MiR-497-5p ameliorates the oxyhemoglobin-induced subarachnoid hemorrhage injury in vitro by targeting orthodenticle homeobox protein 1 (Otx1) to activate the Nrf2/HO-1 pathway.

Subarachnoid hemorrhage (SAH) is a neurological disorder that severely damages the brain and causes cognitive impairment. MicroRNAs are critical regulators in a variety of neurological diseases. MiR-497-5p has been found to be downregulated in the aneurysm vessel walls obtained from patients with aneurysmal subarachnoid hemorrhage, but its functions and mechanisms in SAH have not been reported. Therefore, this study was designed to investigate the effect of miR-497-5p and its related mechanisms in SAH. We established an in vitro SAH model by exposing PC12 cells to oxyhemoglobin (oxyHb). We found that miR-497-5p was downregulated in SAH serum and oxyHb-treated PC12 cells, and its overexpression inhibited the oxyHb-induced apoptosis, inflammatory response and oxidative stress via activation of the Nrf2 pathway. Mechanistically, the targeting relationship between miR-497-5p and Otx1 was verified by luciferase reporter assays. Moreover, Otx1 upregulation abolished the protective effects of miR-497-5p upregulation against oxyHb-induced apoptosis, inflammation and oxidative stress in PC12 cells. Collectively, our findings indicate that miR-497-5p could inhibit the oxyHb-induced SAH damage by targeting Otx1 to activate the Nrf2/HO-1 pathway, which provides a potential therapeutic target for SAH treatment.

Suppression of MALAT1 alleviates neurocyte apoptosis and reactive oxygen species production through the miR-499-5p/SOX6 axis in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH), a common devastating cerebrovascular accident, is a great threat to human health and life. Exploration of the potential therapeutic target of SAH is urgently needed. Previous studies showed that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes cell apoptosis in various diseases, while its role in SAH remains unclear. In our study, we established a mouse model of SAH and used the oxyhemoglobin (OxyHb) to induce neuronal injury in vitro. Interestingly, MALAT1 was found upregulated in brain tissues of SAH mice and OxyHb-stimulated neurons. In addition, knockdown of MALAT1 attenuated apoptosis and decreased reactive oxygen species (ROS) production in OxyHb-stimulated neurons. Mechanistically, we demonstrated that MALAT1 bound with miR-499-5p. Furthermore, our findings indicated that miR-499-5p bound to SOX6 3' untranslated region (UTR) and negatively regulated SOX6 mRNA and protein levels. Rescue assays suggested that SOX6 overexpression counteracted the effects of MALAT1 knockdown on neurocyte apoptosis, and ROS production in OxyHb-stimulated neurons. The in vivo assays indicated that knockdown of MALAT1 improved brain injury of SAH mice. Our study demonstrates that silencing of MALAT1 alleviates neurocyte apoptosis and reduces ROS production through the miR-499-5p/SOX6 axis after SAH injury.

ACE2 Rescues Impaired Autophagic Flux Through the PI3K/AKT Pathway After Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is one of the life-threatening neurosurgical diseases in central nervous system. Autophagy has been previously demonstrated to exert vital roles in SAH development. Angiotensin I converting enzyme 2 (ACE2) has been revealed as a regulator of autophagy in neurosurgical diseases. However, effect of ACE2 on autophagy in SAH progression has not been clarified. First, we explored the relationship between autophagy and SAH progression by establishing a mouse model of SAH under the administration of 3-MA (the autophagy inhibitor). Next, we examined ACE2 expression in the cerebral cortex of SAH mice ex vivo with RT-qPCR. Subsequently, we assessed the biological function of ACE2 on brain injury, the autophagic flux pathway and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling ex vivo via neurological scoring, TUNEL assay, western blot analysis and immunofluorescence staining assay. Finally, we carried out rescue assays under chloroquine (CQ, the autophagic flux inhibitor) and LY294002 (the PI3K/AKT signaling inhibitor) administration. 3-MA mitigated brain injury after SAH, and ACE2 was downregulated in cerebral cortex of SAH mice. Moreover, ACE2 elevation alleviated cell apoptosis, cerebral edema, and neurological deficits, ameliorated the autophagic flux pathway and activated the PI3K/AKT signaling in SAH mice. Furthermore, CQ and LY294002 neutralized the effects of overexpressed ACE2 on neuronal apoptosis, cerebral edema, and neurological deficits in SAH mice. Overall, ACE2 lessened neuronal injury via the autophagic flux and PI3K/AKT pathways. This research might provide a potential novel direction for clinical treatment of SAH.

Baicalin suppresses autophagy-dependent ferroptosis in early brain injury after subarachnoid hemorrhage.

Early brain injury, characterized by massive cell apoptosis or death, is identified as a critical pathophysiological process during subarachnoid hemorrhage (SAH). Ferroptosis, a class of autophagy-dependent cell death discovered in 2012, is induced by iron-dependent lipid peroxidation accumulation. The present study was designed to study the role of baicalin in autophagy-dependent ferroptosis in early brain injury after SAH. Neurological scores and brain water content were measured to evaluate brain injury. Measurement of iron ion, malondialdehyde (MDA), lipid reactive oxygen species was conducted for ferroptosis evaluation. Immunofluorescence staining, western blotting, and flow cytometry analysis were used to evaluate autophagy and apoptosis. First, we observed that, compared with sham rats, SAH rats had lower neurobehavioral scores. Next, baicalin was proven to decrease the Fe2+, malondialdehyde, and ROS levels in the brain tissues of rats. Also, baicalin was confirmed to suppress the beclin1, LC3-II, and LC3-I protein levels in rat brain tissues. Moreover, we found that baicalin inhibited neuronal apoptosis. Finally, the effects of baicalin on brain injury in the SAH rats were verified. Overall, our results demonstrated that baicalin suppressed autophagy-dependent ferroptosis in EBI after SAH.

Endoscopic Anatomic Study Via Grinding Partial Petrous Ridge to the Middle Fossa in Retromastoid Keyhole Approach.

OBJECTIVE: This study aimed to observe the range of exposure, indications, and feasibility of the retromastoid keyhole approach via grinding partial petrous ridge to the middle fossa. METHODS: Simulated endoscopic surgeries via grinding suprameatal tubercle and petrous ridge to expose the middle fossa in retromastoid keyhole approach were performed on 8 adult cadaver heads (16 sides) fixed by formalin. The maximum exposure range in endoscope was observed. The boundaries of Parkinson triangle and the anatomic structures contained by Meckel cave and cavernous sinus (CS) lateral wall were revealed. The distances from midpoint of sigmoid sinus posterior border to every important anatomic structures in the middle fossa and the length of all sides of Parkinson triangle were measured. RESULTS: By using endoscope, the exposure of the cerebellopontine angle, ventrolateral brainstem, incisure of tentorium, petroclival region, and CS lateral wall were satisfactory. Many important anatomic structures in middle fossa were exposed well. The distances from midpoint of posterior border of sigmoid sinus to suprameatal tubercle, trigeminal semilunar ganglion, posterior curve segment of internal carotid artery were 34.42 ± 2.14, 54.52 ±â€Š2.87, and 65.15 ±â€Š3.13 mm. The lengths of all sides of Parkinson triangle were 18.97 ±â€Š2.93, 16.23 ±â€Š2.02, and 8.04 ±â€Š2.34 mm. CONCLUSION: The retromastoid keyhole approach via grinding partial petrous ridge to the middle fossa by using endoscope can increase the exposure of middle fossa effectively, which is proper for most lesions in posterior cranial fossa while some parts extend to middle fossa.

The Influence of Sedation Level Guided by Bispectral Index on Therapeutic Effects for Patients with Severe Traumatic Brain Injury.

BACKGROUND: Sedation therapy is vital for treating severe traumatic brain injury (TBI). Yet, types of sedation assessment tools and sedation levels that are suitable for sedation treatment have not been investigated. OBJECTIVE: To investigate the influence of different sedation levels guided by the Bispectral Index (BIS) on the therapeutic effects for severe TBI. METHODS: According to inclusion, exclusion, and rejection criteria, 35 patients were prospectively included and divided into Richmond Agitation Sedation Scale (RASS), BIS(I), and BIS(II) groups. The RASS group was controlled the level of sedation to within -2 or -3, and the BIS(I) and (II) groups within the range of 40-50 and 50-60, respectively. In addition to clinical data, RASS, BIS, and intracranial pressure (ICP) values were collected. RASS and ICP variability were introduced to investigate the different of sedative control effect with or without BIS monitor, and the control effect of ICP between different sedation levels. Statistical analysis was performed to estimate the effectiveness of different sedation levels guided by BIS in sedation treatment within 72 hours. RESULTS: There were no significant differences in demographics among the 3 groups. RASS variability of the BIS(I) and (II) groups was significantly lower than that of the RASS group (P < 0.05), and in the BIS(I) group it was insignificantly lower than in the BIS(II) group. The ICP of the BIS(I) and (II) groups declined to <13.5 mm Hg significantly earlier than that of the RASS group (P < 0.05), and the difference between BIS(I) and (II) was insignificant. ICP variability of RASS group was higher than those of the BIS(I) and (II) groups (P < 0.05), and ICP variability of the BIS(I) group was significantly lower than that of the BIS(II) group (P < 0.05). Differences in days in the neurosurgery intensive care unit and outcomes among the 3 groups were insignificant. CONCLUSIONS: BIS is more reliable than RASS for maintaining a stable sedation status and ICP. Deeper sedation levels (BIS 40-50) cause ICP to decrease more quickly, with lower ICP variability.

Reprogramming A375 cells to induced­resembled neuronal cells by structured overexpression of specific transcription genes.

Induced-resembled neuronal cells (irNCs) are generated by reprogramming human melanoma cells through the introduction of key transcription factors, providing novel concepts in the treatment of malignant tumor cells and making it possible to supply neural cells for laboratory use. In the present study, irNCs were derived from A375 cells by inducing the 'forced' overexpression of specific genes, including achaete­scute homolog 1 (Ascl1), neuronal differentiation factor 1 (Neurod1), myelin transcription factor 1 (Myt1), brain protein 2 (Brn2, also termed POU3F2) and human brain­derived neurotrophic factor (h­BDNF). irNCs induced from A375 cells express multiple neuronal markers and fire action potentials, exhibiting properties similar to those of motor neurons. The reprogramming procedure comprised reverse transcription­polymerase chain reaction and immunofluorescence staining; furthermore, electrophysiological profiling demonstrated the characteristics of the induced­resembled neurons. The present study obtained a novel type of human irNC from human melanoma, which secreted BDNF continuously, providing a model for neuron­like cells. Thus, irNCs offer promise in investigating various neural diseases by using neural­like cells derived directly from the patient of interest.

Naloxone for severe traumatic brain injury: a meta-analysis.

OBJECTIVE: The efficiency of naloxone for the management of secondary brain injury after severe traumatic brain injury (sTBI) remains undefined. The aim of this study is to evaluate the current evidence regarding the clinical efficiency and safety of naloxone as a treatment for sTBI in mainland China. METHODOLOGY/PRINCIPAL FINDINGS: A systematic search of the China Biology Medicine disc (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Internet (CNKI), and Wan Fang Database was performed to identify randomized controlled trials (RCTs) of naloxone treatment for patients with sTBI in mainland China. The quality of the included trials was assessed, and the RevMan 5.1 software was employed to conduct this meta-analysis. Nineteen RCTs including 2332 patients were included in this study. The odds ratio (OR) showed statistically significant differences between the naloxone group and the control group (placebo) in terms of mortality at 18 months after treatment (OR, 0.51, 95%CI: 0.38-0.67; p<0.00001), prevalence of abnormal heart rates (OR, 0.30, 95%CI: 0.21-0.43; p<0.00001), abnormal breathing rate (OR, 0.25, 95%CI: 0.17-0.36; p<0.00001) at discharge, the level of intracranial pressure at discharge (OR, 2.00, 95%CI: 1.41-2.83; p = 0.0001), verbal or physical dysfunction rate (OR, 0.65, 95%CI: 0.43-0.98; p = 0.04), and severe disability rate (OR, 0.47, 95%CI: 0.30-0.73; p = 0.0001) at 18 months after the treatment. The mean difference (MD) showed statistically significant differences in awakening time at discharge (MD, -4.81, 95%CI: -5.49 to -4.12; p<0.00001), and GCS at 3 days (MD, 1.00, 95%CI: 0.70-1.30; p<0.00001) and 10 days (MD, 1.76, 95%CI: 1.55-1.97; p<0.00001) after treatment comparing naloxone with placebo group. CONCLUSIONS/SIGNIFICANCE: This study indicated that applying naloxone in the early stage for sTBI patients might effectively reduce mortality, control intracranial pressure (ICP), and significantly improve the prognosis.

Neuroendoscopic surgery versus external ventricular drainage alone or with intraventricular fibrinolysis for intraventricular hemorrhage secondary to spontaneous supratentorial hemorrhage: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Although neuroendoscopy (NE) has been applied to many cerebral diseases, the effect of NE for intraventricular hemorrhage (IVH) secondary to spontaneous supratentorial hemorrhage remains controversial. The purpose of this study was to analyze the effect of NE compared with external ventricular drainage (EVD) alone or with intraventricular fibrinolysis (IVF) on the management of IVH secondary to spontaneous supratentorial hemorrhage. METHODOLOGY/ PRINCIPAL FINDINGS: A systematic search of electronic databases (PubMed, EMBASE, OVID, Web of Science, The Cochrane Library, CBM, VIP, CNKI, and Wan Fang database) was performed to identify related studies published from 1970 to 2013. Randomized controlled trials (RCTs) or observational studies (OS) comparing NE with EVD alone or with IVF for the treatment of IVH were included. The quality of the included trials was assessed by Jaded scale and the Newcastle-Ottawa Scale (NOS). RevMan 5.1 software was used to conduct the meta-analysis. RESULTS: Eleven trials (5 RCTs and 6 ORs) involving 680 patients were included. The odds ratio (OR) showed a statistically significant difference between the NE + EVD and EVD + IVF groups in terms of mortality (OR, 0.31; 95% CI, 0.16-0.59; P=0.0004), effective hematoma evacuation rate (OR, 25.50, 95%CI; 14.30, 45.45; P<0.00001), good functional outcome (GFO) (OR, 4.51; (95%CI, 2.81-7.72; P<0.00001), and the ventriculo-peritoneal (VP) shunt dependence rate (OR, 0.16; 95%CI; 0.06, 0.40; P<0.0001). CONCLUSION: Applying neuroendoscopic approach with EVD may be a better management for IVH secondary to spontaneous supratentorial hemorrhage than NE + IVF. However, there is still no conclusive evidence regarding the preference of NE vs. EVD alone in the case of IVH, because insufficient data has been published thus far. This study suggests that the NE approach with EVD could become an alternative to EVD + IVF for IVH in the future.