two new reactive phenotypes with changed morphology, altered gene expression, and secretion profiles, termed detrimental A1 and beneficial A2. This study investigates the effect of 67LR activation by PEDF-34, a PEDF peptide, on neuroinflammation and astrocyte polarization after the experimental SAH. METHODS: A total of 318 male adult Sprague-Dawley rats were used in experiments in vivo, of which 272 rats were subjected to the endovascular perforation model of SAH and 46 rats underwent sham surgery. 67LR agonist (PEDF-34) was administrated intranasally 1 h after SAH. 67LR-specific inhibitor (NSC-47924) and STAT1 transcriptional activator (2-NP) were injected intracerebroventricularly 48 h before SAH. Short- and long-term neurological tests, brain water content, immunostaining, Nissl staining, western blot, and ELISA assay were performed. In experiments in vitro, primary astrocyte culture with hemoglobin (Hb) stimulation was used to mimic SAH. The expression of the PEDF-34/67LR signaling pathway and neuro-inflammatory cytokines were assessed using Western blot, ELISA, and immunohistochemistry assays both in vivo and in vitro. RESULTS: Endogenous PEDF and 67LR expressions were significantly reduced at 6 h after SAH. 67LR was expressed in astrocytes and neurons. Intranasal administration of PEDF-34 significantly reduced brain water content, pro-inflammatory cytokines, and short-term and long-term neurological deficits after SAH. The ratio of p-JNK/JNK and p-STAT1/STAT1 and the expression of CFB and C3 (A1 astrocytes marker), significantly decreased after PEDF-34 treatment, along with fewer expression of TNF-α and IL-1ß at 24 h after SAH. However, 2-NP (STAT1 transcriptional activator) and NSC-47924 (67LR inhibitor) reversed the protective effects of PEDF-34 in vivo and in vitro by promoting A1 astrocyte polarization with increased inflammatory cytokines. CONCLUSION: PEDF-34 activated 67LR, attenuating neuroinflammation and inhibiting astrocyte A1 polarization partly via the JNK/STAT1 pathway, suggesting that PEDF-34 might be a potential treatment for SAH patients.

Fractalkine Enhances Hematoma Resolution and Improves Neurological Function via CX3CR1/AMPK/PPARγ Pathway After GMH.

BACKGROUND: Hematoma clearance has been a proposed therapeutic strategy for hemorrhagic stroke. This study investigated the impact of CX3CR1 (CX3C chemokine receptor 1) activation mediated by r-FKN (recombinant fractalkine) on hematoma resolution, neuroinflammation, and the underlying mechanisms involving AMPK (AMP-activated protein kinase)/PPARγ (peroxisome proliferator-activated receptor gamma) pathway after experimental germinal matrix hemorrhage (GMH). METHODS: A total of 313 postnatal day 7 Sprague Dawley rat pups were used. GMH was induced using bacterial collagenase by a stereotactically guided infusion. r-FKN was administered intranasally at 1, 25, and 49 hours after GMH for short-term neurological evaluation. Long-term neurobehavioral tests (water maze, rotarod, and foot-fault test) were performed 24 to 28 days after GMH with the treatment of r-FKN once daily for 7 days. To elucidate the underlying mechanism, CX3CR1 CRISPR, or selective CX3CR1 inhibitor AZD8797, was administered intracerebroventricularly 24 hours preinduction of GMH. Selective inhibition of AMPK/PPARγ signaling in microglia via intracerebroventricularly delivery of liposome-encapsulated specific AMPK (Lipo-Dorsomorphin), PPARγ (Lipo-GW9662) inhibitor. Western blot, Immunofluorescence staining, Nissl staining, Hemoglobin assay, and ELISA assay were performed. RESULTS: The brain expression of FKN and CX3CR1 were elevated after GMH. FKN was expressed on both neurons and microglia, whereas CX3CR1 was mainly expressed on microglia after GMH. Intranasal administration of r-FKN improved the short- and long-term neurobehavioral deficits and promoted M2 microglia polarization, thereby attenuating neuroinflammation and enhancing hematoma clearance, which was accompanied by an increased ratio of p-AMPK (phosphorylation of AMPK)/AMPK, Nrf2 (nuclear factor erythroid 2-related factor 2), PPARγ, CD36 (cluster of differentiation 36), CD163 (hemoglobin scavenger receptor), CD206 (the mannose receptor), and IL (interleukin)-10 expression, and decreased CD68 (cluster of differentiation 68), IL-1ß, and TNF (tumor necrosis factor) α expression. The administration of CX3CR1 CRISPR or CX3CR1 inhibitor (AZD8797) abolished the protective effect of FKN. Furthermore, selective inhibition of microglial AMPK/PPARγ signaling abrogated the anti-inflammation effects of r-FKN after GMH. CONCLUSIONS: CX3CR1 activation by r-FKN promoted hematoma resolution, attenuated neuroinflammation, and neurological deficits partially through the AMPK/PPARγ signaling pathway, which promoted M1/M2 microglial polarization. Activating CX3CR1 by r-FKN may provide a promising therapeutic approach for treating patients with GMH.

NOTCH4 Single-Nucleotide Polymorphism Is Associated with Brain Arteriovenous Malformation in a Chinese Han Population.

INTRODUCTION: Brain arteriovenous malformations (BAVMs) are high-flow intracranial vascular malformations characterized by the direct connection of arteries to veins without an intervening capillary bed. They are one of the main causes of intracranial hemorrhage and epilepsy, although morbidity is low. Angiogenesis, heredity, inflammation, and arteriovenous malformation syndromes play important roles in BAVM formation. Animal experiments and previous studies have confirmed that NOTCH4 may be associated with BAVM development. Our study identifies a connection between NOTCH4 gene polymorphisms and BAVM in a Chinese Han population. METHODS: We enrolled 150 patients with BAVMs confirmed by digital subtraction angiography (DSA) in the Department of Neurosurgery, Zhujiang Hospital, Southern Medical University from June 2017 to July 2019. Simultaneously, 150 patients without cerebrovascular disease were confirmed by computed tomography angiography/magnetic resonance angiography/DSA. DNA was extracted from peripheral blood and NOTCH4 genotypes were identified by PCR-ligase detection reaction. The χ2 test or Fisher's exact test was used to evaluate the differences in allele and genotype frequencies between the BAVM group, control group, bleeding group, and other complications. RESULTS: Two single-nucleotide polymorphisms (SNPs), rs443198 and rs438475, were significantly associated with BAVM. No SNP genotypes were significantly associated with hemorrhage or epilepsy. SNPs rs443198_AA-SNP and rs438475_AA-SNP may be associated with a lower risk of BAVM (p = 0.011, odds ratio (OR) = 0.459, 95% confidence interval (CI): 0.250-0.845; p = 0.033, OR = 0.759, 95% CI: 0.479-1.204). CONCLUSION: NOTCH4 gene polymorphisms were associated with BAVM and may be a risk factor in a Chinese Han population.

TSG-6 Attenuates Oxidative Stress-Induced Early Brain Injury in Subarachnoid Hemorrhage Partly by the HO-1 and Nox2 Pathways.

BACKGROUND: Early brain injury (EBI) refers to acute brain injury during the first 72 h after subarachnoid hemorrhage (SAH), which is one of the major causes of poor prognosis after SAH. Here, we investigated the effect and the related mechanism of TSG-6 on EBI after SAH. MATERIALS AND METHODS: The Sprague-Dawley rat model of SAH was developed by the endovascular perforation method. TSG-6 (5µg) was administered by an intraventricular injection within 1.5 h after SAH. The effects of TSG-6 on EBI were assessed by neurological score, brain water content (BWC) and TUNEL staining. Immunofluorescence staining was used to assay NF-κB/p-NF-κB expression in microglia. Protein expression levels of heme oxygenase-1 (HO-1), NADPH oxidase 2 (Nox2), Bcl-2, Bax, and cleaved-caspase-3 were measured to investigate the potential mechanism. The enzyme activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and the level of reactive oxygen species (ROS) were analyzed using commercially available kits. RESULTS: The results showed that TSG-6 treatment alleviated the neurobehavioral dysfunction and reduced BWC and the number of TUNEL-positive neurons in EBI after SAH. TSG-6 decreased the ROS level and enhanced the enzyme activity of SOD and GSH-Px after SAH. Furthermore TSG-6 inhibited the NF-κB activation, increased the protein expression levels of HO-1 and Bcl-2 and decreased the expression levels of Nox2, Bax, and cleaved-caspase-3. The administration of TSG-6 siRNA abolished the protective effects of TSG-6 on EBI after SAH. CONCLUSION: We found that TSG-6 attenuated oxidative stress and apoptosis in EBI after SAH partly by inhibiting NF-κB and activating HO-1 pathway in brain tissue.

Mesenchymal stem cells alleviate the early brain injury of subarachnoid hemorrhage partly by suppression of Notch1-dependent neuroinflammation: involvement of Botch.

BACKGROUND: Activated microglia-mediated neuroinflammation has been regarded as an underlying key player in the pathogenesis of subarachnoid hemorrhage (SAH)-induced early brain injury (EBI). The therapeutic potential of bone marrow mesenchymal stem cells (BMSCs) transplantation has been demonstrated in several brain injury models and is thought to involve modulation of the inflammatory response. The present study investigated the salutary effects of BMSCs on EBI after SAH and the potential mechanism mediated by Notch1 signaling pathway inhibition. METHODS: The Sprague-Dawley rats SAH model was induced by endovascular perforation method. BMSCs (3 × 106 cells) were transplanted intravenously into rats, and N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a Notch1 activation inhibitor, and Notch1 small interfering RNA (siRNA) were injected intracerebroventricularly. The effects of BMSCs on EBI were assayed by neurological score, brain water content (BWC), blood-brain barrier (BBB) permeability, magnetic resonance imaging, hematoxylin and eosin staining, and Fluoro-Jade C staining. Immunofluorescence and immunohistochemistry staining, Western blotting, and quantitative real-time polymerase chain reaction were used to analyze various proteins and transcript levels. Pro-inflammatory cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: BMSCs treatment mitigated the neurobehavioral dysfunction, BWC and BBB disruption associated with EBI after SAH, reduced ionized calcium binding adapter molecule 1 and cluster of differentiation 68 staining and interleukin (IL)-1 beta, IL-6 and tumor necrosis factor alpha expression in the left hemisphere but concurrently increased IL-10 expression. DAPT or Notch1 siRNA administration reduced Notch1 signaling pathway activation following SAH, ameliorated neurobehavioral impairments, and BBB disruption; increased BWC and neuronal degeneration; and inhibited activation of microglia and production of pro-inflammatory factors. The augmentation of Notch1 signal pathway agents and phosphorylation of nuclear factor-κB after SAH were suppressed by BMSCs but the levels of Botch were upregulated in the ipsilateral hemisphere. Botch knockdown in BMSCs abrogated the protective effects of BMSCs treatment on EBI and the suppressive effects of BMSCs on Notch1 expression. CONCLUSIONS: BMSCs treatment alleviated neurobehavioral impairments and the inflammatory response in EBI after SAH; these effects may be attributed to Botch upregulation in brain tissue, which subsequently inhibited the Notch1 signaling pathway.

The role of wall shear stress in the parent artery as an independent variable in the formation status of anterior communicating artery aneurysms.

OBJECTIVES: The study aimed to determine which hemodynamic parameters independently characterize anterior communicating artery (AcomA) aneurysm formation and explore the threshold of wall shear stress (WSS) of the parent artery to better illustrate the correlation between the magnitude of WSS and AcomA aneurysm formation. METHODS: Eighty-one patients with AcomA aneurysms and 118 patients without intracranial aneurysms (control population), as confirmed by digital subtraction angiography (DSA) from January 2014 to May 2017, were included in this cross-sectional study. Three-dimensional-DSA was performed to evaluate the morphologic characteristics of AcomA aneurysms. Local hemodynamic parameters were obtained using transcranial color-coded duplex (TCCD). Multivariate logistic regression and a two-piecewise linear regression model were used to determine which hemodynamic parameters are independent predictors of AcomA aneurysm formation and identify the threshold effect of WSS of the parent artery with respect to AcomA aneurysm formation. RESULTS: Univariate analyses showed that the WSS (p < 0.0001), angle between the A1 and A2 segments of the anterior cerebral artery (ACA) (p < 0.001), hypertension (grade II) (p = 0.007), fasting blood glucose (FBG; > 6.0 mmol/L) (p = 0.005), and dominant A1 (p < 0.001) were the significant parameters. Multivariate analyses showed a significant association between WSS of the parent artery and AcomA aneurysm formation (p = 0.0001). WSS of the parent artery (7.8-12.3 dyne/cm2) had a significant association between WSS and aneurysm formation (HR 2.0, 95% CI 1.3-2.8, p < 0.001). CONCLUSIONS: WSS ranging between 7.8 and 12.3 dyne/cm2 independently characterizes AcomA aneurysm formation. With each additional unit of WSS, there was a one-fold increase in the risk of AcomA aneurysm formation. KEY POINTS: • Multivariate analyses and a two-piecewise linear regression model were used to evaluate the risk factors for AcomA aneurysm formation and the threshold effect of WSS on AcomA aneurysm formation. • WSS ranging between 7.8 and 12.3 dyne/cm 2 was shown to be a reliable hemodynamic parameter in the formation of AcomA aneurysms. The probability of AcomA aneurysm formation increased one-fold for each additional unit of WSS. • An ultrasound-based TCCD technique is a simple and accessible noninvasive method for detecting WSS in vivo; thus, it can be applied as a screening tool for evaluating the probability of aneurysm formation in primary care facilities and community hospitals because of the relatively low resource intensity.

TSG-6 attenuates inflammation-induced brain injury via modulation of microglial polarization in SAH rats through the SOCS3/STAT3 pathway.

BACKGROUND: An acute and drastic inflammatory response characterized by the production of inflammatory mediators is followed by stroke, including SAH. Overactivation of microglia parallels an excessive inflammatory response and worsened brain damage. Previous studies indicate that TSG-6 has potent immunomodulatory and anti-inflammatory properties. This study aimed to evaluate the effects of TSG-6 in modulating immune reaction and microglial phenotype shift after experimental SAH. METHODS: The SAH model was established by endovascular puncture method for Sprague-Dawley rats (weighing 280-320 g). Recombinant human protein and specific siRNAs for TSG-6 were exploited in vivo. Brain injury was assessed by neurologic scores, brain water content, and Fluoro-Jade C (FJC) staining. Microglia phenotypic status was evaluated and determined by Western immunoblotting, quantitative real-time polymerase chain reaction (qPCR) analyses, flow cytometry, and immunofluorescence labeling. RESULTS: SAH induced significant inflammation, and M1-dominated microglia polarization increased expression of TSG-6 and neurological dysfunction in rats. rh-TSG-6 significantly ameliorated brain injury, decreased proinflammatory mediators, and skewed microglia towards a more anti-inflammatory property 24-h after SAH. While knockdown of TSG-6 further induced detrimental effects of microglia accompanied with more neurological deficits, the anti-inflammation effects of rh-TSG-6 were associated with microglia phenotypic shift by regulating the level of SOCS3/STAT3 axis. CONCLUSIONS: TSG-6 exerted neuroprotection against SAH-induced EBI in rats, mediated in part by skewing the balance of microglial response towards a protective phenotype, thereby preventing excessive tissue damage and improving functional outcomes. Our findings revealed the role of TSG-6 in modulating microglial response partially involved in the SOCS3/STAT3 pathway and TSG-6 may be a promising therapeutic target for the treatment of brain injury following SAH.

Comparison of polyvinyl alcohol copolymer with detachable balloons for the embolisation of direct carotid cavernous fistula: a single-centre experience.

OBJECTIVES: To characterise the safety, efficacy and cost of direct carotid-cavernous fistula (CCF) treatment using polyvinyl alcohol copolymer or detachable balloons. METHODS: We reviewed retrospectively patients with direct CCFs treated with either a detachable balloon or polyvinyl alcohol copolymer at our hospital from 2005 to 2015 and identified 94 patients with 105 CCFs. All patients had follow-up angiograms. The CCF occlusion rate, procedure complication rate, treatment expense and operation time were recorded. RESULTS: With a mean of 5.4 months of angiographic follow-up, the complete occlusion rate and recanalisation rate of the polyvinyl alcohol copolymer group was not significantly different from that of the detachable balloon group. The treatment expense was much higher and the operation time was much longer in the polyvinyl alcohol copolymer group than the detachable balloon group (P < 0.001). CONCLUSIONS: Embolisation of CCF with polyvinyl alcohol copolymer is as safe and effective as detachable balloon but has a much higher cost and longer operation time. KEY POINTS: • Carotid-cavernous fistula results from a damaged carotid artery. • Detachable balloons have been used with success for many years. • Some reported excellent outcomes after embolisation with polyvinyl alcohol copolymer. • Treatment expense is much higher in the polyvinyl alcohol copolymer group.

CDKN2BAS gene polymorphisms and the risk of intracranial aneurysm in the Chinese population.

BACKGROUND: CDKN2BAS gene polymorphisms has been shown to correlation with intracranial aneurysm(IA) in the study of foreign people. The study, the author selected the Chinese people as the research object to explore whether CDKN2BAS gene polymorphisms associated with Chinese patients with IA. METHODS: We selected 200 patients(52.69 ± 11.50) with sporadic IA as experimental group, 200 participants(49.99 ± 13.00) over the same period to the hospital without cerebrovascular diseases as control group. Extraction of peripheral blood DNA, applying polymerase chain reaction(PCR)-ligase detection reaction (LDR) identified CDKN2BAS Single nucleotide polymorphism(SNP) locus genotype: rs6475606, rs1333040, rs10757272, rs3217992, rs974336, rs3217986, rs1063192. The differences in allelic and genotype frequencies between the patient and control groups were evaluated by the chi-square test or Fisher's exact tests. RESULTS: The genotype of rs1333040 and rs6475606 shown association with sporadic IA(X2 = 8.545, P = 0.014; X2 = 10.961, P = 0.004; respectively);the C allele of rs6475606 showed reduction the occurrence of IA; the rs1333040 and rs6475606 associated with hemorrhage, the C allele of rs1333040 could lower the risk of hemorrhage, and rs6475606 will not, rs1333040 also associated with aneurysm size. CONCLUSION: Our research shows that variant rs1333040 and rs6475606 of CDKN2BAS related to the Chinese han population of sporadic IAs occurs. This study confirms the association between CDKN2BAS and IAs.

Baicalein Attenuates Neurological Deficits and Preserves Blood-Brain Barrier Integrity in a Rat Model of Intracerebral Hemorrhage.

Previous studies have demonstrated that baicalein has protective effects against several diseases, which including ischemic stroke. The effect of baicalein on the blood-brain barrier (BBB) in intracerebral hemorrhage (ICH) and its related mechanisms are not well understood. We aimed to investigate the mechanisms by which baicalein may influence the BBB in a rat model of ICH. The rat model of ICH was induced by intravenous injection of collagenase IV into the brain. Animals were randomly divided into three groups: sham operation, vehicle, and baicalein group. Each group was then divided into subgroups, in which the rats were sacrificed at 24 and 72 h after ICH. We assessed brain edema, behavioral changes, BBB leakage, apoptosis, inducible nitric oxide synthase (iNOS), zonula occludens (ZO)-1, Mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB). Treatment with baicalein reduced brain water content, BBB leakage, apoptosis, and neurologic deficits, compared with vehicle. Baicalein also decreased ICH-induced changes in the levels of iNOS but increased the levels of ZO-1. The protective effect of baicalein on the BBB in ICH rats was possibly invoked by attenuated p-38 MAPK and JNK phosphorylation, and decreased activation of the NF-κB signaling pathway, which may have suppressed gene transcription, including iNOS, and eventually decreased formation of peroxynitrite (ONOO-). Our results suggest that baicalein exerts a protective effect on BBB disruption in the rat model of ICH. The likely mechanism is via inhibition of MAPKs and NF-κB signaling pathways, leading to decreased formation of iNOS and ONOO-, thereby improving neurological function.

Endovascular treatment of cerebellar arteriovenous malformations: management of associated aneurysms first or later.

The purpose of this study was to determine the safety and effectiveness of cerebellar arteriovenous malformations (AVMs) embolization and find out the suitable methods to manage associated aneurysms. Medical records of all patients between 1997 and 2014 with a diagnosis of cerebellar AVMs were retrospectively reviewed. Univariable and multivariable logistic analysis were used to assess AVMs characteristics to calculate for the risk of hemorrhage. Endovascular treatment was the main treatment measure to manage the AVMs and associated aneurysms. Of 142 patients, 115 (81.0 %) presented with hemorrhage and 42 (29.6 %) with associated aneurysms. A significant association with cerebellar AVMs hemorrhage was found for small size, prenidal aneurysms, and deep venous drainage in the univariable and multivariable analysis. Associated aneurysms were treated firstly in 41 patients except for 1 patient with 2 prenidal and 2 intranidal aneurysms. The special case was dealt with AVMs and 2 intranidal aneurysms first and angiography showed that the 2 prenidal associated aneurysms disappeared with time. Hemorrhage appeared in 13/142 patients (9.2 %) during the follow-up period, none of which was with associated aneurysms. Endovascular treatment can be a feasible way for treating cerebellar AVMs. Intranidal associated aneurysms should be treated first. Prenidal associated aneurysms can be treated later depending on the angioarchitecture of AVMs.

Treatment of giant/large internal carotid aneurysms: parent artery occlusion or stent-assisted coiling.

PURPOSE: Treatment of giant/large internal carotid aneurysm is a challenge for neurologists. Previously, parent artery occlusion was the classic therapy; now the stent-assisted coil embolization has become available in recent years, but the optimal therapy is under debate. The goal of the present study was to compare two endovascular treatment modalities in terms of safety, efficacy and short-term outcomes. METHODS: All the patients were divided into two groups: Group A: patients who underwent parent artery occlusion, and Group B: patients who underwent stent-assisted coil embolization. Follow-up outcomes were evaluated using the modified Rankin Scale (mRS). RESULTS: After 12 months of follow-up, the favorable outcome (mRS: 0-2) had no statistical significance in both groups (p = 1.00). Patients in group A had greater ischemia compared with patients in group B, but the difference did not reach statistical significance (p = 0.421). In group B, patients had a higher rate of partial occlusion (p = 0.255) and recurrence (10% vs. 0%; p = 0.586). CONCLUSIONS: Stent-assisted coiling may not be superior to parent artery occlusion in selected patients after short-term follow-up. Parent artery occlusion is a simple, safe and effective treatment for large/giant internal carotid aneurysms.

Treatment of unruptured vertebral dissecting aneurysms: internal trapping or stent-assisted coiling.

PURPOSE: Endovascular treatment is an attractive approach for the treatment of unruptured vertebral dissecting aneurysms, and includes internal trapping and stent-assisted coil embolization. However, the optimal therapy remains debatable. We reviewed our experience with both endovascular treatment modalities and compared the safety, efficacy, and short-term outcomes for each approach. MATERIALS AND METHODS: We retrospectively reviewed 65 consecutive patients with unruptured vertebral dissecting aneurysms who underwent endovascular treatment between January 2003 and January 2014. 24 patients underwent endovascular internal trapping (group A) while 41 patients underwent stent-assisted coiling (group B). Thirteen patients underwent single stent with coiling while 28 patients underwent double or three stent-assisted coiling. Short-term outcomes were evaluated using the modified Rankin Scale. RESULTS: A favorable clinical outcome was achieved in 58 of 65 patients. Procedure-related complications included ischemic symptoms (n = 6) and recurrence (n = 4). There was no statistical difference in modified Rankin Scale scoring between groups. Group A patients had more ischemia symptoms compared with group B patients (p = 0.043), Group B patients had higher recurrence rates compared with group A patients, but the difference had no statistical significance (p = 1.00). However, recurrence only occurred in patients who underwent stent-assisted coiling alone (p = 0.046). CONCLUSION: Stent-assisted coiling for unruptured vertebral dissecting aneurysms may maintain artery patency. Multilayer disposition of stents with coils may decrease complications and facilitate aneurysm occlusion. Larger, prospective studies are necessary to determine the long-term outcomes of reconstructive therapy.

Comparative efficacy of Glubran and polyvinyl-alcohol particles in the embolization of meningiomas.

PURPOSE: Preoperative embolization of meningiomas decreases intraoperative bleeding and shortens operation time. However, in meningiomas predominantly vascularized by the internal carotid artery (ICA) or vertebral artery (VA) branches, embolization of external carotid artery feeder branches may lead to a hemodynamic increase in blood supply from the ICA or VA, whereas embolization of ICA or VA feeder branches with particle embolic agents may be associated with complications. This study investigated the safety and efficacy of Glubran, a liquid embolic agent, for the embolization of this type of meningioma compared with polyvinyl-alcohol (PVA) particles. MATERIALS AND METHODS: From January 2006 to June 2015, 157 consecutive patients (98 females; mean age = 48.3 years) who suffered from meningiomas and were preoperatively referred for embolization were retrospectively analyzed. Glubran (n = 40) and PVA (n = 55) were used to devascularize tumors. Sixty-two patients were not embolized because of dangerous anastomosis or other tumor characteristics. Intraoperative blood loss, intraoperative time, degree of angiographic devascularization and embolization-related complications were analyzed. RESULTS: The intraoperative blood loss and operative time were significantly lower in the Glubran-embolized versus non-embolized group. Furthermore, Glubran embolization significantly reduced intraoperative blood loss and operative time for meningiomas that received their primary blood supply from the ICA and/or VA compared with PVA embolization. CONCLUSIONS: Preoperative meningioma embolization with Glubran decreases intraoperative blood loss and operative time. Furthermore, embolization with Glubran produces more effective devascularization compared with PVA for meningiomas supplied by the ICA and/or VA. Thus, Glubran may represent a better embolic agent for this meningioma subtype.

Nefiracetam Attenuates Pro-Inflammatory Cytokines and GABA Transporter in Specific Brain Regions of Rats with Post-Ischemic Seizures.

BACKGROUND/AIMS: Prior studies demonstrated that pro-inflammatory cytokines (PICs) including IL-1ß, IL-6 and TNF-α contribute to regulation of epilepsy-associated pathophysiological processes in the specific brain regions, namely the parietal cortex, hippocampus and amygdala. Moreover, GABA transporter type 1 and 3 (GAT-1 and GAT-3) modulating extracellular GABA levels are engaged in the role played by PICs in epileptogenesis. Note that brain ischemic injury also elevates cerebral PICs. Thus, in this report we examined the effects of nefiracetam (NEF), a pyrrolidone derivative, on the levels of IL-1ß, IL-6 and TNF-α, and expression of GAT-1 and GAT-3 in the parietal cortex, hippocampus and amygdala using a rat model of post-ischemic nonconvulsive seizure (NCS). METHODS: NCS was evoked by the middle cerebral artery occlusion (MCAO). ELISA and Western Blot analysis were employed to determine the levels of PICs and GAT-1/GAT-3, respectively. RESULTS: MCAO significantly increased IL-1ß, IL-6 and TNF-α in the parietal cortex, hippocampus and amygdala as compared with sham control animals (P<0.05 vs. control rats). Also, in these specific brain regions expression of GAT-1 and GAT-3 was amplified; and the levels of GABA were decreased in rats following MCAO (P<0.05 vs. control rats). Systemic administration of NEF significantly attenuated the elevated PICs, amplified GAT-1 and GAT-3 as well as impaired GABA. NEF also attenuated the number of NCS events following MCAO. CONCLUSION: our data demonstrate that NEF improves post-ischemia evoked-NCS by altering PICs, GABA transporters thereby alleviating GABA in the parietal cortex, hippocampus and amygdala. This support a role for PICs and GABA in engagement of the adaptive responses associated with epileptic activity, but also suggests that NEF has anti-epileptic effects via PICs-GABA mechanisms, having pharmacological implications to target the specific PICs for neuronal dysfunction and vulnerability related to post-ischemic seizures and cognitive impairment.

The inhibitory effect of mesenchymal stem cell on blood-brain barrier disruption following intracerebral hemorrhage in rats: contribution of TSG-6.

BACKGROUND: Mesenchymal stem cells (MSCs) are well known having beneficial effects on intracerebral hemorrhage (ICH) in previous studies. The therapeutic mechanisms are mainly to investigate proliferation, differentiation, and immunomodulation. However, few studies have used MSCs to treat blood-brain barrier (BBB) leakage after ICH. The influence of MSCs on the BBB and its related mechanisms were investigated when MSCs were transplanted into rat ICH model in this study. METHODS: Adult male Sprague-Dawley (SD) rats were randomly divided into sham-operated group, PBS-treated (ICH + PBS) group, and MSC-treated (ICH + MSC) group. ICH was induced by injection of IV collagenase into the rats' brains. MSCs were transplanted intravenously into the rats 2 h after ICH induction in MSC-treated group. The following factors were compared: inflammation, apoptosis, behavioral changes, inducible nitric oxide synthase (iNOS), matrix metalloproteinase 9 (MMP-9), peroxynitrite (ONOO(-)), endothelial integrity, brain edema content, BBB leakage, TNF-α stimulated gene/protein 6 (TSG-6), and nuclear factor-κB (NF-κB) signaling pathway. RESULTS: In the ICH + MSC group, MSCs decreased the levels of proinflammatory cytokines and apoptosis, downregulated the density of microglia/macrophages and neutrophil infiltration at the ICH site, reduced the levels of iNOS and MMP-9, attenuated ONOO(-) formation, and increased the levels of zonula occludens-1 (ZO-1) and claudin-5. MSCs also improved the degree of brain edema and BBB leakage. The protective effect of MSCs on the BBB in ICH rats was possibly invoked by increased expression of TSG-6, which may have suppressed activation of the NF-κB signaling pathway. The levels of iNOS and ONOO(-), which played an important role in BBB disruption, decreased due to the inhibitory effects of TSG-6 on the NF-κB signaling pathway. CONCLUSIONS: Our results demonstrated that intravenous transplantation of MSCs decreased the levels of ONOO(-) and degree of BBB leakage and improved neurological recovery in a rat ICH model. This strategy may provide a new insight for future therapies that aim to prevent breakdown of the BBB in patients with ICH and eventually offer therapeutic options for ICH.

Predictors of Favorable Outcome of Intracranial Basilar Dissecting Aneurysm.

BACKGROUND: Management of intracranial basilar dissecting aneurysms has been controversial and challenging, and surgical and conservative treatments usually have a bad prognosis. Our study aimed at evaluating the outcomes of endovascular treatment for these lesions and exploring the predictors of favorable outcome. METHODS: We retrospectively reviewed 50 consecutive patients with basilar dissecting aneurysms from January 2006 to January 2013. Twenty-four patients underwent stent-assisted coiling whereas 26 patients underwent conservative treatment. Follow-up outcomes were evaluated using modified Rankin Scale (mRS) score. RESULTS: Of the patients treated with stent-assisted coiling, 20 patients had a favorable outcome (mRS score, 0-1), post-treatment recurrence occurred in 3 patients, 1 had rebleeding, and 2 had no rebleeding. Of the patients treated with conservative therapy (observation or anticoagulation), 10 patients had an unfavorable outcome, 2 patients with ruptured aneurysms developed rebleeding, and 8 patients had poor outcome because of infarct progression. Stent-assisted coiling group had a more favorable outcome than the conservatively treated group (83.3% versus 55.2%, P = .019). Initial complete obliteration was related to the favorable outcome in endovascular-treated group (P = .042). Stent placement was the only independent predictor of favorable outcome in the logistic regression analysis (P = .030; odds ratio = 5.828; 95% confidence interval, 1.192-28.503). CONCLUSIONS: Patients with basilar artery dissecting aneurysms treated with stent-assisted coiling had a more favorable outcome than the conservatively treated patients. Stent placement and initial complete occlusion were the favorable factors in patients with basilar dissecting aneurysm.

Endovascular Treatment of Dissecting Aneurysms of the Posterior Inferior Cerebellar Artery and Predictors of Outcome.

BACKGROUND: Isolated dissecting aneurysms of the posterior inferior cerebellar artery (PICA) are rare lesions, which carry high risk of rebleeding and mortality. However, the existing literature concerning predictors of outcome after endovascular treatment is limited and controversial. Our present study retrospectively reviewed and analyzed the clinical outcome of endovascular treatment-ruptured PICA-dissecting aneurysms and explored the predictors of outcome. METHODS: We retrospectively reviewed 17 consecutive patients with ruptured PICA dissecting aneurysms that underwent endovascular treatment from January 2003 to January 2014. Nine patients underwent selective coiling, whereas 7 patients underwent parent artery occlusion and 1 patient underwent stent-assisted coiling. Follow-up outcomes were evaluated using the modified Rankin Scale. The clinical outcomes of patients were categorized as favorable (modified Rankin Scale [mRS] score 0-1) or unfavorable (mRS score 2-6). RESULTS: Favorable outcomes (mRS score 0-1) were obtained in 13 of 17 patients. Post-treatment recurrence occurred in 1 patient with selective coiling in the 15-month follow-up, and the patient received stent-assisted coiling. The only patients with stent-assisted coiling developed PICA occlusion during follow-up. Aneurysm located in distal segment usually presented with intraventricular hemorrhage (P = .015). Hypertension, coexisting hydrocephalus, and time to operation (latter than 2 weeks) were associated with unfavorable outcome. CONCLUSIONS: Endovascular treatment of isolated dissecting aneurysm of PICA had excellent clinical outcomes, hypertension, coexisting hydrocephalus, and time to operation (latter than 2 weeks), which were associated with unfavorable outcome. Long-term follow-ups are necessary to provide stronger conclusions.

Clinical features and endovascular treatment of intracranial arteriovenous malformations in pediatric patients.

PURPOSE: The purpose of this study was to characterize clinical features and evaluate the clinical outcome of endovascular embolization treatment intracranial arteriovenous malformations in pediatric patients. METHODS: A cohort of children (age ≤ 18 years) with arteriovenous malformations (AVMs) from 2000 to 2012 was included. Predictors studied included patient gender, age, and angioarchitectural features, including AVM location, nidus morphology and size, venous drainage, and associated aneurysms. Treatment method, complications and outcomes were recorded. The features of AVMs were evaluated before the treatment. RESULTS: One hundred twenty-seven children (77 males, mean age 13.2 years) were included; 90/127 (70.9 %) children were presented with hemorrhage. AVM size and deep venous drainage were independently associated with hemorrhage; 66/127 patients (52 %) treated with endovascular embolization. Complete obliteration at the end of all endovascular procedures was achieved in 14/66 patients (21.2 %), with an average of 78 % (range, 20-100 %) volume reduction. A mean of 2.9 (range, 1-9) feeding pedicles was embolized per patient. Overall, nine complications occurred in a total of 123 procedures (7.3 %). There was no procedure-related death in this study population. There was no significant difference between patients with and without complications in terms of AVM grade, demographic characteristics, or embolization features. CONCLUSIONS: AVM size and deep venous drainage were independently associated with hemorrhage in pediatric patients. Endovascular procedure is feasible and safe for pediatric AVMs, and complete embolization can be achieved in small AVMs, while large AVMs can be adequately reduced in size for additional microsurgery or stereotactic radiosurgery.