ABSTRACT
BACKGROUND: The use of mechanical thrombectomy for acute intracranial vascular occlusion under general anesthesia with endotracheal intubation is well-established as a safe and effective method. However, the process of extubation post-surgery presents challenges for certain patients. This retrospective study assesses the safety and efficacy of combining mechanical ventilation with high-flow oxygen inhalation as an interim strategy, while also examining its impact on long-term clinical outcomes. METHODS: This research enrolled 119 patients with acute intracranial large vessel occlusion who underwent mechanical thrombectomy under general anesthesia with tracheal intubation between January 2020 and November 2023. Participants were categorized into two groups: Group 1 (n=55), which received high-flow oxygen (HFO) post-extubation, and Group 2 (n=64), which was treated with routine oxygen supplementation (RO). The study compared reintubation and tracheotomy rates between these groups to determine safety and effectiveness. Additionally, it analyzed long-term clinical outcomes by comparing NIHSS and mRS scores before treatment and at 90-day follow-up. RESULTS: The reintubation rate post-extubation was significantly lower in the HFO group (12.7â¯%, n=7) compared to the RO group (31.2â¯%, n=20, p=0.016). The incidence of tracheotomy within 7 days was also reduced in the HFO group compared to the RO group (7.3â¯%, n=4 vs 20.3â¯%, n=13, p=0.043). Moreover, a greater proportion of patients in the HFO group achieved mRS scores of 0-2 at 90 days post-stroke than those in the RO group (60â¯%, n=33 vs 40.6â¯%, n=26, p=0.035). The median NIHSS score at 90 days was more favorable in the HFO group than in the RO group (6, IQR [1-18] vs 8, IQR [1-20], p=0.005). CONCLUSION: The study suggests that high-flow oxygen therapy after mechanical thrombectomy under general anesthesia with tracheal intubation may lessen the need for reintubation and tracheotomy, potentially leading to improved long-term prognosis.
Subject(s)
Anesthesia, General , Ischemic Stroke , Thrombectomy , Humans , Male , Female , Retrospective Studies , Anesthesia, General/methods , Middle Aged , Aged , Ischemic Stroke/surgery , Ischemic Stroke/therapy , Thrombectomy/methods , Oxygen Inhalation Therapy/methods , Treatment Outcome , Intubation, Intratracheal/methodsABSTRACT
Objective: The aim of this study was to examine the factors influencing the prognosis of patients diagnosed with acute basilar artery occlusion (BAO) who receive endovascular treatment. Our particular emphasis was on the predictive implications of the time window for treatment (from symptom onset to femoral artery puncture) and preoperative symptoms for prognosis. Methods: A retrospective analysis of data collected from 51 BAO patients who received endovascular treatment at the Neurosurgery Department of Jinhua Central Hospital from April 2018 to October 2021 was undertaken. The data included immediate post-interventional recanalization rates and the 90-day clinical prognoses of the patients. We used the Modified Rankin Scale (mRs) to categorize patients into two prognosis groups: a favorable prognosis group (mRs score ≤2) and an unfavorable prognosis group (mRs score >2). Preoperative symptoms were gauged using the Glasgow Coma Scale (GCS) and National Institutes of Health Stroke Scale (NIHSS) scores. A logistic regression analysis was conducted to identify risk factors affecting the prognosis of BAO patients following endovascular treatment. Results: The procedure resulted in complete recanalization in all patients (100%). However, four patients (7.8%) passed away during the postoperative hospitalization period. The remaining 47 patients were followed up for 3 months. It was found that 15 patients (31.91%) had a favorable prognosis, while 32 (68.09%) had an unfavorable prognosis. It was generally observed that patients with an unfavorable prognosis had notably higher preoperative GCS and NIHSS scores (p < 0.05). Logistic regression analysis revealed that preoperative symptom severity, as indicated by NIHSS score, and treatment time window were significant prognostic risk factors for patients undergoing endovascular treatment for BAO (p < 0.05). Conclusion: Endovascular intervention for BAO appears to be safe and effective, with greater likelihood of a favorable prognosis in patients treated within ≤6 h. The chances of favorable prognosis could potentially be linked to the severity of the patient's preoperative symptoms.
ABSTRACT
Background: Resolvin D1 (RvD1) possesses anti-inflammatory properties and may be neuroprotective. This study was designed to ascertain the potential role of serum RvD1 in the evaluation of aSAH severity and prognosis of human aneurysmal subarachnoid hemorrhage (aSAH). Methods: In this prospective observational study, serum RvD1 levels were measured in 123 patients with aSAH and in 123 healthy volunteers. Six-month neurological function was assessed using extended Glasgow outcome scale (GOSE). A prognostic prediction model was appraised using a series of evaluative tools, such as a nomogram, receiver operating characteristic (ROC) curve, decision curve, calibration curve, restricted cubic spline, and Hosmer-Lemeshow goodness of fit statistics. Results: Serum RvD1 levels were markedly lower in patients than in controls (median, 0.54 versus 1.47 ng/mL; P<0.001). Serum RvD1 levels were independently correlated with Hunt-Hess scores (beta, -0.154; 95% confidence interval [CI], -0.198--0.109; VIF, 1.769; P=0.001), modified Fisher scores (beta, -0.066; 95% CI, -0.125--0.006; VIF, 1.567; P=0.031) and 6-month GOSE scores (beta, 1.864; 95% CI, 0.759-2.970; VIF, 1.911; P=0.001) and were independently predictive of a poor prognosis (GOSE scores of 1-4) (odds ratio, 0.137; 95% CI, 0.023-0.817; P=0.029). Serum RvD1 levels significantly distinguished the risk of a worse prognosis, with an area under the ROC curve of 0.750 (95% CI, 0.664-0.824). Using the Youden method, serum RvD1 levels < 0.6 ng/mL was effective in predicting worse prognosis with 84.1% sensitivity and 62.0% specificity. Moreover, the model containing serum RvD1 levels, Hunt-Hess scores and modified Fisher scores was efficient, reliable and beneficial in prognostic prediction using a series of the afore-mentioned evaluative tools. Conclusion: A decline in serum RvD1 levels following aSAH is closely correlated with illness severity and independently predicts a worse outcome in patients with aSAH, implying that serum RvD1, as a prognostic biomarker of aSAH, may be of clinical value in aSAH.
ABSTRACT
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.
ABSTRACT
The avian EB66® cell line, derived from duck embryonic stem cells, has been widely used for producing human and animal therapeutic proteins and vaccines. In current study we evaluated the potential use of EB66® cell line in a cell culture-derived duck Tembusu virus (DTMUV) vaccine development. After optimizing the growth conditions of DTMUV HB strain in EB66® cells, we successfully generated three batches of viruses with ELD50 titres of 105.9/0.1â ml, 105.3/0.1â ml and 105.5/0.1â ml, respectively, for using in the preparation of inactivated vaccines. The immunogenicity and protective efficacy of these EB66® cells-derived inactivated vaccines were examined in ducks. Results indicated that all three batches of vaccines induced haemagglutination-inhibition (HI) antibody response in immunized birds at 2 weeks after a single immunization. Immunized ducks and ducklings were protected against a virulent challenge at 4 weeks after a booster immunization. The duration of immunity was for 3-4 months after a booster immunization. These results demonstrated the feasibility of using EB66® cell line to grow up DTMUV for vaccine preparation. RESEARCH HIGHLIGHTS Duck Tembusu virus can be propagated in EB66® cells. EB66® cell-derived inactivated DTMUV vaccines are immunogenic and can provide protection against a virulent challenge. A long-lasting immunity is induced after a booster immunization.
Subject(s)
Antibodies, Viral/immunology , Ducks/virology , Flavivirus Infections/veterinary , Flavivirus/immunology , Poultry Diseases/prevention & control , Viral Vaccines/immunology , Animals , Cell Line , Female , Flavivirus/pathogenicity , Flavivirus Infections/prevention & control , Flavivirus Infections/virology , Hemagglutination Inhibition Tests/veterinary , Immunization/veterinary , Immunogenicity, Vaccine , Male , Poultry Diseases/virology , Vaccines, Inactivated/immunology , VirulenceABSTRACT
This study aims to identify predictive factors related to clinical outcome, reoperation, and complications in patients with brain abscess.Patients with a diagnosis of brain abscess at discharge at the Second Affiliated Hospital of Zhejiang University School of Medicine between 2008 and 2018 were reviewed. Logistic regression was used to identify predictive factors associated with Glasgow Outcome Scale (GOS) at discharge, GOS at 1 year after discharge, reoperation and complications.Among 183 patients enrolled into the study, 142 patients had a good outcome at discharge (GOS ≥ 4) and 41 had a poor outcome (GOS ≤ 3). During the follow-up period, 20 additional patients had a good outcome. A total of 156 patients were treated by open craniotomy excision (nâ=â72) and aspiration (nâ=â84), 10 of whom underwent reoperation. Complications in surgical patients for brain abscess occurred in 54 patients. Poor outcome was related to Glasgow coma scale (Pâ=â.007) and ventricular proximity (Pâ=â.001). Surgical method was associated with reoperation (Pâ=â.04) and complications (Pâ<â.001). Seizure at admission was related to epilepsy (Pâ<â.001). Surgical method was related to postoperative intracranial hemorrhage (Pâ=â.02).Glasgow coma scale (GCS) and ventricular proximity were associated with poor outcome. Further, patients who underwent aspiration were more likely to experience reoperation, while open craniotomy excision (OCE) was related to complications. Patients presenting seizure at admission were more likely to develop epilepsy. Patients who underwent OCE tended to experience postoperative intracranial hemorrhage.
Subject(s)
Brain Abscess/surgery , Glasgow Outcome Scale , Intracranial Hemorrhages/etiology , Postoperative Complications/etiology , Reoperation/statistics & numerical data , Adolescent , Adult , Aged , Aged, 80 and over , Brain Abscess/pathology , Child , Child, Preschool , Craniotomy/adverse effects , Craniotomy/methods , Female , Glasgow Coma Scale , Humans , Male , Middle Aged , Retrospective Studies , Risk Factors , Treatment Outcome , Young AdultABSTRACT
Despite the substantial efforts to elucidate the role of early brain injury in subarachnoid hemorrhage (SAH), an effective pharmaceutical therapy for patients with SAH continues to be unavailable. This study aims to reveal the role of necroptosis after SAH, and explore whether the disruption of the blood-brain barrier (BBB) and RIP3-mediated necroptosis following SAH in a rat SAH model are altered by necrostatin-1 via its selective inhibition of receptor-interacting protein kinase 1 (RIP1). Sixty-five rats were used in the experiments. The SAH model was established using endovascular perforation. Necrostatin-1 was intracerebroventricularly injected 1 h before SAH induction. The neuroprotective effects of necrostatin-1 were evaluated with multiple methods such as magnetic resonance imaging (MRI) scanning, immunohistochemistry, propidium iodide (PI) labeling, and western blotting. Pretreatment with necrostatin-1 attenuated brain swelling and reduced the lesion volume on T2 sequence and ventricular volume on MRI 72 h after SAH induction. Albumin leakage and the degradation of tight junction proteins were also ameliorated by necrostatin-1 administration. In addition, necrostatin-1 decreased the number of PI-positive cells in the basal cortex, reduced the levels of the RIP3 and MLKL proteins, and inhibited the production of the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α. Based on the findings from the present study, the selective RIP1 inhibitor necrostatin-1 functioned as a neuroprotective agent after SAH by attenuating brain swelling and BBB disruption. Moreover, the necrostatin-1 pretreatment prevented SAH-induced necroptosis by suppressing the activity of the RIP3/MLKL signaling pathway. These results will provide insights into new drugs and pharmacological targets to manage SAH, which are worth further study.
Subject(s)
Blood-Brain Barrier/metabolism , Brain/drug effects , Imidazoles/therapeutic use , Indoles/therapeutic use , Necroptosis/drug effects , Neuroprotective Agents/therapeutic use , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Subarachnoid Hemorrhage/drug therapy , Animals , Brain/cytology , Brain/diagnostic imaging , Brain/pathology , Brain Edema/drug therapy , Cytokines/metabolism , Magnetic Resonance Imaging , Matrix Metalloproteinase 9/metabolism , Necroptosis/genetics , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Rats , Rats, Sprague-Dawley , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Subarachnoid Hemorrhage/metabolism , Subarachnoid Hemorrhage/mortality , Subarachnoid Hemorrhage/pathology , Tight Junctions/drug effects , Tight Junctions/pathologyABSTRACT
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.
Subject(s)
Blood-Brain Barrier , Brain Injuries/prevention & control , Nerve Growth Factors/physiology , Proto-Oncogene Proteins c-akt/metabolism , Subarachnoid Hemorrhage/complications , Animals , Brain Injuries/etiology , Brain Injuries/pathology , Brain Injuries/physiopathology , Cell Line, Tumor , Humans , Male , Rats , Rats, Sprague-Dawley , Subcellular Fractions/pathologyABSTRACT
Studies have suggested that blood-brain barrier (BBB) disruption contributes to the pathogenesis of early brain injury after subarachnoid haemorrhage (SAH). Activation of the receptor tyrosine kinase ErbB4 can cause intramembrane proteolysis and release a soluble intracellular domain (ICD) that modulates transcription in the nucleus. This study was carried out to investigate the potential roles of ErbB4 in preserving BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective effects. Endovascular perforation was used to prepare a rat SAH model. The SAH grade, neurological score, brain edema and BBB permeability were evaluated after surgery. Immunohistochemistry was used to determine the localization of ErbB4 and yes-associated protein (YAP). ErbB4 activator Nrg1 isoform ß1 (Nrg1ß1), Specific ErbB4 siRNA, YAP siRNA and PIK3CB specific inhibitor TGX 221 were used to manipulate the proposed pathway. The expression levels of ErbB4 ICD and YAP were markly increased after SAH. Double immunohistochemistry labeling showed that ErbB4 and YAP were expressed in endothelial cells and neurons. Activation of ErbB4 by Nrg1ß1 (dosage 150 ng/kg) treatment promoted the neurobehavioral deficit, alleviated the brain water content and reduced albumin leakage 24 and 72 h after SAH. ErbB4 activation significantly promoted YAP and PIK3CB activity and increased the expression of tight junction proteins Occludin and Claudin-5. Depletion of ErbB4 aggravated neurological impairment and BBB disruption after SAH. The beneficial effects of ErbB4 activation were abolished by YAP small-interfering RNA and specific PIK3CB inhibitor. Activation of ErbB4 improved neurological performance after SAH through the YAP/PIK3CB signaling pathway, this neuroprotective effects may associated with BBB maintenance.
ABSTRACT
Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease with few effective pharmacotherapies available. Salvia miltiorrhiza, a traditional Chinese medicinal herb, has been widely used to treat cardiovascular diseases for centuries. Recent studies have demonstrated that magnesium lithospermate B (MLB), a bioactive ingredient extracted from Salvia miltiorrhiza, exerts neuroprotective effects in several central nervous system insults. However, little is known about the role of MLB in SAH-induced brain injury and the exact molecular mechanism. In the current study, we studied the neuroprotective effects of MLB in SAH and explored the potential mechanism. Adult male Sprague-Dawley rats were subjected to an endovascular perforation process to produce an SAH model. MLB was administrated intraperitoneally at 30[Formula: see text]min after SAH with a dose of 25[Formula: see text]mg/kg or 50[Formula: see text]mg/kg. We found that administration of MLB significantly attenuated brain edema and neurological deficits after SAH. In addition, immunofluorescence staining demonstrated that MLB dose-dependently inhibited the activation of microglia and reduced neuronal apoptosis. Western blot analysis showed that MLB decreased the expression of inflammatory cytokine TNF-[Formula: see text] and pro-apoptotic protein cleaved caspase-3. More importantly, MLB increased the expression of SIRT1, while inhibited the acetylation of NF-[Formula: see text]B. Furthermore, pretreatment with sirtinol (a selective inhibitor of SIRT1) reversed all the aforementioned effects of MLB after SAH. In conclusion, our results indicated that MLB exerted robust neuroprotective effects against SAH via suppressing neuroinflammation and apoptosis. These neuroprotective effects of MLB against SAH might be exerted via regulating the SIRT1/NF-[Formula: see text]B pathway. MLB or the SIRT1/NF-[Formula: see text]B pathway could be a novel and promising therapeutic strategy for SAH management.
Subject(s)
Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/pharmacology , Neuroprotective Agents , Phytotherapy , Subarachnoid Hemorrhage/drug therapy , Animals , Apoptosis , Disease Models, Animal , Dose-Response Relationship, Drug , Drugs, Chinese Herbal/isolation & purification , Inflammation Mediators/metabolism , Infusions, Parenteral , Male , Microglia/pathology , NF-kappa B/metabolism , Neurons/pathology , Rats, Sprague-Dawley , Salvia miltiorrhiza/chemistry , Signal Transduction/drug effects , Sirtuin 1/metabolism , Subarachnoid Hemorrhage/genetics , Subarachnoid Hemorrhage/pathology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Phosphodiesterase-4 (PDE4) plays a fundamental role in a range of central nervous system (CNS) insults, however, the role of PDE4 in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The current study was designed to investigate the role of PDE4 in EBI after SAH and explore the potential mechanism. The SAH model in Sprague-Dawley rat was established by endovascular perforation process. Rats were randomly divided into: sham group, SAH?+?vehicle group, SAH?+?rolipram (PDE4 inhibitor) group, SAH?+?rolipram?+?sirtinol (SIRT1 inhibitor) group and SAH?+?rolipram+MK2206 (Akt inhibitor) group. Mortality, SAH grades, neurological function, brain edema, immunofluorescence staining and western blotting were performed. Double fluorescence labeling staining indicated that PDE4 was located predominately in neurons after SAH. Rolipram reduced brain edema, improved neurological function in the rat model of SAH. Moreover, rolipram increased the expression of Sirtuin1 (SIRT1) and up-regulated the phosphorylation of Akt, which was accompanied by the reduction of neuronal apoptosis. Administration of sirtinol inhibited the phosphorylation of Akt. Moreover, all the beneficial effects of rolipram against SAH were abolished by both sirtinol and MK2206. These data indicated that PDE4 inhibition by rolipram protected rats against EBI after SAH via suppressing neuronal apoptosis through the SIRT1/Akt pathway. Rolipram might be an important therapeutic drug for SAH.
Subject(s)
Neuroprotective Agents/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Rolipram/pharmacology , Subarachnoid Hemorrhage/drug therapy , Animals , Apoptosis/drug effects , Benzamides/administration & dosage , Benzamides/pharmacology , Brain Edema/prevention & control , Brain Injuries/prevention & control , Cyclic Nucleotide Phosphodiesterases, Type 4/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/pharmacology , Male , Naphthols/administration & dosage , Naphthols/pharmacology , Neuroprotective Agents/administration & dosage , Phosphodiesterase 4 Inhibitors/administration & dosage , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Rolipram/administration & dosage , Sirtuin 1/metabolism , Subarachnoid Hemorrhage/pathologyABSTRACT
Early brain injury (EBI) is the primary cause of poor outcome in subarachnoid hemorrhage (SAH) patients. Rolipram, a specific phosphodiesterase-4 inhibitor which is traditionally used as an anti-depressant drug, has been recently proven to exert neuroprotective effects in several central nervous system insults. However, the role of rolipram in SAH remains uncertain. The current study was aimed to investigate the role of rolipram in EBI after SAH and explore the potential mechanism. Adult male Sprague-Dawley rats were subjected to an endovascular perforation process to produce an SAH model. Rolipram was injected intraperitoneally at 2 h after SAH with a dose of 10 mg/kg. We found that rolipram significantly ameliorated brain edema and alleviated neurological dysfunction after SAH. Rolipram treatment remarkably promoted the expression of Sirtuin 1 (SIRT1) while inhibited NF-κB activation. Moreover, rolipram significantly inhibited the activation of microglia as well as down-regulated the expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6. In addition, rolipram increased the expression of protective cytokine IL-10. Furthermore, rolipram significantly alleviated neuronal death after SAH. In conclusion, these data suggested that rolipram exerts neuroprotective effects against EBI after SAH via suppressing neuroinflammation and reducing neuronal loss. The neuroprotective effects of rolipram were associated with regulating the SIRT1/NF-κB pathway. Rolipram could be a novel and promising therapeutic agent for SAH treatment.
Subject(s)
Brain Injuries/prevention & control , NF-kappa B/antagonists & inhibitors , Rolipram/administration & dosage , Sirtuin 1/biosynthesis , Subarachnoid Hemorrhage/drug therapy , Animals , Brain Injuries/metabolism , Brain Injuries/pathology , Injections, Intraperitoneal , Male , NF-kappa B/metabolism , Neuroprotective Agents/administration & dosage , Phosphodiesterase 4 Inhibitors/administration & dosage , Random Allocation , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Signal Transduction/physiology , Subarachnoid Hemorrhage/metabolism , Subarachnoid Hemorrhage/pathologyABSTRACT
Aberrant modulation of mitochondrial dynamic network, which shifts the balance of fusion and fission towards fission, is involved in brain damage of various neurodegenerative diseases including Parkinson's disease, Huntington's disease and Alzheimer's disease. A recent research has shown that the inhibition of mitochondrial fission alleviates early brain injury after experimental subarachnoid hemorrhage, however, the underlying molecular mechanisms have remained to be elucidated. This study was undertaken to characterize the effects of the inhibition of dynamin-related protein-1 (Drp1, a dominator of mitochondrial fission) on blood-brain barrier (BBB) disruption and neuronal apoptosis following SAH and the potential mechanisms. The endovascular perforation model of SAH was performed in adult male Sprague Dawley rats. The results indicated Mdivi-1(a selective Drp1 inhibitor) reversed the morphologic changes of mitochondria and Drp1 translocation, reduced ROS levels, ameliorated the BBB disruption and brain edema remarkably, decreased the expression of MMP-9 and prevented degradation of tight junction proteins-occludin, claudin-5 and ZO-1. Mdivi-1 administration also inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB), leading to decreased expressions of TNF-É, IL-6 and IL-1ß. Moreover, Mdivi-1 treatment attenuated neuronal cell death and improved neurological outcome. To investigate the underlying mechanisms further, we determined that Mdivi-1 reduced p-PERK, p-eIF2α, CHOP, cleaved caspase-3 and Bax expression as well as increased Bcl-2 expression. Rotenone (a selective inhibitor of mitochondrial complexes I) abolished both the anti-BBB disruption and anti-apoptosis effects of Mdivi-1. In conclusion, these data implied that excessive mitochondrial fission might inhibit mitochondrial complex I to become a cause of oxidative stress in SAH, and the inhibition of Drp1 by Mdivi-1 attenuated early brain injury after SAH probably via the suppression of inflammation-related blood-brain barrier disruption and endoplasmic reticulum stress-based apoptosis.
Subject(s)
Blood-Brain Barrier/drug effects , Dynamins/genetics , Mitochondria/drug effects , Mitochondrial Dynamics/drug effects , Quinazolinones/pharmacology , Subarachnoid Hemorrhage/drug therapy , Animals , Apoptosis/drug effects , Blood-Brain Barrier/metabolism , Claudin-5/genetics , Claudin-5/metabolism , Dynamins/antagonists & inhibitors , Dynamins/metabolism , Endoplasmic Reticulum Stress/drug effects , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Interleukin-6/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/metabolism , Male , Matrix Metalloproteinase 9/genetics , Matrix Metalloproteinase 9/metabolism , Mitochondria/genetics , Mitochondria/metabolism , Mitochondrial Dynamics/genetics , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , NF-kappa B/metabolism , Occludin/genetics , Occludin/metabolism , Proto-Oncogene Proteins c-bcl-2/agonists , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Subarachnoid Hemorrhage/genetics , Subarachnoid Hemorrhage/mortality , Subarachnoid Hemorrhage/pathology , Subarachnoid Space/drug effects , Subarachnoid Space/metabolism , Subarachnoid Space/pathology , Survival Analysis , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Zonula Occludens-1 Protein/genetics , Zonula Occludens-1 Protein/metabolism , bcl-2-Associated X Protein/antagonists & inhibitors , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolismABSTRACT
Our previous work has demonstrated that the mammalian interleukin-7 (IL-7) gene can enhance the immunogenicity of DNA vaccine. Whether chicken IL-7 (chIL-7) possesses the ability to enhance the immunogenicity of VP2 DNA vaccine of infectious bursal disease virus (IBDV) remained unknown. To investigate this, we constructed a VP2 antigenic region (VP2366) gene and chIL-7 gene vectors, co-immunized chicken with these vectors and analyzed the effects of the chIL-7 gene on VP2366 gene immunogenicity. Results showed that co-administrated chIL-7 gene with VP2 DNA vaccine significantly increased specific serum antibody titers against IBDV, and enhanced lymphocyte proliferation and IFN-γ and IL-4 productions. More importantly, chIL-7 gene significantly increased VP2366 gene-induced protection against virulent IBDV infection, indicating that the chIL-7 gene possessed the capacity to enhance VP2366 DNA vaccine immunogenicity, and therefore might function as a novel adjuvant for IBDV VP2 DNA vaccine. Mechanically, chIL-7 could stimulate the common cytokine receptor γ chain (γc) expressions in vitro and in vivo, which might be involved in chIL-7 enhancement of the immunogenicity of VP2 DNA vaccine.
Subject(s)
Birnaviridae Infections/veterinary , Chickens/immunology , Infectious bursal disease virus/immunology , Interleukin-7/administration & dosage , Poultry Diseases/prevention & control , Vaccines, DNA/administration & dosage , Adjuvants, Immunologic/administration & dosage , Amino Acid Sequence , Animals , Base Sequence , Birnaviridae Infections/immunology , Birnaviridae Infections/prevention & control , Birnaviridae Infections/virology , Immunization , Immunogenicity, Vaccine , Infectious bursal disease virus/genetics , Interferon-gamma/immunology , Interleukin-4/immunology , Poultry Diseases/immunology , Poultry Diseases/virology , Sequence Analysis, DNA/veterinary , Viral Structural Proteins/genetics , Viral Structural Proteins/immunologyABSTRACT
To evaluate the potential use of an inactivated virus-based vaccine for the control and prevention of the newly emerged duck Tembusu virus infection in China, a duck Tembusu virus isolate, Tembusu-HB, was propagated in 12-day-old duck embryos and inactivated by treatment with formaldehyde. The inactivated viral antigen was emulsified with mineral oil, and five batches of the vaccine were manufactured. The immunogenicity and protection efficacy of the vaccine were evaluated in Beijing ducks and Beijing white geese. Results showed that more than 80% of immunized ducks were protected against virulent virus challenge after two intramuscular or subcutaneous injections of the inactivated vaccine, as evidenced by the negative virus isolation results. The protection is also correlated with a positive virus-specific antibody response as detected by ELISA. In contrast, none of the control ducks and geese had any detectable antibody response. Virus was isolated from all control ducks and geese after virulent virus challenge. Interestingly, a variable level of protection (20%-80%) was observed in Beijing white geese immunized twice with the same batches of vaccine, suggesting a species-specific effect of the vaccine. Overall, the results clearly suggest that the inactivated duck Tembusu virus vaccine is immunogenic and provides protection against virulent virus challenge.