HSP70 attenuates neuronal necroptosis through the HSP90α-RIPK3 pathway following neuronal trauma.

BACKGROUND: Necroptosis, a newly defined regulatable necrosis with membrane disruption, has been demonstrated to participate in trauma brain injury (TBI) related neuronal cell death. Heat shock protein 70 (HSP70) is a stress protein with neuroprotective activity, but the potential protective mechanisms are not fully understood. METHODS AND RESULTS: Here, we investigated the effects of HSP70 regulators in a cellular TBI model induced by traumatic neuronal injury (TNI) and glutamate treatment. We found that necroptosis occurred in cortical neurons after TNI and glutamate treatment. Neuronal trauma markedly upregulated HSP70 protein expression within 24 h. The results of immunostaining and lactate dehydrogenase release assay showed that necroptosis following neuronal trauma was inhibited by HSP70 activator TRC051384 (TRC), but promoted by the HSP70 inhibitor 2-phenylethyenesulfonamide (PES). In congruent, the expression and phosphorylation of receptor interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) were differently regulated by HSP70. Furthermore, the expression of HSP90α induced by neuronal trauma was further promoted by PES but decreased by TRC. The data obtained from western blot showed that the phosphorylation of RIPK3 and MLKL induced by HSP70 inhibition were reduced by RIPK3 inhibitor GSK-872 and HSP90α inhibitor geldanamycin (GA). Similarly, inhibition of HSP90α with GA could partially prevented the increased necroptosis induced by PES. CONCLUSIONS: Taken together, HSP70 activation exerted protective effects against neuronal trauma via inhibition of necroptosis. Mechanistically, the HSP90α-mediated activation of RIPK3 and MLKL is involved in these effects.

A Predictive Model for Chronic Hydrocephalus After Clipping Aneurysmal Subarachnoid Hemorrhage.

Chronic hydrocephalus after clipping aneurysmal subarachnoid hemorrhage (aSAH) often results in poor outcomes. This study was to establish and validate model to predict chronic hydrocephalus after aSAH by least absolute shrinkage and selection operator logistic regression. The model was constructed from a retrospectively analyzed. Two hundred forty-eight patients of aSAH were analyzed retrospectively in our hospital from January 2019 to December 2021, and the patients were divided into chronic hydrocephalus (CH) group (n=55) and non-CH group (n=193) according to whether occurred CH within 3 months. In summary, 16 candidate risk factors related to chronic hydrocephalus after aSAH were analyzed. Univariate analysis was performed to judging the risk factors for CH. The least absolute shrinkage and selection operator regression was used to filter risk factors. Subsequently, the nomogram was designed by the above variables. And area under the curve and calibration chart were used to detect the discrimination and goodness of fit of the nomogram, respectively. Finally, decision curve analysis was constructed to assess the practicability of the risk of chronic hydrocephalus by calculating the net benefits. Univariate analysis showed that age (60 y or older), aneurysm location, modified Fisher grade, Hunt-Hess grade, and the method for cerebrospinal fluid drainage, intracranial infections, and decompressive craniectomy were significantly related to CH ( P <0.05). Whereas 5 variables [age (60 y or older), posterior aneurysm, modified Fisher grade, Hunt-Hess grade, decompression craniectomy] from 16 candidate factors were filtered by LASSO logistic regression for further research. Area under the curve of this model was 0.892 (95% confidence interval: 0.799-0.981), indicating a good discrimination ability. Meanwhile, the result of calibration indicated a good fitting between the prediction probability and the actual probability. Finally, decision curve analysis showed a good clinical efficacy. In summary, this model could conveniently predict the occurrence of chronic hydrocephalus after aSAH. Meanwhile, it could help physicians to develop personalized treatment and close follow-up for these patients.

Striatal asymmetry index and its correlation with the Hoehn & Yahr stage in Parkinson's disease.

PURPOSE: Striatal asymmetry is a common feature in Parkinson's disease (PD), which changes with the progression of the disease. However, the correlation between the striatal asymmetry and severity of PD remains unclear. The present study aimed to investigate the characteristics of asymmetry in PD, and analyze the correlation between the striatal asymmetry index (SAI) and disease severity. MATERIALS AND METHODS: This retrospective study enrolled 63 patients with idiopathic PD. The severity of PD was classified according to the Hoehn & Yahr (H&Y) staging system. The SAI in the subregions of the striatum was measured using 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (11C-CFT) positron emission tomography (PET). RESULTS: There was a significant difference in the SAI of the posterior putamen among the three groups (H&Y stage I, H&Y stage II, and H&Y stage III-IV; p = 0.001). However, there was no difference in the SAI of the anterior putamen (p = 0.340) or SAI of the caudate nucleus (p = 0.342) among the three groups. The SAI of the posterior putamen in patients with PD was significantly higher than that in patients with multiple system atrophy or progressive supranuclear palsy (p = 0.008). CONCLUSION: The SAI of the posterior putamen is associated with the severity of PD, and may be correlated to the loss of dopamine cells in the pars compacta of the ventrolateral substantia nigra projecting to the posterior putamen. The SAI may be a potential indicator for evaluating the severity of PD, and distinguishing PD from other degenerative diseases.

RNF216 mediates neuronal injury following experimental subarachnoid hemorrhage through the Arc/Arg3.1-AMPAR pathway.

Subarachnoid hemorrhage (SAH), mostly caused by aneurysm rupture, is a pathological condition associated with oxidative stress and neuroinflammation. Toll-like receptors (TLRs) are a family of key regulators of neuroinflammation, and RNF216 is an E3 ubiquitin-protein ligase that regulates TLRs via ubiquitination and proteolytic degradation. However, the role of RNF216 in SAH has not been determined. In this study, we investigated the biological function of RNF216 in experimental SAH models both in vitro and in vivo. The expression of RNF216 was found to be upregulated in cortical neurons after oxyhemoglobin (OxyHb) treatment, and increased RNF216 expression was also observed in brain tissues in the single-hemorrhage model of SAH. Downregulation of RNF216 expression by short interfering RNA (siRNA) transfection significantly reduced cytotoxicity and apoptosis after OxyHb exposure. The results of western blot showed that the RNF216-mediated neuronal injury in vitro was associated with the regulation of the Arc-AMPAR pathway, which was related to intracellular Ca2+ dysfunction, as evidenced by Ca2+ imaging. In addition, knockdown of RNF216 in vivo using intraventricular injection of siRNA was found to attenuate brain injury and neuroinflammation via the Arc-AMPAR pathway after SAH in the animal model. In summary, we demonstrated that silence of RNF216 expression protects against neuronal injury and neurological dysfunction in experimental SAH models. These data support for the first time that RNF216 may represent a novel candidate for therapies against SAH.

Posttraumatic Giant Intradiploic Epidermoid Cyst of Orbital Roof.

ABSTRACT: Epidermoid cysts are rare benign tumors that account for 0.3% to 1.8% of all intracranial space-occupying lesions. They are usually congenital in origin and are thought to derived from ectodermal cell inclusions occurring during closure of the neural tube around third to fifth week of gestation. They are most commonly located in the cerebellopontine angle and the parasellar area, and their location in the diploic space is very rare. In this article, a case of giant epidermoid cyst located in the orbital roof intradiploic space is presented with clinical, radiologic features and surgical treatment.

The Value of Managing Severe Traumatic Brain Injury During the Perioperative Period Using Intracranial Pressure Monitoring.

This study aimed to investigate the clinical efficacy of intracranial pressure (ICP) monitoring regarding the perioperative management of patients with severe traumatic brain injury (sTBI). This was a cohort study performed between Jan 2013 and Jan 2016 and included all patients with sTBI. All patients were split into ICP monitoring and non-ICP monitoring groups. The primary outcomes were in-hospital mortality and Glasgow Outcome Scale (GOS) scores 6 months after injury, whereas the secondary outcomes include rate of successful nonsurgical treatment, rate of decompression craniotomy (DC), the length of stay in the ICU, and the hospital and medical expenses. This retrospective analysis included 246 ICP monitoring sTBI patients and 695 without ICP monitoring sTBI patients. No significant difference between groups regarding patient demographics. All patients underwent a GOS assessment 6 months after surgery. Compared to the non-ICP monitoring group, a lower in-hospital mortality (20.3% vs 30.2%, P < 0.01) and better GOS scores after 6 months (3.3 ±â€Š1.6 vs 2.9 ±â€Š1.6, P < 0.05) with ICP monitoring. In addition, patients in the ICP monitoring group had a lower craniotomy rate (41.1% vs 50.9%, P < 0.01) and a lower DC rate (41.6% vs 55.9%, P < 0.05) than those in the non-ICP monitoring group. ICU length of stay (12.4 ±â€Š4.0 days vs 10.2 ±â€Š4.8 days, P < 0.01) was shorter in the non-ICP monitoring group, but it had no difference between 2 groups on total length of hospital stay (22.9 ±â€Š13.6 days vs 24.6 ±â€Š13.6 days, P = 0.108); Furthermore, the medical expenses were significantly higher in the non-ICP monitoring group than the ICP monitoring group (11.5 ±â€Š7.2 vs 13.3 ±â€Š9.1, P < 0.01). Intracranial pressure monitoring has beneficial effects for sTBI during the perioperative period. It can reduce the in-hospital mortality and DC rate and also can improve the 6-month outcomes. However, this was a single institution and observational study, well-designed, multicenter, randomized control trials are needed to evaluate the effects of ICP monitoring for perioperative sTBI patients.

[Optimization of SFE-CO2 Extraction for Ursolic Acid from Punica granatum Peel by Plackett-Burman and Central Composite Design].

OBJECTIVE: The optimum extraction of ursolic acid from Punica granatum peel by SFE-CO2 was investigated. METHODS: Based on the design of Plackett-Burman(PB), significant factors influencing the yield of ursolic acid in the operation process were filtered, with the extraction rate of ursolic acid as the index. The results obtained by steepest ascent method approximated the maximum area of ursolic acid yield. Then the Central Composite Design(CCD) design was used to carry on the response surface optimization of significant factors, getting a two order mathematical model affecting the ursolic acid yield, as well as the optimum process conditions. RESULTS: The best technological conditions of the extraction of ursolic acid from Punica granatum peel by SFE-CO2 were that the extraction temperature was 46. 29 °C, extraction time was 91. 6 min and the extraction pressure was 34. 49 MPa. Under the optimal conditions, verification test of ursolic acid yield was 12. 508 mg/g, approximating to the predicted value of 12. 645 mg/g. CONCLUSION: The PB test and CCD test design are combined to optimize the extraction process of ursolic acid from Punica granatum peel by SFE-CO2. The screening results are statistically significant and the process operation is feasible.

[Mass Transfer Kinetics Model of Ultrasonic Extraction of Pomegranate Peel Polyphenols].

OBJECTIVE: The dynamic mathematical model of ultrasonic extraction of polyphenols from pomegranate peel was constructed with the Fick's second law as the theoretical basis. METHODS: The spherical model was selected, with mass concentrations of pomegranate peel polyphenols as the index, 50% ethanol as the extraction solvent and ultrasonic extraction as the extraction method. In different test conditions including the liquid ratio, extraction temperature and extraction time, a series of kinetic parameters were solved, such as the extraction process (k), relative raffinate rate, surface diffusion coefficient(D(S)), half life (t½) and the apparent activation energy (E(a)). RESULTS: With the extraction temperature increasing, k and D(S) were gradually increased with t½ decreasing,which indicated that the elevated temperature was favorable to the extraction of pomegranate peel polyphenols. The exponential equation of relative raffinate rate showed that the established numerical dynamics model fitted the extraction of pomegranate peel polyphenols, and the relationship between the reaction conditions and pomegranate peel polyphenols concentration was well reflected by the model. CONCLUSION: Based on the experimental results, a feasible and reliable kinetic model for ultrasonic extraction of polyphenols from pomegranate peel is established, which can be used for the optimization control of engineering magnifying production.

Sirt3 protects cortical neurons against oxidative stress via regulating mitochondrial Ca2+ and mitochondrial biogenesis.

Oxidative stress is a well-established event in the pathology of several neurobiological diseases. Sirt3 is a nicotinamide adenine nucleotide (NAD+)-dependent protein deacetylase that regulates mitochondrial function and metabolism in response to caloric restriction and stress. This study aims to investigate the role of Sirt3 in H2O2 induced oxidative neuronal injury in primary cultured rat cortical neurons. We found that H2O2 treatment significantly increased the expression of Sirt3 in a time-dependent manner at both mRNA and protein levels. Knockdown of Sirt3 with a specific small interfering RNA (siRNA) exacerbated H2O2-induced neuronal injury, whereas overexpression of Sirt3 by lentivirus transfection inhibited H2O2-induced neuronal damage reduced the generation of reactive oxygen species (ROS), and increased the activities of endogenous antioxidant enzymes. In addition, the intra-mitochondrial Ca2+ overload, but not cytosolic Ca2+ increase after H2O2 treatment, was strongly attenuated after Sirt3 overexpression. Overexpression of Sirt3 also increased the content of mitochondrial DNA (mtDNA) and the expression of mitochondrial biogenesis related transcription factors. All these results suggest that Sirt3 acts as a prosurvival factor playing an essential role to protect cortical neurons under H2O2 induced oxidative stress, possibly through regulating mitochondrial Ca2+ homeostasis and mitochondrial biogenesis.

The mGluR5-mediated Arc activation protects against experimental traumatic brain injury in rats.

INTRODUCTION: Traumatic brain injury (TBI) is a complex pathophysiological process, and increasing attention has been paid to the important role of post-synaptic density (PSD) proteins, such as glutamate receptors. Our previous study showed that a PSD protein Arc/Arg3.1 (Arc) regulates endoplasmic reticulum (ER) stress and neuronal necroptosis in traumatic injury in vitro. AIM: In this study, we investigated the expression, regulation and biological function of Arc in both in vivo and in vitro experimental TBI models. RESULTS: Traumatic neuronal injury (TNI) induced a temporal upregulation of Arc in cortical neurons, while TBI resulted in sustained increase in Arc expression up to 24 h in rats. The increased expression of Arc was mediated by the activity of metabotropic glutamate receptor 5 (mGluR5), but not dependent on the intracellular calcium (Ca2+) release. By using inhibitors and antagonists, we found that TNI regulates Arc expression via Gq protein and protein turnover. In addition, overexpression of Arc protects against TBI-induced neuronal injury and motor dysfunction both in vivo and in vitro, whereas the long-term cognitive function was not altered. To determine the role of Arc in mGluR5-induced protection, lentivirus-mediated short hairpin RNA (shRNA) transfection was performed to knockdown Arc expression. The mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG)-induced protection against TBI was partially prevented by Arc knockdown. Furthermore, the CHPG-induced attenuation of Ca2+ influx after TNI was dependent on Arc activation and followed regulation of AMPAR subunits. The results of Co-IP and Ca2+ imaging showed that the Arc-Homer1 interaction contributes to the CHPG-induced regulation of intracellular Ca2+ release. CONCLUSION: In summary, the present data indicate that the mGluR5-mediated Arc activation is a protective mechanism that attenuates neurotoxicity following TBI through the regulation of intracellular Ca2+ hemostasis. The AMPAR-associated Ca2+ influx and ER Ca2+ release induced by Homer1-IP3R pathway might be involved in this protection.

Ablation of Shank1 Protects against 6-OHDA-induced Cytotoxicity via PRDX3-mediated Inhibition of ER Stress in SN4741 Cells.

BACKGROUND: Postsynaptic density (PSD) is an electron-dense structure that contains various scaffolding and signaling proteins. Shank1 is a master regulator of the synaptic scaffold located at glutamatergic synapses, and has been proposed to be involved in multiple neurological disorders. METHODS: In this study, we investigated the role of shank1 in an in vitro Parkinson's disease (PD) model mimicked by 6-OHDA treatment in neuronal SN4741 cells. The expression of related molecules was detected by western blot and immunostaining. RESULTS: We found that 6-OHDA significantly increased the mRNA and protein levels of shank1 in SN4741 cells, but the subcellular distribution was not altered. Knockdown of shank1 via small interfering RNA (siRNA) protected against 6-OHDA treatment, as evidenced by reduced lactate dehydrogenase (LDH) release and decreased apoptosis. The results of RT-PCR and western blot showed that knockdown of shank1 markedly inhibited the activation of endoplasmic reticulum (ER) stress associated factors after 6-OHDA exposure. In addition, the downregulation of shank1 obviously increased the expression of PRDX3, which was accompanied by the preservation of mitochondrial function. Mechanically, downregulation of PRDX3 via siRNA partially prevented the shank1 knockdowninduced protection against 6-OHDA in SN4741 cells. CONCLUSION: In summary, the present study has provided the first evidence that the knockdown of shank1 protects against 6-OHDA-induced ER stress and mitochondrial dysfunction through activating the PRDX3 pathway.

Rosiglitazone regulates astrocyte polarization and neuroinflammation in a PPAR-γ dependent manner after experimental traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of high mortality and disability worldwide. Overactivation of astrocytes and overexpression of inflammatory responses in the injured brain are characteristic pathological features of TBI. Rosiglitazone (ROS) is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist known for its anti-inflammatory activity. However, the relationship between the inflammatory response involved in ROS treatment and astrocyte A1 polarization remains unclear. OBJECTIVE: This study aimed to investigate whether ROS treatment improves dysfunction and astrocyte A1 polarization induced after TBI and to elucidate the underlying mechanisms of these functions. METHODS: SD rats were randomly divided into sham operation group, TBI group, TBI+ROS group, and TBI+ PPAR-γ antagonist group (GW9662 + TBI). The rat TBI injury model was prepared by the CCI method; brain water content test and wire grip test scores suggested the prognosis; FJB staining showed the changes of ROS on the morphology and number of neurons in the peripheral area of cortical injury; ELISA, immunofluorescence staining, and western blotting analysis revealed the effects of ROS on inflammatory response and astrocyte activation with the degree of A1 polarization after TBI. RESULTS: Brain water content, inflammatory factor expression, and astrocyte activation in the TBI group were higher than those in the sham-operated group (P < 0.05); compared with the TBI group, the expression of the above indexes in the ROS group was significantly lower (P < 0.05). Compared with the TBI group, PPAR-γ content was significantly higher and C3 content was considerably lower in the ROS group (P < 0.05); compared with the TBI group, PPAR-γ content was significantly lower and C3 content was substantially higher in the inhibitor group (P < 0.05). CONCLUSION: ROS can exert neuroprotective effects by inhibiting astrocyte A1 polarization through the PPAR-γ pathway based on the reduction of inflammatory factors and astrocyte activation in the brain after TBI.

Arc regulates brain damage and neuroinflammation via Sirt1 signaling following subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) accounts for only 5 % of all stroke cases, but carries a heavy burden of morbidity and mortality. Activity regulated cytoskeleton associated protein (Arc) is an immediate early gene (IEG)-coded postsynaptic protein that is involved in synaptic plasticity. Increasing evidence and our previous studies have shown that Arc might be involved in the pathological mechanism of various neurological diseases, such as traumatic brain injury (TBI). In this study, we investigated the level of Arc in cerebrospinal fluids (CSF) of aSAH patients and its potential role in brain damage following experimental SAH model. We found that the levels of Arc in aSAH patients' CSF positively correlated with Hunt-Hess (H&H) grades. Knockdown of endogenous Arc expression by small interfere RNA (siRNA) significantly increased brain edema and oxidative stress following SAH. The results of immunostaining in brain sections showed that knockdown of Arc enhanced activation of microglia and astrocytes. In congruent, generation of inflammatory cytokines following SAH was increased by Si-Arc transfection. The results of western blot analysis showed that knockdown of Arc inhibited the expression of Sirt1 and Nrf2, which was accompanied by decreased enzymatic activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px). In addition, activation of sirtuin 1 (Sirt1) via agonist SRT2104 markedly decreased the brain damage and neuroinflammation induced by Arc knockdown. In conclusion, knockdown of endogenous Arc could aggravate brain damage and neuroinflammation following experimental SAH, and Arc levels in aSAH patients' CSF might be a potential indicator of brain damage and prognosis.

Effects of ulinastatin therapy in deep vein thrombosis prevention after brain tumor surgery: A single-center randomized controlled trial.

BACKGROUND: Venous thromboembolism (VTE) is a common neurosurgical complication after brain tumor resection, and its prophylaxis has been widely studied. There are no effective drugs in the clinical management of venous thromboembolism, and there is an absence of evidence-based medicine concerning the treatment of severe multiple traumas. AIM: To explore whether ulinastatin (UTI) can prevent VTE after brain tumor resection. METHODS: The present research included patients who underwent brain tumor resection. Patients received UTIs (400,000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were the incidence of VTE, coagulation function, pulmonary emboli, liver function, renal function, and drug-related adverse effects. RESULTS: A total of 405 patients were evaluated between January 2019 and December 2021, and 361 of these were initially enrolled in the study to form intention-to-treat, which was given UTI (n = 180) or placebo (n = 181) treatment in a random manner. There were no statistically significant differences in baseline clinical data between the two groups. The incidence of VTE in the UTI group was remarkably improved compared with that in the placebo group. UTI can improve coagulation dysfunction, pulmonary emboli, liver function, and renal function. No significant difference was identified between the two groups in the side effects of UTI-induced diarrhea, vomiting, hospital stays, or hospitalization costs. The incidence of allergies was higher in the UTI group than in the placebo group. CONCLUSION: The findings from the present research indicated that UTI can decrease the incidence of VTE and clinical outcomes of patients after brain tumor resection and has fewer adverse reactions.

Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice.

The mitochondrial permeability transition pore is a nonspecific transmembrane channel. Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling, calcium overload, and axonal degeneration. Cyclophilin D is an important component of the mitochondrial permeability transition pore. Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear. In this study, we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice, in which pyramidal neurons and axons express yellow fluorescent protein. We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin. We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening. We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage. We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury. In addition, inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage. Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage; inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage. Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.

Endoscopy-assisted cerebral falx incision via unilateral approach for treatment of dissymmetric bilateral frontal contusion.

OBJECTIVE: To investigate the clinical features and treatment strategy of dissymmetric bilateral frontal contusion, and to summarize our experience in treating these patients by minimally invasive surgery. METHODS: Over the past 3 years, we have treated a total of 31 patients with dissymmetric bilateral frontal contusion using endoscopy-assisted unilateral cerebral falx incision. Other 30 patients treated by routine bilateral approaches within the same period were taken as control. RESULTS: Seventeen cases (54.8%) in the unilateral operation group survived and were in good condition, 8 (25.8%) had moderate disability, 4 (12.9%) had severe disability, 1 (3.2%) was in vegetative state, and 1 (3.2%) died. Compared with the control group, the Glasgow Outcome Scale score was not significantly different in the unilateral operation group, but the operation time, blood transfusion volume, the length of hospital stay, the incidences of mental disorder and olfactory nerve injury were greatly reduced in the unilateral operation group. CONCLUSIONS: Endoscopy-assisted unilateral cerebral falx incision can shorten the operation time, reduce surgical trauma and complications in treatment of patients with dissymmetric bilateral frontal contusion. It can obviously diminish the chance of delayed intracerebral hematoma and subsequently minimize the incidences of subfalcial and centrencephalic herniation.

The Mfn1-ßIIPKC Interaction Regulates Mitochondrial Dysfunction via Sirt3 Following Experimental Subarachnoid Hemorrhage.

Neuronal injury following subarachnoid hemorrhage (SAH) has been shown to be associated with mitochondrial dysfunction and oxidative stress. ßIIPKC, a subtype of protein kinase C (PKC), accumulates on the mitochondrial outer membrane and phosphorylates mitofusin 1 (Mfn1) at serine 86. Here, we investigated the role of Mfn1-ßIIPKC interaction in brain damage and neurological function in both in vivo and in vitro experimental SAH models. The expression of ßIIPKC protein and the interaction of Mfn1-ßIIPKC were found to be increased after OxyHb treatment in primary cultured cortical neurons and were also observed in the brain following SAH in rats. Treatment with the ßIIPKC inhibitor ßIIV5-3 or SAMßA, a peptide that selectively antagonizes Mfn1-ßIIPKC association, significantly attenuated the OxyHb-induced neuronal injury and apoptosis. These protective effects were accompanied by inhibited mitochondrial dysfunction and preserved mitochondrial biogenesis. The results of western blot showed that ßIIV5-3 or SAMßA markedly increased the expression of Sirt3 and enhanced the activities of its downstream mitochondrial antioxidant enzymes in OxyHb-treated neurons. Knockdown of Sirt3 via specific targeted small interfering RNA (siRNA) partially prevented the ßIIV5-3- or SAMßA-induced protection and antioxidative effects. In addition, treatment with ßIIV5-3 or SAMßA in vivo was found to obviously reduce brain edema, alleviate neuroinflammation, and preserve neurological function after experimental SAH in rats. In congruent with in vitro data, the protection induced by ßIIV5-3 or SAMßA was reduced by Sirt3 knockdown in vivo. In summary, our present results showed that blocking Mfn1-ßIIPKC interaction protects against brain damage and mitochondrial dysfunction via Sirt3 following experimental SAH.

Microglial polarization in TBI: Signaling pathways and influencing pharmaceuticals.

Traumatic brain injury (TBI) is a serious disease that threatens life and health of people. It poses a great economic burden on the healthcare system. Thus, seeking effective therapy to cure a patient with TBI is a matter of great urgency. Microglia are macrophages in the central nervous system (CNS) and play an important role in neuroinflammation. When TBI occurs, the human body environment changes dramatically and microglia polarize to one of two different phenotypes: M1 and M2. M1 microglia play a role in promoting the development of inflammation, while M2 microglia play a role in inhibiting inflammation. How to regulate the polarization direction of microglia is of great significance for the treatment of patients with TBI. The polarization of microglia involves many cellular signal transduction pathways, such as the TLR-4/NF-κB, JAK/STAT, HMGB1, MAPK, and PPAR-γ pathways. These provide a theoretical basis for us to seek therapeutic drugs for the patient with TBI. There are several drugs that target these pathways, including fingolimod, minocycline, Tak-242 and erythropoietin (EPO), and CSF-1. In this study, we will review signaling pathways involved in microglial polarization and medications that influence this process.

Edonerpic maleate regulates glutamate receptors through CRMP2- and Arc-mediated mechanisms in response to brain trauma.

Dysfunction of ionotropic glutamate receptors (iGluRs) is a key molecular mechanism of excitotoxic neuronal injury following traumatic brain injury (TBI). Edonerpic maleate is a low molecular-weight compound that was screened as a candidate neuroprotective agent. In this study, we investigated its effects on TBI and GluRs signaling. Traumatic neuronal injury (TNI) induced by scratch followed by glutamate treatment was performed to mimic TBI in vitro. Edonerpic maleate at 1 and 10 µM exerted protective activity when it was added within 2 h following injury. The protective activities were also confirmed by the reduction of lipid peroxidation and oxidative stress. In addition, edonerpic maleate inhibited the expression of surface NR2B, total GluR1, and surface GluR1, and mitigated the intracellular Ca2+ responses following injury in vitro. Western blot analysis showed that edonerpic maleate reduced the cleavage of collapsing response mediator protein 2 (CRMP2), but increased the expression of postsynaptic protein Arc. By using gene overexpression and silencing technologies, CRMP2 was overexpressed and Arc was knockdown in cortical neurons. The results showed that the effect of edonerpic maleate on NMDA receptor expression was mediated by CRMP2, whereas the edonerpic maleate-induced AMPA receptor regulation was dependent on Arc activation. In in vivo TBI model, 30 mg/kg edonerpic maleate alleviated the TBI-induced brain edema, neuronal loss, and microglial activation, with no effect on locomotor function at 24 h. However, edonerpic maleate improves long-term neurological function after TBI. Furthermore, edonerpic maleate inhibited CRMP2 cleavage but increased Arc activation in vivo. In summary, our results identify edonerpic maleate as a clinically potent small compound with which to attenuate TBI-related brain damage through regulating GluRs signaling.

Whole Body Vibration Attenuates Brain Damage and Neuroinflammation Following Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) is still a major public health problem worldwide, and the research of neuroprotective drugs has encountered great difficulties. Whole body vibration (WBV) is a safe and powerful rehabilitative intervention in various clinical settings, but its effect on neurological diseases is not well documented. In this study, we investigated the effects of WBV pretreatment on brain damage following experimental TBI mimicked by controlled cortical impact (CCI) in mice. C57BL/6 J male mice were expose to WBV at 30 Hz twice per day for 20 days and injured by CCI. WBV had no effect on animal body weight, but significantly reduced the TBI-induced brain edema in the cortex. The results of immunostaining showed that the activation of microglia and astrocytes induced by TBI in brain sections was attenuated by WBV. In consistent, WBV markedly inhibited the expression of pro-inflammatory cytokines, while increased the levels of anti-inflammatory cytokine interleukin 10 (IL-10). In addition, WBV pretreatment alleviated neuronal apoptosis in the cortex and suppressed the cleavage of the apoptotic executive molecule caspase-1. The neurological dysfunction following TBI was determined by open field test and Morris Water Maze (MWM) assay. The results showed that motor activity, learning and memory ability were preserved by WBV compared to TBI-injured mice. In summary, our present data identified WBV as a clinically potent strategy with which to attenuate TBI-related brain damage through regulating neuroinflammation.