Aims: Currently, mannitol and hypertonic saline (HTS) are mostly used in treatment of adult with elevated intracranial pressure (ICP). However, there is no high-level evidence on the superiority of mannitol versus HTS. Therefore, a systematic review and meta-analysis was performed to compare effects of hypertonic saline and mannitol for treatment of adults with elevated ICP. Methods: We performed a search on lots of databases for eligible studies. Prospective randomized control trials comparing HTS and mannitol in adults with elevated ICP were included, and ICP monitoring should be applied. Primary outcome was change of ICP values, and secondary outcomes were changes of cerebral perfusion pressure (CPP), mean arterial pressure (MAP), heart rate, serum sodium, serum osmolarity and hematocrit (HCT). Results: A total of ten studies (384 patients, 1578 episodes) were included. A pooled result indicated HTS reduced ICP more effectively than mannitol. At 0.5 h, 1 h, and 2 h after intervention, results also showed a better efficiency of HTS than mannitol. In addition, results indicated elevation of CPP, serum sodium and serum osmolarity were all more in HTS group than in mannitol group. And there were no statistical significance in changes of MAP, HCT and HR between the two interventions. Conclusion: Our study indicated HTS had a better efficiency in reduction of elevated ICP than mannitol in earlier stage. Based on the current level of evidence of ICP control and effects in other physiological indicators, HTS could be recommended as a first-line agent for managing patients with elevated ICP.

Traumatic brain injury (TBI) has become a major health concern worldwide, and the poor outcome of TBI increases the need for therapeutic improvement. Secondary injuries following TBI, including excitotoxicity, lead to synaptic dysfunction and provide potential targets for intervention. Postsynaptic scaffold proteins, which are involved in the regulation of excitotoxicity after neuronal injury, play a crucial role in modulating synaptic function. Therefore, exploring the role of postsynaptic scaffold proteins in TBI might uncover new treatments. In this study, we demonstrated that downregulated expression of the postsynaptic scaffold protein Preso protects against neuronal injury after TBI in vitro and in vivo, and these effects are related to the inhibition of N-methyl-D-aspartate receptor (NMDAR) function. Further study showed that Preso facilitates signaling from NMDAR to nitric oxide (NO) and calcium (Ca2+) responses. First, the complex constituting NMDAR, postsynaptic density-95 (PSD-95), and neuronal nitric oxide synthase (nNOS) was shown to be involved in the Preso regulation of the NO response. Uncoupling the linkage between Preso and PSD-95 attenuated the stability of this complex and suppressed the regulatory effect of Preso on the NO response. In addition, phosphorylation of NMDAR by cyclin-dependent kinase 5 (CDK5) was shown to be responsible for the Preso-mediated Ca2+ response, which was dependent on the interaction between Preso and CDK5. These results suggested that the association of Preso with NMDAR signaling can serve as a target for neuroprotection against TBI.

Neuronal oxidative stress is involved in diverse neurological disorders. Homer1a, as an important member of the Homer family and localized at the postsynaptic density, is known to protect cells against oxidative injury. However, the exact neuroprotective mechanism of Homer1a has not been fully elucidated. Here, we found that Homer1a promoted cell viability and reduced H2O2-induced LDH release. The overexpression of Homer1a enhanced autophagy after H2O2 treatment, which was confirmed by increased expression of LC3II, Beclin-1, and greater autophagosome formation. In addition, we demonstrated that activating autophagy improved cell survival and reduced H2O2-induced oxidative stress and mitochondrial damage. Moreover, the autophagy inhibitor 3-MA partially prevented the protective effects of Homer1a against oxidative challenge. We also found that the upregulation of Homer1a after H2O2 treatment increased the phosphorylation of AMPK. Furthermore, the AMPK inhibitor compound C inhibited Homer1a-induced autophagy and abolished Homer1a-mediated neuroprotection. All the above data suggests that Homer1a confers protection against H2O2-induced oxidative damage via AMPK-dependent autophagy.

Background/Aims: Autophagy is essential for maintaining cellular homeostasis and the survival of terminally differentiated cells as neurons. In this study, we aim to investigate whether mitofusin 2, a mitochondrial fusion protein, mediates autophagy in cerebral ischemia/reperfusion (I/R) injury. Methods: Primary cultured neurons were treated with oxygen-glucose deprivation/reperfusion to mimic cerebral I/R injury in vitro. Autophagosomes were visualized upon TEM. Autophagy-markers were then detected to monitor autophagy by western-blot and real-time PCR, and the autophagic flux was tracked with a mRFP-GFP-LC3 construct by fluorescence as well as autophagy inhibitors and agonists. The up- and downregulation of Mfn2 were through transfecting a lentivirusexpression vector respectively. And neuronal injury was detected by cell counting kit and TUNEL assay. Results: Results showed I/R increased autophagosome formation and inhibited autolysosome degradation. Furthermore, use of autophagy related agents demonstrated that I/R injury was caused by insufficient autophagy and aggravated by impaired autophagic degradation. The results also indicated that mitofusin 2 could ameliorate I/R injury through increasing autophagosome formation and promoting the fusion of autophagosomes and lysosomes. In contrast, downregulation of mitofusin 2 aggravated the I/R injury by inhibiting autophagosome formation and the fusion of autophagosomes and lysosomes. Additionly, mitofusin 2 overexpression did not lead to autolysosome accumulation induced by I/R. Conclusions: In summary, this study explicitly demonstrated that mitofusin 2 could ameliorate I/R injury mainly through promoting autophagy, which represented a potential novel strategy for neuroprotection against cerebral I/R damage.

Glutamate induced excitotoxicity is common in diverse neurological disorders. RNF146 as an E3 ubiquitin ligase protects neurons against excitotoxicity via interfering with Poly (ADP-ribose) (PAR) polymer-induced cell death (parthanatos). However, the neuroprotective role of RNF146 has not been fully understood. We aimed to investigate the role of RNF146 in modulating autophagy in HT22 cells under glutamate excitotoxicity injury. Here we found that induction of RNF146 decreased the cellular damage and excitotoxicity induced by glutamate. RNF146 also suppressed the excessive autophagy, which is detrimental to HT22 cells survival, induced by glutamate or rapamycin treatment. In addition, we find that Wnt/β-catenin was a negative regulation factor for autophagy in glutamate excitotoxicity. Over-expression of RNF146 promoted Wnt/β-catenin signaling, which was related to destabilization of β-catenin destruction complex. These results indicated that RNF146 acted as a neuroprotective agent against glutamate-induced excitatory damage, and this neuroprotection might be at least partly dependent on the inhibition of excessive autophagy by regulating Wnt/β-catenin signaling.

Objective The goal of this study is to investigate the cytotoxic effects of licochalcone A on the human glioblastoma cell proliferation and apoptosis and to identify the underlying molecular mechanism.Methods The growth-inhibiting effect of licochalcone A(LCA) in the human glioblastoma cells were detected by methyl thiazolyl tetrazolium (MTT) assay and calculated the half maximal inhibitory concentration (ICS0),according to different concentrations grouping IC50 or 100 μM.The cell morphological changes were observed under inverted microscope,the cell apoptosis was examined by the flow cytometry and the protein levels of apoptosis-related molecules were detected by Western Blot.Results The results of MTT revealed that LCA could significantly inhibit U87 and U251 glioma cells proliferation in a dose-and time-dependent manner.The inhibitory concentrations of LCA for U87 and U251 glioma cells at 48 h were 61.54μm and 53.02 μm,respectively.The density and morphology of the U87 and U251 gliona cells were remarkably changed under inverted microscope.Results of flow cytometry showed that LCA could induce apoptosis in U87 and U251 glioma cells (P ＜0.01).Furthermore,LCA significantly reduced the level of B-cell lymphoma-2 (Bcl-2) (P ＜ 0.01),while increased the levels of Bc12-Associated X (Bax) (P＜0.05) in a dose-dependent manner.Conclusion LCA could significantly inhibit the cell proliferation of the human glioblastoma cells,subsequently triggering the mitochondrial apoptotic pathway.

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Objective To investigate the expression of Wnt3a and β-catenin in the cortex and the hippocampus after traumatic brain injury in mice and its clinical significance.Methods A mouse model of traumatic brain injury was established,and Western blotting and immunohistochemistry were used to measure the changes in the protein expression of Wnt3a and β-catenin after traumatic brain injury.Results The control group had low expression of Wnt3a and β-catenin in brain tissue.At 1 hour after traumatic brain injury,the content of β-catenin and Wnt3a in the cortex and the hippocampus started to increase.At 6 hours and 7 days after traumatic brain injury,the traumatic group had significant increases in the protein expression of β-catenin and Wnt3a (P ＜ 0.05).Immunofluorescent staining showed that at 24 hours after brain injury,there were increases in the expression of β-catenin and Wnt3a in the cortex and the hippocampus.Conclusions The protein expression of Wnt3a and β-catenin increases significantly in the early stage and recovery stage after traumatic brain injury,suggesting that Wnt3a and β-catenin may play important roles in the pathophysiological mechanism of traumatic brain injury.

Objective This study aims to investigate the influence of high-altitude (6000 m) hypoxia exposure for different duration on negative emotions and hippocampal neuronal injury and autophagy of mouse and their interrelation.Methods Hypobaric oxygen chamber was used to simulate 6000 m altitude circumstances.Treatment groups were exposed to high-altitude hypoxia circumstances for different time,and control group was raised outside the hypobaric oxygen chamber.Elevated plus maze (EMP) test was used to investigate the negative emotions after high-altitude hypoxia exposure.The pathological morphology of hippocampal neurons in CA1 area was examined by HE staining.Expressions of hypoxia-inducible factor 1α (HIF-1α),Bcelin-1 and microtubule-associated protein 1 light 3-Ⅱ (LC3-Ⅱ) was assayed by Western Blot.Results Significant reductions after high altitude hypoxia exposure for 1,3,and 14 d in the percentage of residence time and the entries in the open arms indicated by EMP test was observed.HE staining showed that the hippocampal neurons in CA1 area after high-altitude hypoxia exposure for 1,3,and 14 d were arranged disorderly,with dilatate intercellular spaces and irregular shape and karyopyknosis.And compared with other treatment groups,injury of hippocampal neurons after 7 d high-altitude hypoxia exposure was attenuated relatively.The expressions of HIF-1α,Beclin-1 and LC3-Ⅱ peaked after high altitude hypoxia exposure for 1 d and then decreased.At treatment for 7 d,there were no significant difference in the expressions of HIF-1α and LC3-Ⅱ compared with the control group.Conclusion At high-altitude hypoxia circumstances,increased negative emotions of mouse were related with the damage of hippocampal neurons,and the activation of autophagy may be involved in the damage of hippocampal neurons.

目的 探讨γ-分泌酶抑制剂(GSI)对神经元机械性损伤的保护作用.方法 原代培养小鼠皮层神经元,培养基中加入10 μmol/L GSI共同孵育24h后,使用微量移液器枪头做机械性划伤.测定培养液中乳酸脱氢酶(LDH)活力的变化;Hochest染色测定神经元凋亡情况;Western blot方法检测切冬酶-3(caspase-3)蛋白表达情况.结果 GSI预处理可抑制因细胞损伤引起的LDH的释放,可降低损伤后Hochest阳性细胞的数量以及活化caspase-3的表达.结论 GSI对神经元机械性损伤有保护作用.

Calcium disequilibrium is extensively involved in oxidative stress-induced neuronal injury. Although Homer1a is known to regulate several neuronal calcium pathways, its effects on, or its exact relationship with, oxidative stress-induced neuronal injury has not yet been fully elucidated. We found that Homer1a protected HT-22 cells from glutamate-induced oxidative stress injury by inhibiting final-phase intracellular calcium overload and mitochondrial oxidative stress. In these cells, stromal interactive molecule 1 (STIM1) puncta, but not the protein level, was significantly increased after glutamate treatment. Store-operated calcium entry (SOCE) inhibitors and cells in which a key component of SOCE (STIM1) was knocked out were used as glutamate-induced oxidative stress injury models. Both models demonstrated significant improvement of HT-22 cell survival after glutamate treatment. Additionally, increased Homer1a protein levels significantly inhibited SOCE and decreased the association of STIM1-Orai1 triggered by glutamate. These results suggest that up-regulation of Homer1a can protect HT-22 cells from glutamate-induced oxidative injury by disrupting the STIM1-Oria1 association, and then by inhibiting the SOCE-mediated final-phrase calcium overload. Thus, regulation of Homer1a, either alone or in conjunction with SOCE inhibition, may serve as key therapeutic interventional targets for neurological diseases in which oxidative stress is involved in the etiology or progression of the disease.

Objective The objective of the research is to study the roles and mechanisms of mitochondrial fission inhibitor (Mdivi-1) in primary cultured cortex neurons of mice after Oxygen-glucose deprivation/Reperfusion (OGD/R) injury.Methods Occurrence of autophagy was detected after establishing OGD/R model in primary cultured cortex neurons.The mRNA and protein levels of autophagy-related genes were detected accompanied treatment with autophagy inhibitor (3-MA), autophagy agonist (rapamycin) and Mdivi-1.Moreover, the neural injury was measured.Results Following OGD/R treatment, autophagy was increased dependent on reperfusion times.And both levels of Beclin 1 and Microtubule-associated protein light chain 3 II ( LC3 II ) peaked at 24 h ( P<0.001, P<0.01).Results of cell counting kit-8 (CCK-8) after OGD/R treatment showed that Mdivi-1 could aggravate the injury (P <0.05), however, rapamycin could reduce not only the OGD/R injury (P <0.01), but also the aggravating damage induced by Mdivi-1 (P<0.05).Furthermore, Mdivi-1 significantly reduced the levels of Beclin 1 and LC3 II following OGD/R injury (P<0.05).Conclusion Mdivi-1 could aggravate the injury induced by OGD/R through inhibiting the occurrence of autophagy .

Traumatic brain injury (TBI) is the leading cause of mortality and morbidity worldwide and is characterized by immediate brain damage and secondary injuries, such as brain edema and ischemia. However, the exact pathological mechanisms that comprise these associated secondary injuries have not been fully elucidated. This study aimed to investigate the role of the Na(+)-K(+)-2Cl(-) cotransporter-1 (NKCC1) in the disruption of ion homeostasis and neuronal apoptosis in TBI. Using a traumatic neuron injury (TNI) model in vitro and a controlled cortex injury (CCI) model in vivo, the present study investigated changes in the expression and effects of NKCC1 in TBI using western blot, RNA interference, a lactate dehydrogenase (LDH) release assay, TdT-mediated dUTP Nick end-labeling (TUNEL) analysis, sodium imaging, brain water content, and neurological severity scoring. TBI induced the expression of NKCC1 to be significantly upregulated in the cortex, both in vitro and in vivo. Pharmacological inhibitor bumetanide (Bume) or NKCC1 RNA interference significantly attenuated TBI-induced intracellular Na(+) increase, inhibited neuronal apoptosis, and improved brain edema and neurological function. Furthermore, NKCC1 inhibition also significantly inhibited TBI-induced extracellular signal-regulated kinase (Erk) activation. Erk inhibition significantly protected neurons from TBI injury; however, Erk inhibition had no effect on NKCC1 expression or the neuroprotective effect of NKCC1 inhibition against TBI. This study demonstrates the role of NKCC1 in TBI-induced brain cortex injury, establishing that NKCC1 may play a neurotoxic role in TBI and that the inhibition of NKCC1 may protect neurons from TBI via the regulation of Erk signaling.

Although store-operated calcium entry (SOCE) has been implicated in several neurological disorders, the exact mechanism for its role in traumatic brain injury (TBI) has not been elucidated. In this study, we found that TBI upregulated the expression of a calcium sensor protein called stromal interactive molecule 2 (STIM2); however, the levels of its homologue, STIM1, were unaffected. Both STIM1 and STIM2 are crucial components of SOCE, both in vivo and in vitro. Using shRNA, we discovered that downregulation of STIM2, but not STIM1, significantly improved neuronal survival in both an in vitro and in vivo model of TBI, decreasing neuronal apoptosis, and preserving neurological function. This neuroprotection was associated with alleviating TBI-induced calcium overload and preserving mitochondrial function. Additionally, downregulation of STIM2 not only inhibited Ca(2+) release from the endoplasmic reticulum (ER), but also reduced SOCE-mediated Ca(2+) influx, decreased mitochondrial Ca(2+), restored mitochondrial morphology and improved mitochondrial function, including MMP maintenance, ROS production and ATP synthesis. These results indicate that inhibition of STIM2 can protect neurons from TBI by inhibiting calcium overload and preserving mitochondrial function. This suggests that STIM2 might be an effective interventional target for TBI.

This study investigated the protective effects and mechanisms of crocin, an extract of saffron, on brain damage after traumatic brain injury (TBI) in mice. C57BL/6 mice were subjected to controlled cortical impact (CCI)-induced TBI. Pretreatment with crocin (20mg/kg) had protective effects against TBI, demonstrated by improved neurological severity score (NSS) and brain edema, decreased microglial activation and release of several pro-inflammatory cytokines, and decreased cell apoptosis. TBI activated Notch signaling, as shown by upregulated levels of Notch intracellular domain (NICD) and Hes1 mRNA, and pretreatment with crocin further increased Notch activation. However, pretreatment with DAPT (100mg/kg), a gamma-secretase inhibitor, significantly suppressed crocin-induced activation of Notch signaling and attenuated the ability of crocin to protect mice against TBI-induced inflammation and apoptosis. Therefore, these results suggest that crocin has neuroprotective effects against TBI in mice, and these effects are at least partially dependent on activation of Notch signaling.

The aim of this study is to investigate the incidence of unplanned reoperations from all causes due to bleeding in neurosurgical patients.The medical records of patients who received neurosurgical procedures at our hospital were retrospectively reviewed and data of patients who received reoperations were extracted and summarized. A literature review was conducted of the Medline, Cochrane, EMBASE, and Google Scholar databases up to November 2013. The main outcome measure was the rate of unplanned reoperations due to bleeding.At our hospital, 68 patients with a mean age of 41.521.5 years (range, 7 months to 76 years) received an unplanned reoperation. More than 70% of the patients were older than 18 years, 64.7% were males, and 94.1% had cranial surgery. Almost 60% of the patients received >1 blood transfusion (58.8%) after the first surgery. Of the 68 patients, 35 (51.5%) received a second operation due to bleeding. Univariate logistic regression analysis only showed that an increasing time interval between the first and second surgery was associated with a decreased chance of the reoperation being performed due to bleeding (odds ratio [OR]=0.843, 95% confidence interval [CI]: 0.720-0.987; P=.033). Of 229 studies identified, 5 retrospective reports with a total of 1375 patients were included in the analysis. The rate of reoperations for bleeding in the 5 studies ranged from 4.2% to 31.5%.Employing measures to reduce postoperative bleeding may help reduce the rate of unplanned neurosurgical reoperations.

Mitochondrial dynamics play a critical role in mitochondrial function and signaling. Although mitochondria play a critical role in hypoxia/ischemia, the further mechanisms between mitochondrial dynamics and ischemia are still unclear. The current study aimed to determine the role of mitofusin 2, a key regulator of mitochondrial fusion, in a hypoxic model and to explore a novel strategy for cerebral ischemia via modulation of mitochondrial dynamics. To the best of our knowledge, this is the first study to investigate both mitochondrial function and molecular pathways to determine the role of mitofusin 2 in hypoxia-induced neuronal apoptosis. In vivo, C57BL/6 mice (male, 19–25g) underwent a permanent middle cerebral artery occlusion for 12 or 24h (n=6 per group). In vitro, cobalt chloride was used to mimic hypoxia in immortalized hippocampal neurons. Down- or up-regulation of Mfn2 was induced to investigate the role of Mfn2 in hypoxia, especially in mitochondrial function and signaling pathways. The findings demonstrated that decreased mitofusin 2 occurred both in vivo and in vitro hypoxic models; second, the anti-apoptotic effect of Mfn2 may work via restoration of mitochondrial function; third, the modulation of the B Cell Leukemia 2/Bcl-2 Associated X protein and extracellular signal-regulated kinase 1/2 signaling pathways highlight the role of Mfn2 in signaling pathways beyond fusion. In summary, depletion of mitofusin 2 would lead to apoptosis both in normal or hypoxic conditions; however, mitofusin 2 overexpression could attenuate hypoxia-induced apoptosis, which represents a potential novel strategy for neuroprotection against ischemic brain damage.

Retinal ischemia and reperfusion (I/R) is extensively involved in ocular diseases, causing retinal ganglion cell (RGCs) death resulting in visual impairment and blindness. Homer1a is considered as an endogenous neuroprotective protein in traumatic brain injury. However, the roles of Homer1a in RGCs I/R injury have not been elucidated. The present study investigated the changes in expression and effect of Homer1a in RGCs both in vitro and in vivo after I/R injury using Western blot, TUNEL assay, gene interference and overexpression, and gene knockout procedures. The levels of Homer1a and phosphorylated Erk (p-Erk) increased in RGCs and retinas after I/R injury. Upregulation of Homer1a in RGCs after I/R injury decreased the level of p-Erk, and mitigated RGCs apoptosis. Conversely, downregulation of Homer1a increased the level of p-Erk, and augmented RGCs apoptosis. Furthermore, inhibition of the p-ERK reduced RGCs apoptosis, and increased the expression of Homer 1a after I/R injury. Finally, the retinas of Homer1a KO mice treated with I/R injury had significantly less dendrites and RGCs, compared with Homer1a WT mice. These findings demonstrated that Homer1a may contribute to RGCs survival after I/R injury by interacting with Erk pathway.

Glioblastoma is the most common brain tumor and is characterized with robust invasion and migration potential resulting in poor prognosis. Previous investigations have demonstrated that modeled microgravity (MMG) could decline the cell proliferation and attenuate the metastasis potential in several cell lines. In this study, we studied the effects of MMG on the invasion and migration potentials of glioblastoma in human glioblastoma U87 cells. We found that MMG stimulation significantly attenuated the invasion and migration potentials, decreased thapsigargin (TG) induced store-operated calcium entry (SOCE) and downregulated the expression of Orai1 in U87 cells. Inhibition of SOCE by 2-APB or stromal interaction molecule 1 (STIM1) downregulation both mimicked the effects of MMG on the invasion and migration potentials in U87 cells. Furthermore, upregulation of Orai1 significantly weakened the effects of MMG on the invasion and migration potentials in U87 cells. Therefore, these findings indicated that MMG stimulation inhibited the invasion and migration potentials of U87 cells by downregulating the expression of Orai1 and sequentially decreasing the SOCE, suggesting that MMG might be a new potential therapeutic strategy in glioblastoma treatment in the future.