Targeting Oxidative Stress and Inflammatory Response for Blood-Brain Barrier Protection in Intracerebral Hemorrhage.

Significance: Blood-brain barrier (BBB) disruption is a major pathological change after intracerebral hemorrhage (ICH) and is both the cause and result of oxidative stress and of the immune response post-ICH. These processes contribute to ICH-induced brain injury. Recent Advances: After the breakdown of cerebral vessels, blood components, including erythrocytes and their metabolites, thrombin, and fibrinogen, can access the cerebral parenchyma through the compromised BBB, triggering oxidative stress and inflammatory cascades. These aggravate BBB disruption and contribute to further infiltration of blood components, resulting in a vicious cycle that exacerbates brain edema and neurological injury after ICH. Experimental and clinical studies have highlighted the role of BBB disruption in ICH-induced brain injury. Critical Issues: In this review, we focus on the strategies to protect the BBB in ICH. Specifically, we summarize the evidence and the underlying mechanisms, including the ICH-induced process of oxidative stress and inflammatory response, and we highlight the potential therapeutic targets to protect BBB integrity after ICH. Future Directions: Future studies should probe the mechanism of ferroptosis as well as oxidative stress-inflammation coupling in BBB disruption after ICH and investigate the effects of antioxidants and immunomodulatory agents in more ICH clinical trials. Antioxid. Redox Signal. 37, 115-134.

Long non-coding RNAs as a predictive markers of group 3 medulloblastomas.

ObjectiveThe appropriate treatments for the different molecular subgroups of medulloblastomas are challenging to determine. Hence, this study aimed to examine the expression profiles of long non-coding RNAs (LncRNAs) to determine a marker that may be important for treatment selection in these subgroups.MethodsChanges in the expression of LncRNAs in the tissues of patients with medulloblastoma, which are classified into four subgroups according to their clinical characteristics and gene expression profiles, were examined via reverse transcription polymerase chain reaction. Moreover, there association with patient prognosis was evaluated.ResultsThe expression levels of MALAT1 and SNGH16 were significantly higher in patients with group 3 medulloblastoma than in those with other subtypes. Patients with high expression levels of MALAT1 and SNGH16 had a relatively shorter overall survival than those with low expression levels.ConclusionsPatients with group 3 medulloblastoma have a high MALAT1 level, which is associated with poor prognosis. Therefore, MALAT1 can be a new therapeutic target in medulloblastoma.

Coexistence of TERT C228T mutation and MALAT1 dysregulation in primary glioblastoma: new prognostic and therapeutic targets.

Objective: This study was designed to conduct molecular classification based on IDH1/2, TERT, ATRX, and DAXX changes in pediatric and adult primary glioblastoma (GB) and to analyze the potential interaction of LncRNA MALAT1 in the determined homogeneous subgroups.Methods: We analyzed the expression profiles of ATRX/DAXX and MALAT1 using the qRT-PCR method and IDH and TERT mutation status using DNA sequencing analysis in 85 primary pediatric and adult GB patients.Results: IDH1 mutation was observed in 5 (5.88%) and TERT mutation in 65 (76.47%) primary pediatric and adult GB patients. ATRX and DAXX were detected in 18 (21.18%) and 7 (8.24%) patients. TERT mutation and loss of ATRX/DAXX were associated with short overall survival (p < 0.001, p < 0.001, respectively). Patients carrying especially TERT C228T mutation had worse prognosis (p < 0.001). Six subgroups were obtained from the genetic analysis. Among the subgroups, MALAT1 was highly expressed in group A that had a single TERT mutation as compared to that in groups D and E (p = 0.001 and p < 0.001, respectively); further, high MALAT1 expression was associated with worse prognosis in patients with C228T mutation (p < 0.001).Conclusions: Our findings highlight that the presence of TERT C228T mutation and expression of MALAT1 can be used as primary targets during the follow-up of primary GB patients and in the development of new treatment strategies.

Comparison of Clinical and Molecular Wnt and SHH Subgroups in Medulloblastoma Tumor Cases.

AIM: To determine the Wnt and SHH subtypes at the molecular level, and to compare them clinically by examining the changes in CTNNB1, AXIN, PTCH1, SMO, SUFU, and GLI1 mRNA expression in the medulloblastoma of a Turkish population determined according to patient selection criteria. In this context, the clinical distinction between Wnt and SHH groups are realized by considering the age, gender, survival time, location of the lesion, and radiological features of the patients. MATERIAL AND METHODS: Molecular separation was performed by RT-PCR analysis of CTNNB1, AXIN, PTCH1, SMO, SUFU, and GLI1 mRNA expression changes. RESULTS: About 17.8% and 22.2% of the cases were included in the Wnt and the SHH group, respectively. When comparing group differences based on clinical and molecular data, 72.7% and 66.6% of matches were observed in the Wnt and the SHH group, respectively. CONCLUSION: It has been revealed that molecular analysis and grouping of patients with medulloblastoma can provide support for clinically determined subgroups.

Inhibition of PAR-2 Attenuates Neuroinflammation and Improves Short-Term Neurocognitive Functions Via ERK1/2 Signaling Following Asphyxia-Induced Cardiac Arrest in Rats.

OBJECTIVE: Global cerebral ischemia-induced neuroinflammation causes neurofunctional impairment following cardiac arrest. Previous studies have demonstrated that the activation of protease-activated receptor-2 (PAR-2) contributes to neuroinflammation. In the present study, we aimed to determine the potential treatment effect of PAR-2 inhibition against neuroinflammation in the setting of asphyxial CA (ACA) in rats. METHODS: A total of 116 adult, male Sprague-Dawley rats were randomly divided into Sham (n = 18) and ACA (n = 98) groups. Time course, short-term outcome, and mechanism studies were conducted. All drugs were delivered intranasally. The effect of PAR-2 inhibitor FSLLRY-NH2 on neurocognitive functions was assessed by neurologic deficit score, number of seizures, and T-maze test, while hippocampal neuronal degeneration was evaluated by Fluoro-Jade C staining after ACA. Western blotting was performed for the mechanism study at 24 h following ACA. Selective PAR-2 agonist (AC55541) and ERK1/2 inhibitor (PD98059) were used for intervention. RESULTS: Inhibition of PAR-2 decreased neuroinflammation, reduced the number of degenerating hippocampal neurons and improved neurocognitive functions following ACA. PAR-2 activator alone exerted opposite effects to PAR-2 inhibitor. PAR-2 mediated the augmented brain levels of proinflammatory cytokines by promoting the phosphorylation of ERK1/2. CONCLUSIONS: PAR-2 inhibition diminished neuroinflammation and thereby reduced hippocampal neuronal degeneration and neurocognitive impairment following ACA. This effect was at least partly mediated via the PAR-2/ERK1/2 signaling.

Mitoquinone attenuates blood-brain barrier disruption through Nrf2/PHB2/OPA1 pathway after subarachnoid hemorrhage in rats.

BACKGROUND AND PURPOSE: Mitochondrial dysfunction is involved in the mechanism of early brain injury (EBI) following subarachnoid hemorrhage (SAH). Blood-brain barrier disruption is a devastating outcome in the early stage of SAH. In this study, we aimed to investigate the role of a mitochondria-related drug Mitoquinone (MitoQ) in blood-brain barrier disruption after SAH in rats. METHODS: A total of 181 male Sprague-Dawley SAH rats with the endovascular perforation model were utilized. Intraperitoneal MitoQ was given 1 h (h) post-SAH. Cerebroventricular ML385, an inhibitor of NF-E2-related factor 2 (Nrf2) and Small interfering ribonucleic acid (siRNA) for Prohibitin 2 (PHB2) were injected respectively 24 h and 48 h before SAH. Neurological function evaluation was performed before sacrifice. SAH grade was measured during the sacrifice of each animal. Brain water content was performed at 24 h. Co-immunoprecipitation was used to demonstrate the relationship of proteins Nrf2 and PHB2. Mitochondrial and cytoplasmic fractions were gathered using mitochondria isolation kits. Pathway related proteins were investigated with Western blot and immunofluorescence staining. Transmission electron microscopy was performed for mitochondrial morphology. RESULTS: Expression of Nrf2 levels peaked at the 3 h time point following SAH and then decreased to normal levels at 24 h, while PHB2 and Optic Atrophy 1 (OPA1) decreased at 24 h and 72 h after SAH compared with the Sham group. MitoQ treatment attenuated neurological deficits and brain edema, thereby resulting in a decreased expression of Albumin, while an increase of Nrf2, PHB2, OPA1 and Claudin-5 proteins compared with SAH + vehicle group. With co-immunoprecipitation, Nrf2 and PHB2 were further demonstrated to show their interaction. And MitoQ administration lead to more binding of the two proteins. ML385 abolished the effects of MitoQ on neurobehavior and protein levels post-SAH. Similarly, PHB2 siRNA reversed the neuroprotection of MitoQ administration with the decreased expression of PHB2 and OPA1 after SAH. Further, MitoQ treatment improved mitochondrial morphology after SAH with an increase of PHB2 and OPA1 in mitochondrial extraction. CONCLUSIONS: MitoQ attenuates blood-brain barrier disruption via Nrf2/PHB2/OPA1 pathway after SAH in rats. MitoQ may serve as a potential therapeutic strategy for SAH patients.

Endovascular Treatment of Ruptured Tiny Intracranial Aneurysms with Low-Profile Visualized Intraluminal Support Device.

BACKGROUND: Ruptured tiny intracranial aneurysms (TIAs) have been challenging both for endovascular and neurosurgical interventions. Thus, we aimed to evaluate the safety and efficacy of low-profile visualized intraluminal support (LVIS) device in the treatment of ruptured TIAs (rTIAs). MATERIAL AND METHODS: Among 761 intracranial aneurysms which were treated either surgically or endovascularly, 32 rTIAs underwent stent-assisted coiling with LVIS device between 2014 and 2017. Patient data were reviewed retrospectively. Clinical and radiological outcomes were recorded at discharge and mid-term follow-up. RESULTS: Mean patient ages were 53 ± 14.5 years. Mean aneurysm size was 2.28 ± .53 mm (range, 1-2.9 mm) with a mean dome:neck ratio of 1.08 (range, .75-2.14). The LVIS stents were successfully implanted in all patients. Mean follow-up period was 9.3 ± 1.9 months (range, 6-15 months). Immediate angiographic evaluation demonstrated complete occlusion in 13 (40.6%) patients, while neck remnant and residual sac were observed in 12 (37.5%) and 7 (21.9%), respectively. All patients had moderate disability (mRS 2-3) at discharge. Number of aneurysms with complete occlusion significantly increased and 82.1% of the patients (23 of 28) demonstrated complete occlusion at follow-up (P = .0015). Among these, 27 had good outcome (mRS 0-1; 96.9%) with significant improvement compared to discharge (P = .0001). There was no recurrence or enlargement of the residual aneurysms. Additionally, there were no procedure-related complications except the one (3.6%) showing asymptomatic stenosis of the posterior cerebral artery in follow-up imagings. CONCLUSIONS: Stent-assisted coiling of rTIAs with LVIS device provides high rates of technical success and complete occlusion at mid-term follow-up with an excellent safety profile.

Targeting mast cell as a neuroprotective strategy.

Background: Mast cells (MCs) are perivascularly located immune cells of haematopoietic origin. Emerging evidences suggest that the activation of MCs play important roles in the pathogenesis of blood brain barrier disruption, neuroinflammation, and neurodegeneration. Objectives: In this review, we aimed to discuss the detrimental effects of MCs in response to various types of brain injury, as well as the therapeutic potential and neuroprotective effects of targeting the activation and degranulation of MCs, particularly in the management of the acute phase. Methods: An extensive online literature search was conducted through Pubmed/Central on March 2018. Then, we comprehensively summarized the effects of the activation of brain MCs in acute brain injury along with current pharmacological strategies targeting at the activation of MCs. Results: The review of the current literature indicated that the activation and degranulation of brain MCs significantly contribute to the acute pathological process following different types of brain injury including focal and global cerebral ischaemia, intracerebral haemorrhage, subarachnoid haemorrhage, and traumatic brain injury. Conclusions: Brain MCs significantly contribute to the acute pathological processes following brain injury. In that regard, targeting brain MCs may provide a novel strategy for neuroprotection.

Resection of middle petroclival meningioma via combined anterior transpetrosal and retrosigmoid approaches at two separate stages: 3D operative video.

Surgical access to the petroclival region poses a challenge to neurosurgeons. A wide range of approaches has been demonstrated in the past. In this video, the authors present a 69-year-old male patient who presented with 3-month history of worsening left-sided numbness. The tumor was totally removed in 2 sessions via anterior transpetrosal and retrosigmoid approaches, respectively. The authors demonstrate 2 separate skull base approaches to resect a petroclival meningioma and discuss pitfalls and problems of management for challenging meningiomas. The authors suggest that surgical approaches to petroclival meningiomas should be selected based on an individual case. A skull base team should be versatile in performing all these approaches. The video can be found here: https://youtu.be/BCVrn3TeNvE .

Resection of complex occipital arteriovenous malformation with giant varix: demonstration of microsurgical technique.

The complexity of arteriovenous malformations (AVMs) does not necessarily preclude surgical resection. In this video the authors present a 72-year-old male who was known to have an occipital AVM with a large draining varix for the previous 10 years. The patient had progressively worsening visual and cognitive deficits over several years. Total surgical resection was achieved following single stage preoperative embolization. Although resection of the AVMs is challenging, even in experienced hands, it offers a cure and may improve patient clinical outcome. The video can be found here: https://youtu.be/YI1AwGjJdvo .