Selective autophagy as a therapeutic target for neurological diseases.

The neurological diseases primarily include acute injuries, chronic neurodegeneration, and others (e.g., infectious diseases of the central nervous system). Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Recent studies have suggested that autophagy, particularly selective autophagy, such as mitophagy, pexophagy, ER-phagy, ribophagy, lipophagy, etc., is closely implicated in neurological diseases. These forms of selective autophagy are controlled by a group of important proteins, including PTEN-induced kinase 1 (PINK1), Parkin, p62, optineurin (OPTN), neighbor of BRCA1 gene 1 (NBR1), and nuclear fragile X mental retardation-interacting protein 1 (NUFIP1). This review highlights the characteristics and underlying mechanisms of different types of selective autophagy, and their implications in various forms of neurological diseases.

Inhibition of P2X4R attenuates white matter injury in mice after intracerebral hemorrhage by regulating microglial phenotypes.

BACKGROUND: White matter injury (WMI) is a major neuropathological event associated with intracerebral hemorrhage (ICH). P2X purinoreceptor 4 (P2X4R) is a member of the P2X purine receptor family, which plays a crucial role in regulating WMI and neuroinflammation in central nervous system (CNS) diseases. Our study investigated the role of P2X4R in the WMI and the inflammatory response in mice, as well as the possible mechanism of action after ICH. METHODS: ICH was induced in mice via collagenase injection. Mice were treated with 5-BDBD and ANA-12 to inhibit P2X4R and tropomyosin-related kinase receptor B (TrkB), respectively. Immunostaining and quantitative polymerase chain reaction (qPCR) were performed to detect microglial phenotypes after the inhibition of P2X4R. Western blots (WB) and immunostaining were used to examine WMI and the underlying molecular mechanisms. Cylinder, corner turn, wire hanging, and forelimb placement tests were conducted to evaluate neurobehavioral function. RESULTS: After ICH, the protein levels of P2X4R were upregulated, especially on day 7 after ICH, and were mainly located in the microglia. The inhibition of P2X4R via 5-BDBD promoted neurofunctional recovery after ICH as well as the transformation of the pro-inflammatory microglia induced by ICH into an anti-inflammatory phenotype, and attenuated ICH-induced WMI. Furthermore, we found that TrkB blockage can reverse the protective effects of WMI as well as neuroprotection after 5-BDBD treatment. This result indicates that P2X4R plays a crucial role in regulating WMI and neuroinflammation and that P2X4R inhibition may benefit patients with ICH. CONCLUSIONS: Our results demonstrated that P2X4R contributes to WMI by polarizing microglia into a pro-inflammatory phenotype after ICH. Furthermore, the inhibition of P2X4R promoted pro-inflammatory microglia polarization into an anti-inflammatory phenotype, enhanced brain-derived neurotrophic factor (BDNF) production, and through the BDNF/TrkB pathway, attenuated WMI and improved neurological function. Therefore, the regulation of P2X4R activation may be beneficial for the reducing of ICH-induced brain injury.

Mesencephalic astrocyte-derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage via activating Akt-dependent prosurvival pathway and defending blood-brain barrier integrity.

This study aimed to explore the neuroprotective effect of mesencephalic astrocyte-derived neurotrophic factor (MANF) protein on early brain injury caused by subarachnoid hemorrhage (SAH) and the relevant mechanisms in experimental rats, expecting to understand whether MANF was a potential therapeutic target for SAH treatment. A perforation model of SAH was introduced into the study. Recombinant human MANF (rh-MANF) and protein kinase B (Akt) inhibitor (MK2206) were used to explore the effect and the mechanisms. Multiple approaches for systemic assessment were employed in the research, including the Garcia test, the SAH grade, Evans blue (EB) dye leakage, brain-water content (BWC), the rotarod test, and the Morris water-navigation task, as were biotechniques, such as immunohistochemistry, Western blot, transmission electron microscopy, and flow cytometry. MANF was mainly expressed in rat neurons, and its expression increased significantly at 3 h after SAH induction and peaked at 24 h. Stereotactic injection of rh-MANF into the cerebroventricle significantly increased the level of MANF, p-Akt, p-mouse double minute 2 homolog (p-MDM2), and B-cell lymphoma 2 (Bcl-2) in brain tissue, whereas it down-regulated the expression of P53, Bcl-2-associated X protein (Bax), and cleaved caspase-3, which indicated that neuronal apoptosis was remarkably suppressed. Expression of matrix metallopeptidase 9 (MMP-9) was also suppressed by the rh-MANF injection. Furthermore, neurologic deficits, EB dye leakage, and BWC were reduced, and long-lasting neuroprotection was noted with rh-MANF administration. The antiapoptotic and blood-brain barrier (BBB) protective effect could be offset by administering MK2206. MANF could alleviate neuronal apoptosis by activating Akt-dependent prosurvival pathway and abate BBB damage via MMP-9 suppression. MANF showed not only transient but also long-lasting neuroprotective properties. The rh-MANF as a potential drug for treating SAH might be of clinical use.-Li, T., Xu, W., Gao, L., Guan, G., Zhang, Z., He, P., Xu, H., Fan, L., Yan, F., Chen, G. Mesencephalic astrocyte-derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage via activating Akt-dependent prosurvival pathway and defending blood-brain barrier integrity.

Apelin-13/APJ system attenuates early brain injury via suppression of endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation and oxidative stress in a AMPK-dependent manner after subarachnoid hemorrhage in rats.

BACKGROUND: Neuroinflammation and oxidative stress play important roles in early brain injury following subarachnoid hemorrhage (SAH). This study is the first to show that activation of apelin receptor (APJ) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-associated inflammation and oxidative stress after SAH. METHODS: Apelin-13, apelin siRNA, APJ siRNA, and adenosine monophosphate-activated protein kinase (AMPK) inhibitor-dorsomorphin were used to investigate if the activation of APJ could provide neuroprotective effects after SAH. Brain water content, neurological functions, blood-brain barrier (BBB) integrity, and inflammatory molecules were evaluated at 24 h after SAH. Western blotting and immunofluorescence staining were applied to assess the expression of target proteins. RESULTS: The results showed that endogenous apelin, APJ, and p-AMPK levels were significantly increased and peaked in the brain 24 h after SAH. In addition, administration of exogenous apelin-13 significantly alleviated neurological functions, attenuated brain edema, preserved BBB integrity, and also improved long-term spatial learning and memory abilities after SAH. The underlying mechanism of the neuroprotective effects of apelin-13 is that it suppresses microglia activation, prevents ER stress from overactivation, and reduces the levels of thioredoxin-interacting protein (TXNIP), NOD-like receptor pyrin domain-containing 3 protein (NLRP3), Bip, cleaved caspase-1, IL-1ß, TNFα, myeloperoxidase (MPO), and reactive oxygen species (ROS). Furthermore, the use of APJ siRNA and dorsomorphin abolished the neuroprotective effects of apelin-13 on neuroinflammation and oxidative stress. CONCLUSIONS: Exogenous apelin-13 binding to APJ attenuates early brain injury by reducing ER stress-mediated oxidative stress and neuroinflammation, which is at least partly mediated by the AMPK/TXNIP/NLRP3 signaling pathway.

Diagnostic performance of DWI for differentiating primary central nervous system lymphoma from glioblastoma: a systematic review and meta-analysis.

OBJECTIVE: The purpose of this meta-analysis was to evaluate the diagnostic performance of diffusion-weighted imaging (DWI) for differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma (GBM). MATERIALS AND METHODS: A thorough search of the databases including PubMed, EMBASE, and Cochrane Library was carried out and the data acquired were up to November 1, 2017. The quality of the studies involved was evaluated using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies, revised version). Multiple analytic values including sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the summary receiver operating characteristic (SROC) curve were calculated and pooled for the statistical analysis. The subgroup analysis was also performed to explore the heterogeneity. RESULTS: Eight retrospective studies (461 patients with 461 lesions) were included. The pooled SEN, SPE, PLR, NLR, and DOR with 95% confidence interval (CI) were 0.82 [95% CI 0.70-0.90], 0.84 [95% CI 0.75-0.90], 4.96 [95% CI 3.20-7.69], 0.22 [95% CI 0.13-0.37], and 22.85 [95% CI 10.42-50.11], respectively. The area under the curve (AUC) given by SROC curve was 0.90 [95% CI 0.87-0.92]. The subgroup analysis indicated the slice thickness of the images (> 3 mm versus ≤ 3 mm) was a significant factor affecting the heterogeneity. No existence of significant publication bias was confirmed with Deeks' test. CONCLUSIONS: DWI showed moderate diagnostic performance for differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma (GBM). Moreover, it is of clinical significance using DWI combined with conventional MRI to differentiate PCNSL from GBM.

[Evacuation of spontaneous supratentorial intracerebral hematoma with double targets-single channel and multiaxial stereotaxis].

OBJECTIVE: To evaluate the efficacy and safety of evacuation of spontaneous supratentorial hemorrhage with double targets-single channel and multiaxial stereotaxis. METHODS: Thirty-four patients with supratentorial intracerebral hemorrhage, who underwent hematoma evacuation with the method of double targets-single channel between January 2014 and November 2014 in the Second Affiliated Hospital, Zhejiang University School of Medicine, were included in the study. We classified the hematoma into four types based on the principle of double targets-single channel calculation method (DTSC). And the appropriate stereotactic surgery path and operation opportunity were designed individually according to the hematoma volume and mass effect. Twenty-seven patients with supratentorial hemorrhage who underwent hematoma evacuation with the method of single targets-single channel between January 2013 and November 2014 were selected as single target group. RESULTS: Volumes of initial hematoma in DTSC and single target groups were(38.6 ± 19.2)mL and(40.1 ± 18.1)mL, respectively. Initial Glasgow Coma Scale were 9.6 ± 3.2 (3~15) and 9.1 ± 2.9(3~13) (all P >0.05). Residual volume of hematoma and clearance ratio were (11.1 ± 4.2) mL and(73.1 ± 5.4)% in DTSC group and (18.5 ± 5.3) mL and(55.1 ± 5.1)% in single target group by CT scan 24 h after operation(all P <0.05). There was no significant difference in Glasgow Outcome Scale between two groups in one-month follow-up. Average length of postoperative stay of two groups were(12.6 ± 9.8)d and (14.2 ± 7.1)d, respectively. CONCLUSION: Evacuation of spontaneous supratentorial intracerebral hematoma with DTSC and multi-axial stereotaxis can increase clearance ratio remarkably and decrease average length of stay.

Intraventricular haemorrhage treated by extra ventricular drainage with catheter mistakenly penetrating the cisterna ambiens: A case report.

Intraventricular haemorrhage (IVH) is a severe and acute type of stroke with a complex pathophysiology and is a therapeutic challenge. This case report described a man in his early 50's diagnosed with IVH by computed tomography (CT). Although bilateral extraventricular drainage (EVD) was undertaken, a postoperative CT scan showed that while the left catheter was correctly positioned, the right catheter had been wrongly inserted into the cisterna ambiens. The procedure was equivalent to simultaneous EVD combined with cisternostomy. As a consequence, the haematoma was rapidly removed, the risk of infection and long-term hydrocephalus was reduced, and prognosis was improved. Large case-control studies or prospective studies are needed to evaluate the safety and effectiveness of this treatment modality.

DJ-1 Alleviates Neuroinflammation and the Related Blood-Spinal Cord Barrier Destruction by Suppressing NLRP3 Inflammasome Activation via SOCS1/Rac1/ROS Pathway in a Rat Model of Traumatic Spinal Cord Injury.

DJ-1 has been shown to play essential roles in neuronal protection and anti-inflammation in nervous system diseases. This study aimed to explore how DJ-1 regulates neuroinflammation after traumatic spinal cord injury (t-SCI). The rat model of spinal cord injury was established by the clamping method. The Basso, Beattie, Bresnahan (BBB) score and the inclined plane test (IPT) were used to evaluate neurological function. Western blot was then applied to test the levels of DJ-1, NLRP3, SOCS1, and related proinflammatory factors (cleaved caspase 1, IL-1ß and IL-18); ROS level was also examined. The distribution of DJ-1 was assessed by immunofluorescence staining (IF). BSCB integrity was assessed by the level of MMP-9 and tight junction proteins (Claudin-5, Occludin and ZO-1). We found that DJ-1 became significantly elevated after t-SCI and was mainly located in neurons. Knockdown of DJ-1 with specific siRNA aggravated NLRP3 inflammasome-related neuroinflammation and strengthened the disruption of BSCB integrity. However, the upregulation of DJ-1 by Sodium benzoate (SB) reversed these effects and improved neurological function. Furthermore, SOCS1-siRNA attenuated the neuroprotective effects of DJ-1 and increased the ROS, Rac1 and NLRP3. In conclusion, DJ-1 may alleviate neuroinflammation and the related BSCB destruction after t-SCI by suppressing NLRP3 inflammasome activation by SOCS1/Rac1/ROS pathways. DJ-1 shows potential as a feasible target for mediating neuroinflammation after t-SCI.

Progress in Stem Cell Therapy for Spinal Cord Injury.

BACKGROUND: Spinal cord injury (SCI) is one of the serious neurological diseases that occur in young people with high morbidity and disability. However, there is still a lack of effective treatments for it. Stem cell (SC) treatment of SCI has gradually become a new research hotspot over the past decades. This article is aimed at reviewing the research progress of SC therapy for SCI. METHODS: Review the literature and summarize the effects, strategies, related mechanisms, safety, and clinical application of different SC types and new approaches in combination with SC in SCI treatment. RESULTS: A large number of studies have focused on SC therapy for SCI, most of which showed good effects. The common SC types for SCI treatment include mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and embryonic stem cells (ESCs). The modes of treatment include in vivo and in vitro induction. The pathways of transplantation consist of intravenous, transarterial, nasal, intraperitoneal, intrathecal, and intramedullary injections. Most of the SC treatments for SCI use a number of cells ranging from tens of thousands to millions. Early or late SC administration, application of immunosuppressant or not are still controversies. Potential mechanisms of SC therapy include tissue repair and replacement, neurotrophy, and regeneration and promotion of angiogenesis, antiapoptosis, and anti-inflammatory. Common safety issues include thrombosis and embolism, tumorigenicity and instability, infection, high fever, and even death. Recently, some new approaches, such as the pharmacological activation of endogenous SCs, biomaterials, 3D print, and optogenetics, have been also developed, which greatly improved the application of SC therapy for SCI. CONCLUSION: Most studies support the effects of SC therapy on SCI, while a few studies do not. The cell types, mechanisms, and strategies of SC therapy for SCI are very different among studies. In addition, the safety cannot be ignored, and more clinical trials are required. The application of new technology will promote SC therapy of SCI.

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase Suppresses Neuronal Apoptosis by Increasing Glycolysis and "cyclin-dependent kinase 1-Mediated Phosphorylation of p27 After Traumatic Spinal Cord Injury in Rats.

Apoptosis is a vital pathological factor that accounts for the poor prognosis of traumatic spinal cord injury (t-SCI). The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is a critical regulator for energy metabolism and proven to have antiapoptotic effects. This study aimed to investigate the neuroprotective role of PFKFB3 in t-SCI. A compressive clip was introduced to establish the t-SCI model. Herein, we identified that PFKFB3 was extensively distributed in neurons, and PFKFB3 levels significantly increased and peaked 24 h after t-SCI. Additionally, knockdown of PFKFB3 inhibited glycolysis, accompanied by aggravated neuronal apoptosis and white matter injury, while pharmacological activation of PFKFB3 with meclizine significantly enhanced glycolysis, attenuated t-SCI-induced spinal cord injury, and alleviated neurological impairment. The PFKFB3 agonist, meclizine, activated cyclin-dependent kinase 1 (CDK1) and promoted the phosphorylation of p27, ultimately suppressing neuronal apoptosis. However, the neuroprotective effects of meclizine against t-SCI were abolished by the CDK1 antagonist, RO3306. In summary, our data demonstrated that PFKFB3 contributes robust neuroprotection against t-SCI by enhancing glycolysis and modulating CDK1-related antiapoptotic signals. Moreover, targeting PFKFB3 may be a novel and promising therapeutic strategy for t-SCI.

Recovered bone flap tilting after encephalo-myo-synangiosis: A complication.

OBJECTIVES: The aim of this study was to analyze the clinical data concerning the loosening and tilting of the recovered bone flap after encephalo-myo-synangiosis (EMS) and explore the potential underlying mechanisms. PATIENTS AND METHODS: Clinical data of all patients who underwent an EMS procedure from January 1, 2014 to April 30, 2018 at our hospital were collected. The cases with postoperative tilting of the recovered bone flap were identified and the clinical characteristics of the patients involved were analyzed. RESULTS: There were totally 204 patients who underwent EMS, among whom 12 patients (Male/Female = 6/6) experienced tilting of the recovered bone flap after craniotomy. The average age was 44.3 years. The average height of the tilt was 8.3 ± 3.1 mm. The shortest time for the bone flap to tilt to a height of 5 mm was found to be one day after surgery and the longest was up to 7 months. In cases in which maximum height was observed in a short duration after surgery, the average time for the tilted bone flap to reach the maximum height was 6.1 ± 3.6 days. In addition, a second craniotomy on the opposite side might be an important factor, and three cases were noted with second surgeries (Cases 2, 7, and 9). CONCLUSION: Recovered bone flap tilting after EMS should be listed as a complication after roofing of the temporal muscle. This complication may be related to the temporal muscle edema, the increase of intracranial pressure and no bandage compression.

Spontaneous thrombosis in main draining veins of unruptured cerebral arteriovenous malformations: A case report.

RATIONALE: Spontaneous obliteration of unruptured arteriovenous malformations (AVMs) is rare. It occurs in <1.5% of cerebral AVMs and only 7 cases have been reported so far. This phenomenon, together with the formation and outcome of cerebral AVMs, remains barely understood. In this work, we presented a case that spontaneous venous thrombosis in main draining veins of an unruptured AVM were confirmed, and reviewed the relevant literature in order to discuss the possible mechanisms. PATIENT CONCERNS: Clinical data and treatment of a 33-year-old man with a preliminary diagnosis as right parietal mass with secondary epilepsy. DIAGNOSES: The diagnosis of the mass was a right parietal arteriovenous malformation (AVM) that was 3.5 cm in size and supplied mainly by multiple feeders of right middle cerebral artery (MCA). INTERVENTIONS: An operation was performed with meticulous hemostasis of the extracranial soft tissue and the AVM was resected completely. OUTCOMES: The patient's neurological deficits improved postoperatively and he was subsequently discharged 1 week after surgery. LESSONS: Thrombosis of the draining veins may be due to venous stagnation. Spontaneous venous thrombosis in an unruptured AVM is rare. Spontaneous obliteration of an AVM can occur by 2 mechanisms: occlusion of the feeding arteries or of the draining veins. Surgical or interventional treatment of an unruptured AVM with thrombosed draining veins is highly controversial now. However, we favor an aggressive treatment strategy.

Sodium Benzoate Attenuates Secondary Brain Injury by Inhibiting Neuronal Apoptosis and Reducing Mitochondria-Mediated Oxidative Stress in a Rat Model of Intracerebral Hemorrhage: Possible Involvement of DJ-1/Akt/IKK/NFκB Pathway.

Intracerebral hemorrhage (ICH) is a devastating disease with high rates of mortality and morbidity. The aim of this study was to explore whether Sodium Benzoate (NaB) could reduce neural cell apoptosis and alleviate neurological deficits after ICH. To assess the therapeutic effects of NaB, first, we measured brain water content, neurobehavior, and blood-brain barrier (BBB) integrity at 24 h after ICH in different groups. Then western blot and immunofluorescence staining (IF) were applied to test the levels of different proteins. Transmission electron microscope (TEM) was used to observe ultra-structures within the cells in different groups. The results showed that levels of DJ-1, p-Akt and p-IκB kinase (IKK) increased after ICH and peaked at 24 h. Besides, NaB significantly upregulated DJ-1 in both cytoplasm and mitochondria, and also increased the levels of p-Akt, p-IKK and Bcl-2/Bax ratio, but decreased the levels of caspase-3 and caspase-9. Additionally, NaB decreased reactive oxygen species (ROS) while increased adenosine triphosphate (ATP), which then improving the neurological functions at 24 h and long-term (21 days) memory and spatial learning ability after ICH. However, the results mentioned above could be greatly reversed by MK2206 and rotenone. Therefore, we concluded that NaB could attenuate secondary brain injury via inhibiting neuronal apoptosis and reducing mitochondria-mediated oxidative stress via DJ-1/Akt/IKK/NFκB pathway.

Natrium Benzoate Alleviates Neuronal Apoptosis via the DJ-1-Related Anti-oxidative Stress Pathway Involving Akt Phosphorylation in a Rat Model of Traumatic Spinal Cord Injury.

This study aimed to explore the neuroprotective effects and mechanisms of natrium benzoate (NaB) and DJ-1 in attenuating reactive oxygen species (ROS)-induced neuronal apoptosis in traumatic spinal cord injury (t-SCI) in rats. T-SCI was induced by clip compression. The protein expression and neuronal apoptosis was evaluated by Western blotting, double immunofluorescence staining and transmission electron microscope (TEM). ROS level, spinal cord water content (SCWC) and Evans blue (EB) extravasation was also examined. Locomotor function was evaluated by Basso, Beattie, and Bresnahan (BBB) and inclined plane test (IPT) scores. We found that DJ-1 is expressed in spinal cord neurons and increased after t-SCI. At 24 h post-injury, the levels of DJ-1, p-Akt, SOD2, ROS, p-p38 MAPK/p38 MAPK ratio, and CC-3 increased, while the Bcl-2/Bax ratio decreased. NaB upregulated DJ-1, p-Akt, and SOD2, decreased ROS, p-p38 MAPK/p38 MAPK ratio, and CC-3, and increased the Bcl-2/Bax ratio, which were reversed by DJ-1 siRNA. The proportion of CC-3- and TUNEL-positive neurons also increased after t-SCI and was reduced by NaB. These effects were reversed by MK2206. Moreover, the level of oxDJ-1 increased after t-SCI, which was decreased by DJ-1 siRNA, NaB or the combination of them. NaB also reduced mitochondrial vacuolization, SCWC and EB extravasation, and improved locomotor function assessed by the BBB and IPT scores. In conclusion, NaB increased DJ-1, and thus reduced ROS and ROS-induced neuronal apoptosis by promoting Akt phosphorylation in t-SCI rats. NaB shows potential as a therapeutic agent for t-SCI, with DJ-1 as its main target.

Intracerebral hematoma after endoscopic fenestration of an arachnoid cyst: A case report.

RATIONALE: An intracranial arachnoid cyst is a relatively common congenital benign lesion. A small number of patients present with neurological symptoms. Endoscopic fenestration has become a common treatment for arachnoid cysts in recent years, but intracerebral hematoma after surgery is rarely reported. PATIENT CONCERNS: A 60-year-old woman with an arachnoid cyst in the left parietal and occipital lobes showed obvious progressive neurological deficits. She had weakness in her right limbs for 2 years and a sudden convulsion in her left limbs. DIAGNOSIS: An arachnoid cyst in the left parietal and occipital lobes was detected on magnetic resonance imaging. INTERVENTION: Endoscopic fenestration was performed for the cyst. However, she developed an intracerebral hematoma after surgery, which was detected by computed tomography. Due to the exacerbation of the patient's condition in the early stage after surgery, reoperation was performed to remove the hematoma. OUTCOMES: The patient was finally cured with no serious neurological deficits. LESSONS: The rare complication of intracerebral hematoma after surgery for an arachnoid cyst can lead to a rapid deterioration in the patient's condition. More-adequate preoperative examination and neuronavigation should be conducted during surgery. Appropriate enlargement of the bone hole may help protect against this complication. Moreover, prompt reoperation for the intracerebral hematoma may improve the prognosis.

Apelin-13 Alleviates Early Brain Injury after Subarachnoid Hemorrhage via Suppression of Endoplasmic Reticulum Stress-mediated Apoptosis and Blood-Brain Barrier Disruption: Possible Involvement of ATF6/CHOP Pathway.

Neuronal apoptosis plays important roles in the early brain injury after subarachnoid hemorrhage (SAH). This study first showed that inhibition of activating transcription factor 6 (ATF6) by apelin-13 could reduce endoplasmic reticulum (ER)-stress-mediated apoptosis and blood-brain-barrier (BBB) disruption after SAH. We chose apelin-13, ATF6 and CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) siRNAs to verify the hypothesis. Brain water content, neurological behavior and Evans Blue (EB) were assessed at 24 h after SAH. Western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) were applied to evaluate the expression of targets in both protein and mRNA levels. Neuronal apoptosis was assessed with Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) and caspase-3 staining. The results showed that the levels of ATF6, and its downstream protein, CHOP were upregulated and reached the peak at 24 h after SAH. ATF6 was highly expressed in neurons. The administration of apelin-13 could significantly reduce the mRNA and protein levels of ATF6, and its downstream targets, CHOP and caspase-3, but increase the Bcl-2/Bax ratio, Claudin-5, Occludin and ZO-1. What's more, the administration of apelin-13 could reduce brain edema, ameliorate BBB disruption and improve neurological functions. However, the CHOP siRNA could significantly reverse the pro-apoptotic effect induced by the increased ATF6 level after SAH. Apelin-13 could exert its neuroprotective effects via suppression of ATF6/CHOP arm of ER-stress-response pathway in the early brain injury after SAH.

Accuracy of 11C-choline positron emission tomography in differentiating glioma recurrence from radiation necrosis: A systematic review and meta-analysis.

OBJECTIVES: Distinguishing glioma recurrence from the necrosis after radiation therapy and/or chemotherapy is a crucial clinical issue, for the different diagnosis will lead to divergent treatments. The accurate judgment is barely achieved by conventional imaging methods. We therefore assume it is of need to exert a meta-analysis to evaluate the diagnostic accuracy of 11C-choline positron emission tomography (PET), to achieve this goal. MATERIAL AND METHODS: We searched the PubMed, Embase, and Chinese Biomedical databases comprehensively to select eligible studies and assessed the quality of each article included (up to May 31, 2018). Fixed-effects models were used. Summary diagnostic accuracy of 11C-choline PET was obtained from pooled analysis. RESULTS: Five articles comprising 6 studies with total 118 patients (134 scans) were enrolled for the meta-analysis. There was no heterogeneity or publication bias among the included studies. The pooled sensitivity and specificity were 0.87 (95% confidence interval [CI]: 0.78, 0.93) and 0.820 (95% CI: 0.69, 0.91), respectively. The pooled diagnostic odds ratio was 35.50 (95% CI: 11.70, 107.75). The area under the curve was 0.9170 (95% CI: 0.8504, 0.9836), with Q* index equaling to 0.8499. The diagnostic accuracy of each subgroup showed no statistical differences with that of the overall group. CONCLUSIONS: This meta-analysis indicated 11C-choline has high diagnostic accuracy for the identification of tumor relapse from radiation induced necrosis in gliomas.

Neuroprotective Role of Agmatine in Neurological Diseases.

BACKGROUND: Neurological diseases have always been one of the leading cause of mobility and mortality world-widely. However, it is still lacking efficient agents. Agmatine, an endogenous polyamine, exerts its diverse biological characteristics and therapeutic potential in varied aspects. METHODS: This review would focus on the neuroprotective actions of agmatine and its potential mechanisms in the setting of neurological diseases. RESULTS: Numerous studies had demonstrated the neuroprotective effect of agmatine in varied types of neurological diseases, including acute attack (stroke and trauma brain injury) and chronic neurodegenerative diseases (Parkinson's disease, Alzheimer's disease). The potential mechanism of agmatine induced neuroprotection includes anti-oxidation, anti-apoptosis, anti-inflammation, brain blood barrier (BBB) protection and brain edema prevention. CONCLUSIONS: The safety and low incidence of adverse effects indicate the vast potential therapeutic value of agmatine in the treatment of neurological diseases. However, most of the available studies relate to the agmatine are conducted in experimental models, more clinical trials are needed before the agmatine could be extensively clinically used.

The Performance of CT versus MRI in the Differential Diagnosis of Cerebral Venous Thrombosis.

BACKGROUND: Cerebral venous thrombosis (CVT) is a rare disease, and with poor prognosis. Computed tomography (CT) and magnetic resonance imaging (MRI) are the most commonly used image modalities for patients with non-specific neurologic symptoms. We present here a meta-analysis to assess the accuracy of CT and MRI in the differential diagnosis of CVT and cerebral venous sinus thrombosis (CVST). MATERIALS AND METHODS: A comprehensive search of the PubMed, EMBASE, Web of Science, Cochrane Database and Chinese Biomedical (CBM) databases was conducted prior to March 20, 2017. In this report, we assess the methodological quality of each article individually and perform a meta-analysis to obtain the summary of the diagnostic accuracy of CT and MRI in correctly identifying CVT and CVST. RESULTS: Twenty-four eligible articles comprising 48 studies (4,595 cases) were included. The pooled sensitivity for CT-CVT/CT-CVST groups is 0.79 (95% confidence interval [CI]: 0.76, 0.82)/0.81(95% CI: 0.78, 0.84), and pooled specificity is 0.90 (95% CI: 0.89, 0.91)/0.89 (0.88, 0.91), with an area under the curve (AUC) for the summary receiver operating characteristic (SROC) of 0.9314/0.9161, respectively. No significant heterogeneity and publication bias was observed across each study. For MRI-CVT/MRI-CVST, the pooled sensitivity is 0.82 (95% CI: 0.78, 0.85)/0.80 (95% CI: 0.76, 0.83), and pooled specificity is 0.92 (95% CI: 0.91, 0.94)/0.91(0.89, 0.92), with an AUC for the SROC of 0.9221/0.9273, respectively. CONCLUSION: This meta-analysis indicates that both CT and MRI have a high level of diagnostic accuracy in the differential diagnosis of CVT and CVST, independent of stage, target for analysis or analysis methods. They could be chosen as alternative sub-optimal gold standards for diagnosing CVT and CVST, especially in emergency.

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Protects Against Neuronal Apoptosis via Activation of Akt/MDM2/p53 Signaling Pathway in a Rat Model of Intracerebral Hemorrhage.

Neuronal apoptosis plays key roles in secondary brain injury caused by intracerebral hemorrhage (ICH). This study first reported the role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in alleviating secondary brain injury through anti-apoptosis in rat model of ICH. The recombinant human-MANF (rh-MANF) and selective Akt inhibitor MK2206 was administrated intracerebroventricularly 1 h after ICH. Brain water content, behavioral assessment, BBB (blood brain barrier) leakage was evaluated 24 h after the induction of ICH. Western blot analysis was used to evaluate the expression level of target proteins (MANF, mouse 3T3 cell double-minute 2 (MDM2), P53, Akt, Bcl-2, Bax, and caspase-3). Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) was applied to evaluate the neuronal cell death. Besides, whether MANF was expressed in neurons was verified with double immunofluorescence staining. The results suggested that the level of MANF, and its downstream proteins, Akt, MDM2 was upregulated and reached peak at 24 h after ICH. MANF was mainly expressed in neurons. The administration of rh-MANF could significantly increase the level of p-Akt, p-MDM2, Bcl/Bax ratio, but reduce the expression of p53, caspase-3 and neuronal death, thus ameliorate the neurological functions at 24 h after ICH. However, these effects of rh-MANF could be obviously reversed by MK2206. MANF could exert its neuronal anti-apoptotic effects via Akt/MDM2/P53 pathways. Therefore, MANF could be a valuable drug target in the treatment of ICH.