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Migdady I, Gusdon AM, Everett AD, Cho SM. Blood and cerebrospinal fluid biomarkers in disorders of consciousness. HANDBOOK OF CLINICAL NEUROLOGY 2025; 207:165-181. [PMID: 39986720 DOI: 10.1016/b978-0-443-13408-1.00006-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/24/2025]
Abstract
The study of blood and cerebrospinal fluid biomarkers is a promising and rapidly advancing field in the research of disorders of consciousness (DoC). The use of advanced biochemical and analytic techniques in biomarker research has improved our ability to identify new biomarkers that can aid in the diagnosis, prognosis, and treatment of patients with brain injury. However, the use of biomarkers in clinical practice is limited by several challenges, including the lack of standardization in test and research methodologies. Despite this, identifying the most promising biomarkers and supporting their findings with strong evidence can improve their clinical utility. This chapter discusses the most promising biomarkers for DoC, which fall into four categories: neuronal, glial, inflammatory, and metabolic biomarkers. Understanding the role of each category in DoC can provide valuable insights into the mechanisms of brain injury and inform the development of more effective diagnostic and treatment strategies. By integrating biomarker research with clinical practice, we can improve our understanding of DoC and provide better care for these patients.
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Affiliation(s)
- Ibrahim Migdady
- Departments of Neurology, Medicine and Neurosurgery, Division of Critical Care Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY, United States
| | - Aaron M Gusdon
- Department of Neurosurgery, McGovern Medical School at UTHealth Houston, Houston, TX, United States
| | - Allen D Everett
- Division of Pediatric Cardiology, Johns Hopkins Hospital, Baltimore, MD, United States
| | - Sung-Min Cho
- Departments of Neurology, Neurosurgery, Surgery, and Anesthesia/Critical Care, Johns Hopkins Hospital, Baltimore, MD, United States
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2
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Paragond S, Dhatt SS, Kumar V, Zohmangaihi D, Gaurav A, Neradi D, Pal A. Prognosticating acute traumatic spinal cord injury using Neurofilament (NF), Neuron Specific Enolase (NSE), Matrix Metalloproteinases (MMPs), and S-100B as biomarkers. Ir J Med Sci 2024; 193:769-775. [PMID: 37528246 DOI: 10.1007/s11845-023-03476-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 07/24/2023] [Indexed: 08/03/2023]
Abstract
BACKGROUND Spinal cord injury (SCI) can result in lifelong disability. Currently, the literature suggests that biomarkers are helpful in prognosticating SCI, but there is no specific biomarker to date. This is the first study that predicted the prognosis dynamically using biomarkers. AIM To elucidate the role of biomarkers in prognosticating acute traumatic SCI. METHODS Blood samples were obtained from 35 patients of acute traumatic SCI at presentation, immediate post-op, and at 6 weeks. At 6 months follow-up, patients were divided into two groups, i.e, improved and non-improved based on the improvement in the ASIA grade compared to presentation. A non-parametric test was used for comparing mean NSE, MMP-2, S100-B, and NF serum levels at presentation, immediate post-op, and 6 weeks post-op follow-up between the two groups. RESULTS There was a significant difference (p = 0.03) in the NF values at presentation between the two groups. The difference of NSE values at 6 weeks was also significant (p = 0.016) between the two groups. S-100B levels were also significantly different between both groups at presentation (p=0.016), and at the immediate post-op stage (p=0.007). MMP-2 levels neither displayed any specific trend nor any significant difference between the two groups. CONCLUSION Higher NF values at presentation, and higher S-100B levels at presentation and immediate post-operative period correlated with poor outcome. Also, increased NSE values after surgery are indicative of no improvement. These levels can be used at various stages to predict the prognosis. However, further studies are required on this topic extensively to know the exact cut-off values of these markers to predict the prognosis accurately. CLINICAL TRIALS REGISTRY NUMBER REF/2020/01/030616.
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Affiliation(s)
- Sachin Paragond
- Department of Orthopaedics, ESIC Medical College and Hospital, Kalaburagi, Karnataka, India
| | | | - Vishal Kumar
- Department of Orthopaedics, PGIMER, Chandigarh, India.
| | | | - Ankit Gaurav
- Department of Orthopaedics, PGIMER, Chandigarh, India
| | - Deepak Neradi
- Department of Orthopaedics, PGIMER, Chandigarh, India
| | - Arnab Pal
- Department of Biochemistry, PGIMER, Chandigarh, India
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3
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Graves CL, Norloff E, Thompson D, Kosyk O, Sang Y, Chen A, Zannas AS, Wallet SM. Chronic early life stress alters the neuroimmune profile and functioning of the developing zebrafish gut. Brain Behav Immun Health 2023; 31:100655. [PMID: 37449287 PMCID: PMC10336164 DOI: 10.1016/j.bbih.2023.100655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 05/30/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023] Open
Abstract
Chronic early life stress (ELS) potently impacts the developing central nervous and immune systems and is associated with the onset of gastrointestinal disease in humans. Though the gut-brain axis is appreciated to be a major target of the stress response, the underlying mechanisms linking ELS to gut dysfunction later in life is incompletely understood. Zebrafish are a powerful model validated for stress research and have emerged as an important tool in delineating neuroimmune mechanisms in the developing gut. Here, we developed a novel model of ELS and utilized a comparative transcriptomics approach to assess how chronic ELS modulated expression of neuroimmune genes in the developing gut and brain. Zebrafish exposed to ELS throughout larval development exhibited anxiety-like behavior and altered expression of neuroimmune genes in a time- and tissue-dependent manner. Further, the altered gut neuroimmune profile, which included increased expression of genes associated with neuronal modulation, correlated with a reduction in enteric neuronal density and delayed gut transit. Together, these findings provide insights into the mechanisms linking ELS with gastrointestinal dysfunction and highlight the zebrafish model organism as a valuable tool in uncovering how "the body keeps the score."
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Affiliation(s)
- Christina L. Graves
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Carolina Stress Initiative, University of North Carolina School of Medicine, Chapel Hill, NC, 27514, USA
| | - Erik Norloff
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Darius Thompson
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Oksana Kosyk
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yingning Sang
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Angela Chen
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Anthony S. Zannas
- Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA
- Carolina Stress Initiative, University of North Carolina School of Medicine, Chapel Hill, NC, 27514, USA
| | - Shannon M. Wallet
- Division of Oral and Craniofacial Health Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Shaughness MC, Pierron N, Smith AN, Byrnes KR. The Integrin Pathway Partially Mediates Stretch-Induced Deficits in Primary Rat Microglia. Mol Neurobiol 2023; 60:3396-3412. [PMID: 36856961 DOI: 10.1007/s12035-023-03291-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 02/21/2023] [Indexed: 03/02/2023]
Abstract
Stretch-injured microglia display significantly altered morphology, function and inflammatory-associated gene expression when cultured on a synthetic fibronectin substrate. However, the mechanism by which stretch induces these changes is unknown. Integrins, such as α5β1, mediate microglial attachment to fibronectin via the RGD binding peptide; following integrin ligation the integrin-associated signaling enzyme, focal adhesion kinase (FAK), autophosphorylates tyrosine residue 397 and mediates multiple downstream cellular processes. We therefore hypothesize that blocking the RGD binding/integrin pathway with a commercially available RGD peptide will mimic the stretch-induced morphological alterations and functional deficits in microglia. Further, we hypothesize that upregulation of stretch-inhibited downstream integrin signaling will reverse these effects. Using primary rat microglia, we tested the effects of RGD binding peptide and a FAK activator on cellular function and structure and response to stretch-injury. Similar to injured cells, RGD peptide administration significantly decreases media nitric oxide (NO) levels and iNOS expression and induced morphological alterations and migratory deficits. While stretch-injury and RGD peptide administration decreased phosphorylation of the tyrosine 397 residue on FAK, 20 nM of ZINC 40099027, an activator specific to the tyrosine 397 residue, rescued the stretch-induced decrease in FAK phosphorylation and ameliorated the injury-induced decrease in media NO levels, iNOS expression and inflammatory associated gene expression. Additionally, treatment alleviated morphological changes observed after stretch-injury and restored normal migratory behavior to control levels. Taken together, these data suggest that the integrin/FAK pathway partially mediates the stretch-injured phenotype in microglia, and may serve as a pathway to modulate microglial responses.
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Affiliation(s)
- Michael C Shaughness
- Neuroscience Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA.,Operational and Undersea Medicine Directorate (OUMD), En Route & Critical Care Department (ECD), Naval Medical Research Center (NMRC), Silver Spring, MD, USA
| | - Nathan Pierron
- F.E. Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Austin N Smith
- Neuroscience Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA
| | - Kimberly R Byrnes
- Neuroscience Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD, 20814, USA. .,Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
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5
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Mafuika SN, Naicker T, Harrichandparsad R, Lazarus L. The potential of serum S100 calcium-binding protein B and glial fibrillary acidic protein as biomarkers for traumatic brain injury. TRANSLATIONAL RESEARCH IN ANATOMY 2022. [DOI: 10.1016/j.tria.2022.100228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Forensic biomarkers of lethal traumatic brain injury. Int J Legal Med 2022; 136:871-886. [PMID: 35226180 PMCID: PMC9005436 DOI: 10.1007/s00414-022-02785-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 01/21/2022] [Indexed: 11/01/2022]
Abstract
AbstractTraumatic brain injury (TBI) is a major cause of death and its accurate diagnosis is an important concern of daily forensic practice. However, it can be challenging to diagnose TBI in cases where macroscopic signs of the traumatic head impact are lacking and little is known about the circumstances of death. In recent years, several post-mortem studies investigated the possible use of biomarkers for providing objective evidence for TBIs as the cause of death or to estimate the survival time and time since death of the deceased. This work systematically reviewed the available scientific literature on TBI-related biomarkers to be used for forensic purposes. Post-mortem TBI-related biomarkers are an emerging and promising resource to provide objective evidence for cause of death determinations as well as survival time and potentially even time since death estimations. This literature review of forensically used TBI-biomarkers revealed that current markers have low specificity for TBIs and only provide limited information with regards to survival time estimations and time since death estimations. Overall, TBI fatality-related biomarkers are largely unexplored in compartments that are easily accessible during autopsies such as urine and vitreous humor. Future research on forensic biomarkers requires a strict distinction of TBI fatalities from control groups, sufficient sample sizes, combinations of currently established biomarkers, and novel approaches such as metabolomics and mi-RNAs.
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Amoo M, Henry J, O'Halloran PJ, Brennan P, Husien MB, Campbell M, Caird J, Javadpour M, Curley GF. S100B, GFAP, UCH-L1 and NSE as predictors of abnormalities on CT imaging following mild traumatic brain injury: a systematic review and meta-analysis of diagnostic test accuracy. Neurosurg Rev 2021; 45:1171-1193. [PMID: 34709508 DOI: 10.1007/s10143-021-01678-z] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 09/03/2021] [Accepted: 10/20/2021] [Indexed: 12/25/2022]
Abstract
Biomarkers such as calcium channel binding protein S100 subunit beta (S100B), glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase L1 (UCH-L1) and neuron-specific enolase (NSE) have been proposed to aid in screening patients presenting with mild traumatic brain injury (mTBI). As such, we aimed to characterise their accuracy at various thresholds. MEDLINE, SCOPUS and EMBASE were searched, and articles reporting the diagnostic performance of included biomarkers were eligible for inclusion. Risk of bias was assessed using the QUADAS-II criteria. A meta-analysis was performed to assess the predictive value of biomarkers for imaging abnormalities on CT. A total of 2939 citations were identified, and 38 studies were included. Thirty-two studies reported data for S100B. At its conventional threshold of 0.1 μg/L, S100B had a pooled sensitivity of 91% (95%CI 87-94) and a specificity of 30% (95%CI 26-34). The optimal threshold for S100B was 0.72 μg/L, with a sensitivity of 61% (95% CI 50-72) and a specificity of 69% (95% CI 64-74). Nine studies reported data for GFAP. The optimal threshold for GFAP was 626 pg/mL, at which the sensitivity was 71% (95%CI 41-91) and specificity was 71% (95%CI 43-90). Sensitivity of GFAP was maximised at a threshold of 22 pg/mL, which had a sensitivity of 93% (95%CI 73-99) and a specificity of 36% (95%CI 12-68%). Three studies reported data for NSE and two studies for UCH-L1, which precluded meta-analysis. There is evidence to support the use of S100B as a screening tool in mild TBI, and potential advantages to the use of GFAP, which requires further investigation.
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Affiliation(s)
- Michael Amoo
- Department of Neurosurgery, Royal College of Surgeons in Ireland, Dublin, Ireland. .,National Neurosurgical Centre, Beaumont Hospital, Dublin 9, Ireland. .,Beacon Academy, Beacon Hospital, Sandyford, Dublin 18, Ireland.
| | - Jack Henry
- National Neurosurgical Centre, Beaumont Hospital, Dublin 9, Ireland.,School of Medicine, University College Dublin, Dublin, Ireland
| | - Philip J O'Halloran
- Department of Neurosurgery, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Paul Brennan
- Department of Neurosurgery, Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Radiology, Beaumont Hospital, Dublin 9, Ireland
| | - Mohammed Ben Husien
- Department of Neurosurgery, Royal College of Surgeons in Ireland, Dublin, Ireland.,National Neurosurgical Centre, Beaumont Hospital, Dublin 9, Ireland
| | - Matthew Campbell
- Department of Genetics, Trinity College Dublin, Dublin 2, Ireland
| | - John Caird
- Department of Neurosurgery, Royal College of Surgeons in Ireland, Dublin, Ireland.,National Neurosurgical Centre, Beaumont Hospital, Dublin 9, Ireland
| | - Mohsen Javadpour
- Department of Neurosurgery, Royal College of Surgeons in Ireland, Dublin, Ireland.,National Neurosurgical Centre, Beaumont Hospital, Dublin 9, Ireland.,Department of Academic Neurology, Trinity College Dublin, Dublin 2, Ireland
| | - Gerard F Curley
- Department of Neurosurgery, Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Anaesthesia and Critical Care, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
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8
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Amoo M, O'Halloran PJ, Henry J, Husien MB, Brennan P, Campbell M, Caird J, Curley GF. Permeability of the Blood-Brain Barrier after Traumatic Brain Injury; Radiological Considerations. J Neurotrauma 2021; 39:20-34. [PMID: 33632026 DOI: 10.1089/neu.2020.7545] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability, especially in young persons, and constitutes a major socioeconomic burden worldwide. It is regarded as the leading cause of mortality and morbidity in previously healthy young persons. Most of the mechanisms underpinning the development of secondary brain injury are consequences of disruption of the complex relationship between the cells and proteins constituting the neurovascular unit or a direct result of loss of integrity of the tight junctions (TJ) in the blood-brain barrier (BBB). A number of changes have been described in the BBB after TBI, including loss of TJ proteins, pericyte loss and migration, and altered expressions of water channel proteins at astrocyte end-feet processes. There is a growing research interest in identifying optimal biological and radiological biomarkers of severity of BBB dysfunction and its effects on outcomes after TBI. This review explores the microscopic changes occurring at the neurovascular unit, after TBI, and current radiological adjuncts for its evaluation in pre-clinical and clinical practice.
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Affiliation(s)
- Michael Amoo
- National Centre for Neurosurgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.,Royal College of Surgeons in Ireland, Dublin, Ireland.,Beacon Academy, Beacon Hospital, Sandyford, Dublin, Ireland
| | - Philip J O'Halloran
- Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Neurosurgery, Royal London Hospital, Whitechapel, London, United Kingdom
| | - Jack Henry
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Mohammed Ben Husien
- National Centre for Neurosurgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland.,Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Paul Brennan
- Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Radiology, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | | | - John Caird
- National Centre for Neurosurgery, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
| | - Gerard F Curley
- Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Anaesthesia and Critical Care, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
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Treatment with Cyclic AMP Activators Reduces Glioblastoma Growth and Invasion as Assessed by Two-Photon Microscopy. Cells 2021; 10:cells10030556. [PMID: 33806549 PMCID: PMC8000435 DOI: 10.3390/cells10030556] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 01/02/2023] Open
Abstract
(1) Background: Despite progress in surgery and radio-chemotherapy of glioblastoma (GB), the prognosis remains very poor. GB cells exhibit a preference for hypoxia to maintain their tumor-forming capacity. Enhancing oxidative phosphorylation—known as the anti-Warburg effect—with cyclic AMP activators has been demonstrated to drive GB cells from proliferation to differentiation thereby reducing tumor growth in a cell culture approach. Here we re-evaluate this treatment in a more clinically relevant model. (2) Methods: The effect of treatment with dibutyryl cyclic AMP (dbcAMP, 1 mM) and the cAMP activator forskolin (50µM) was assessed in a GB cell line (U87GFP+, 104 cells) co-cultured with mouse organotypic brain slices providing architecture and biochemical properties of normal brain tissue. Cell viability was determined by propidium-iodide, and gross metabolic effects were excluded in the extracellular medium. Tumor growth was quantified in terms of area, volume, and invasion at the start of culture, 48 h, 7 days, and 14 days after treatment. (3) Results: The tumor area was significantly reduced following dbcAMP or forskolin treatment (F2,249 = 5.968, p = 0.0029). 3D volumetric quantification utilizing two-photon fluorescence microscopy revealed that the treated tumors maintained a spheric shape while the untreated controls exhibited the GB typical invasive growth pattern. (4) Conclusions: Our data demonstrate that treatment with a cAMP analog/activator reduces GB growth and invasion.
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Scherschel K, Hedenus K, Jungen C, Lemoine MD, Rübsamen N, Veldkamp MW, Klatt N, Lindner D, Westermann D, Casini S, Kuklik P, Eickholt C, Klöcker N, Shivkumar K, Christ T, Zeller T, Willems S, Meyer C. Cardiac glial cells release neurotrophic S100B upon catheter-based treatment of atrial fibrillation. Sci Transl Med 2020; 11:11/493/eaav7770. [PMID: 31118294 DOI: 10.1126/scitranslmed.aav7770] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 04/12/2019] [Indexed: 01/02/2023]
Abstract
Atrial fibrillation (AF), the most common sustained heart rhythm disorder worldwide, is linked to dysfunction of the intrinsic cardiac autonomic nervous system (ICNS). The role of ICNS damage occurring during catheter-based treatment of AF, which is the therapy of choice for many patients, remains controversial. We show here that the neuronal injury marker S100B is expressed in cardiac glia throughout the ICNS and is released specifically upon catheter ablation of AF. Patients with higher S100B release were more likely to be AF free during follow-up. Subsequent in vitro studies revealed that murine intracardiac neurons react to S100B with diminished action potential firing and increased neurite growth. This suggests that release of S100B from cardiac glia upon catheter-based treatment of AF is a hallmark of acute neural damage that contributes to nerve sprouting and can be used to assess ICNS damage.
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Affiliation(s)
- Katharina Scherschel
- Department of Cardiology-Electrophysiology, cNEP (cardiac Neuro- and Electrophysiology research group), University Heart Centre, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany
| | - Katja Hedenus
- Department of Cardiology-Electrophysiology, cNEP (cardiac Neuro- and Electrophysiology research group), University Heart Centre, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany
| | - Christiane Jungen
- Department of Cardiology-Electrophysiology, cNEP (cardiac Neuro- and Electrophysiology research group), University Heart Centre, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany
| | - Marc D Lemoine
- Department of Cardiology-Electrophysiology, cNEP (cardiac Neuro- and Electrophysiology research group), University Heart Centre, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.,Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Nicole Rübsamen
- Department of General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Marieke W Veldkamp
- Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, 1105 AZ, Amsterdam, Netherlands
| | - Niklas Klatt
- Department of Cardiology-Electrophysiology, cNEP (cardiac Neuro- and Electrophysiology research group), University Heart Centre, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany
| | - Diana Lindner
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.,Department of General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Dirk Westermann
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.,Department of General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Simona Casini
- Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, 1105 AZ, Amsterdam, Netherlands
| | - Pawel Kuklik
- Department of Cardiology-Electrophysiology, cNEP (cardiac Neuro- and Electrophysiology research group), University Heart Centre, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany
| | - Christian Eickholt
- Department of Cardiology-Electrophysiology, cNEP (cardiac Neuro- and Electrophysiology research group), University Heart Centre, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany
| | - Nikolaj Klöcker
- Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, 40225 Düsseldorf, Germany
| | - Kalyanam Shivkumar
- Cardiac Arrhythmia Center and Neurocardiology Research Center of Excellence, Molecular, Cellular and Integrative Physiology Interdepartmental Program, UCLA, Los Angeles, CA 90095, USA
| | - Torsten Christ
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.,Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Tanja Zeller
- DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany.,Department of General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Stephan Willems
- Department of Cardiology-Electrophysiology, cNEP (cardiac Neuro- and Electrophysiology research group), University Heart Centre, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany
| | - Christian Meyer
- Department of Cardiology-Electrophysiology, cNEP (cardiac Neuro- and Electrophysiology research group), University Heart Centre, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany. .,DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 13347 Berlin, Germany
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11
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Rezaei F, Abbasi H, Sadeghi M, Imani MM. The effect of obstructive sleep apnea syndrome on serum S100B and NSE levels: a systematic review and meta-analysis of observational studies. BMC Pulm Med 2020; 20:31. [PMID: 32024492 PMCID: PMC7003338 DOI: 10.1186/s12890-020-1063-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 01/27/2020] [Indexed: 12/29/2022] Open
Abstract
Background Obstructive sleep apnea syndrome (OSAS) is a common disorder that is accompanied by structural brain changes. This meta-analysis aimed to evaluate the effect of OSAS on the serum levels of astrocytic protein (S100B) and neuron-specific enolase (NSE) in observational studies. Methods A comprehensive search was performed in the PubMed/Medline, Web of Science, Scopus, ScienceDirect, and Cochrane Library databases to assess the serum level of S100B and/or NSE in patients with OSAS and/or controls. The quality of the study was evaluated by the Newcastle-Ottawa Scale (NOS). A random-effects model was performed using RevMan 5.3 with the mean difference (MD) and 95% confidence intervals (CIs). Results Out of 63 studies found in the mentioned databases and one identified by a manual search, nine studies were included and analyzed in this meta-analysis (three cross-sectional and six case-control studies). The analysis showed that the S100B [MD = 53.58 pg/ml, 95%CI: 1.81, 105.35; P = 0.04] and NSE levels [MD = 3.78 ng/ml, 95%CI: 2.07, 5.48; P < 0.0001] were significantly higher in patients than the controls. However, there were no significant differences between the S100B [MD = -28.00 pg/ml, 95%CI: − 79.48, 23.47; P = 0.29] and NSE levels [MD = 0.49 ng/ml, 95%CI: − 0.82, 1.80; P = 0.46]. Conclusions This meta-analysis found elevated serum S100B and NSE levels in OSAS patients compared to the controls, which suggests that these markers may be used as peripheral indicators of brain damage in OSAS.
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Affiliation(s)
- Farzad Rezaei
- Department of Oral and Maxillofacial Surgery, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Hooshyar Abbasi
- Department of Oral and Maxillofacial Surgery, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masoud Sadeghi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Students Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Moslem Imani
- Department of Orthodontics, School of Dentistry, Kermanshah University of Medical Sciences, Kermanshah, Iran.
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12
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Mathew AS, Shi X, Yau ST. Detection of a Traumatic Brain Injury Biomarker at the 10 fg/mL Level. Mol Diagn Ther 2019; 22:729-735. [PMID: 30377977 DOI: 10.1007/s40291-018-0365-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND The detection of minute amounts of protein biomarkers in body fluids is believed to provide early diagnosis and prognosis of mild traumatic brain injury (mTBI). An ultrasensitive detection method was used to detect S100B, the most studied potential marker for the diagnosis of mTBI. METHODS The detection method was a modified electrochemical immunoassay technique that provides voltage controlled intrinsic current signal amplification. The sandwich immune complex of S100B was formed on the working electrode of the screen-printed electrode. The gating voltage provides amplification of the current signal that flows through the complex. RESULTS S100B was spiked in human serum. The limit of detection of S100B in human serum was 10 fg/mL. The calibration curves cover four orders of magnitudes from 10 fg/mL to 10 ng/mL. The specificity of the detection was demonstrated using TAU protein, which is another marker for mTBI. CONCLUSION The results reported in this work using the field effect enzymatic detection (FEED)-based immunoassay indicate the feasibility of using this method for the detection of extremely low concentrations of markers of mTBI in human serum. This method can be developed as a platform for a range of markers of mTBI.
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Affiliation(s)
- Anup S Mathew
- Department of Electrical Engineering and Computer Science, Cleveland State University, Cleveland, OH, 44115, USA
| | - Xuyang Shi
- Department of Electrical Engineering and Computer Science, Cleveland State University, Cleveland, OH, 44115, USA
| | - Siu-Tung Yau
- Department of Electrical Engineering and Computer Science, Cleveland State University, Cleveland, OH, 44115, USA. .,The Applied Bioengineering Program, Cleveland State University, Cleveland, OH, 44115, USA.
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Medkova A, Srovnal J, Potomkova J, Volejnikova J, Mihal V. Multifarious diagnostic possibilities of the S100 protein family: predominantly in pediatrics and neonatology. World J Pediatr 2018; 14:315-321. [PMID: 29858979 DOI: 10.1007/s12519-018-0163-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 05/11/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND Numerous articles related to S100 proteins have been recently published. This review aims to introduce this large protein family and its importance in the diagnostics of many pathological conditions in children and adults. DATA SOURCES Based on original publications found in database systems, we summarize the current knowledge about the S100 protein group and highlight the most important proteins with focus on pediatric use. RESULTS The S100 family is composed of Ca2+ and Zn2+ binding proteins, which are present only in vertebrates. Some of these proteins can be used as diagnostic markers in cardiology (S100A1, S100A12), oncology (S100A2, S100A5, S100A6, S100A14, S100A16, S100P, S100B), neurology (S100B), rheumatology (S100A8/A9, S100A4, S100A6, and S100A12), nephrology and infections (S100A8, S100A9, S100A8/A9, S100A12). The most useful S100 proteins in pediatrics are S100A8, S100A9, heterodimers S100A8/A9, S100B and S100A12. CONCLUSIONS The S100 family members are promising biomarkers and provide numerous possibilities for implementation into clinical practice to optimize the differential diagnostic process.
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Affiliation(s)
- Anna Medkova
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, 779 00, Olomouc, Czech Republic.
| | - Josef Srovnal
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, 779 00, Olomouc, Czech Republic
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc, Hněvotínská, 1333/5, 779 00, Olomouc, Czech Republic
| | - Jarmila Potomkova
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, 779 00, Olomouc, Czech Republic
- Department of Science and Research, University Hospital Olomouc, I. P. Pavlova 6, 779 00, Olomouc, Czech Republic
| | - Jana Volejnikova
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, 779 00, Olomouc, Czech Republic
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc, Hněvotínská, 1333/5, 779 00, Olomouc, Czech Republic
| | - Vladimir Mihal
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, 779 00, Olomouc, Czech Republic
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University Olomouc, Hněvotínská, 1333/5, 779 00, Olomouc, Czech Republic
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Du J, Zhang C, Na X, Li A, Zhang Q, Li K, Ding Y. Andrographolide protects mouse astrocytes against hypoxia injury by promoting autophagy and S100B expression. ACTA ACUST UNITED AC 2018; 51:e7061. [PMID: 29694508 PMCID: PMC5937729 DOI: 10.1590/1414-431x20177061] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2017] [Accepted: 12/21/2017] [Indexed: 11/21/2022]
Abstract
Andrographolide (ANDRO) has been studied for its immunomodulation, anti-inflammatory, and neuroprotection effects. Because brain hypoxia is the most common factor of secondary brain injury after traumatic brain injury, we studied the role and possible mechanism of ANDRO in this process using hypoxia-injured astrocytes. Mouse cortical astrocytes C8-D1A (astrocyte type I clone from C57/BL6 strains) were subjected to 3 and 21% of O2 for various times (0–12 h) to establish an astrocyte hypoxia injury model in vitro. After hypoxia and ANDRO administration, the changes in cell viability and apoptosis were assessed using CCK-8 and flow cytometry. Expression changes in apoptosis-related proteins, autophagy-related proteins, main factors of JNK pathway, ATG5, and S100B were determined by western blot. Hypoxia remarkably damaged C8-D1A cells evidenced by reduction of cell viability and induction of apoptosis. Hypoxia also induced autophagy and overproduction of S100B. ANDRO reduced cell apoptosis and promoted cell autophagy and S100B expression. After ANDRO administration, autophagy-related proteins, S-100B, JNK pathway proteins, and ATG5 were all upregulated, while autophagy-related proteins and s100b were downregulated when the jnk pathway was inhibited or ATG5 was knocked down. ANDRO conferred a survival advantage to hypoxia-injured astrocytes by reducing cell apoptosis and promoting autophagy and s100b expression. Furthermore, the promotion of autophagy and s100b expression by ANDRO was via activation of jnk pathway and regulation of ATG5.
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Affiliation(s)
- Juan Du
- Department of Anesthesiology, Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Chunyan Zhang
- Department of Anesthesiology, Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Xueqing Na
- Department of Anesthesiology, Hospital of Kunming Medical University, Kunming, China
| | - Aizhi Li
- Department of Anesthesiology, Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Qingfeng Zhang
- Department of Anesthesiology, Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Kezhong Li
- Department of Anesthesiology, Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Yongbo Ding
- Department of Anesthesiology, Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
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Miller AP, Shah AS, Aperi BV, Kurpad SN, Stemper BD, Glavaski-Joksimovic A. Acute death of astrocytes in blast-exposed rat organotypic hippocampal slice cultures. PLoS One 2017; 12:e0173167. [PMID: 28264063 PMCID: PMC5338800 DOI: 10.1371/journal.pone.0173167] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Accepted: 02/16/2017] [Indexed: 01/06/2023] Open
Abstract
Blast traumatic brain injury (bTBI) affects civilians, soldiers, and veterans worldwide and presents significant health concerns. The mechanisms of neurodegeneration following bTBI remain elusive and current therapies are largely ineffective. It is important to better characterize blast-evoked cellular changes and underlying mechanisms in order to develop more effective therapies. In the present study, our group utilized rat organotypic hippocampal slice cultures (OHCs) as an in vitro system to model bTBI. OHCs were exposed to either 138 ± 22 kPa (low) or 273 ± 23 kPa (high) overpressures using an open-ended helium-driven shock tube, or were assigned to sham control group. At 2 hours (h) following injury, we have characterized the astrocytic response to a blast overpressure. Immunostaining against the astrocytic marker glial fibrillary acidic protein (GFAP) revealed acute shearing and morphological changes in astrocytes, including clasmatodendrosis. Moreover, overlap of GFAP immunostaining and propidium iodide (PI) indicated astrocytic death. Quantification of the number of dead astrocytes per counting area in the hippocampal cornu Ammonis 1 region (CA1), demonstrated a significant increase in dead astrocytes in the low- and high-blast, compared to sham control OHCs. However only a small number of GFAP-expressing astrocytes were co-labeled with the apoptotic marker Annexin V, suggesting necrosis as the primary type of cell death in the acute phase following blast exposure. Moreover, western blot analyses revealed calpain mediated breakdown of GFAP. The dextran exclusion additionally indicated membrane disruption as a potential mechanism of acute astrocytic death. Furthermore, although blast exposure did not evoke significant changes in glutamate transporter 1 (GLT-1) expression, loss of GLT-1-expressing astrocytes suggests dysregulation of glutamate uptake following injury. Our data illustrate the profound effect of blast overpressure on astrocytes in OHCs at 2 h following injury and suggest increased calpain activity and membrane disruption as potential underlying mechanisms.
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Affiliation(s)
- Anna P. Miller
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States of America
| | - Alok S. Shah
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States of America
| | - Brandy V. Aperi
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States of America
| | - Shekar N. Kurpad
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States of America
| | - Brian D. Stemper
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States of America
| | - Aleksandra Glavaski-Joksimovic
- Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
- Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, United States of America
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16
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Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochir (Wien) 2017; 159:209-225. [PMID: 27957604 PMCID: PMC5241347 DOI: 10.1007/s00701-016-3046-3] [Citation(s) in RCA: 194] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 11/28/2016] [Indexed: 12/12/2022]
Abstract
Background In order to improve injury assessment of brain injuries, protein markers of pathophysiological processes and tissue fate have been introduced in the clinic. The most studied protein “biomarker” of cerebral damage in traumatic brain injury (TBI) is the protein S100B. The aim of this narrative review is to thoroughly analyze the properties and capabilities of this biomarker with focus on clinical utility in the assessment of patients suffering from TBI. Results S100B has successfully been implemented in the clinic regionally (1) to screen mild TBI patients evaluating the need to perform a head computerized tomography, (2) to predict outcome in moderate-to-severe TBI patients, (3) to detect secondary injury development in brain-injured patients and (4) to evaluate treatment efficacy. The potential opportunities and pitfalls of S100B in the different areas usually refer to its specificity and sensitivity to detect and assess intracranial injury. Conclusion Given some shortcomings that should be realized, S100B can be used as a versatile screening, monitoring and prediction tool in the management of TBI patients.
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Affiliation(s)
- Eric Peter Thelin
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
- Neurosurgical Research Laboratory, Karolinska University Hospital, Building R2:02, S-171 76, Stockholm, Sweden.
| | - David W Nelson
- Division of Perioperative Medicine and Intensive Care (PMI), Section Neuro, Karolinska University Hospital, Stockholm, Sweden
- Department of Physiology and Pharmacology, Section of Anesthesiology and Intensive Care, Karolinska Institutet, Stockholm, Sweden
| | - Bo-Michael Bellander
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
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17
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Thelin EP, Nelson DW, Bellander BM. A review of the clinical utility of serum S100B protein levels in the assessment of traumatic brain injury. Acta Neurochir (Wien) 2017; 159. [PMID: 27957604 PMCID: PMC5241347 DOI: 10.1007/s00701-016-3046-3;] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND In order to improve injury assessment of brain injuries, protein markers of pathophysiological processes and tissue fate have been introduced in the clinic. The most studied protein "biomarker" of cerebral damage in traumatic brain injury (TBI) is the protein S100B. The aim of this narrative review is to thoroughly analyze the properties and capabilities of this biomarker with focus on clinical utility in the assessment of patients suffering from TBI. RESULTS S100B has successfully been implemented in the clinic regionally (1) to screen mild TBI patients evaluating the need to perform a head computerized tomography, (2) to predict outcome in moderate-to-severe TBI patients, (3) to detect secondary injury development in brain-injured patients and (4) to evaluate treatment efficacy. The potential opportunities and pitfalls of S100B in the different areas usually refer to its specificity and sensitivity to detect and assess intracranial injury. CONCLUSION Given some shortcomings that should be realized, S100B can be used as a versatile screening, monitoring and prediction tool in the management of TBI patients.
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Affiliation(s)
- Eric Peter Thelin
- Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
- Neurosurgical Research Laboratory, Karolinska University Hospital, Building R2:02, S-171 76, Stockholm, Sweden.
| | - David W Nelson
- Division of Perioperative Medicine and Intensive Care (PMI), Section Neuro, Karolinska University Hospital, Stockholm, Sweden
- Department of Physiology and Pharmacology, Section of Anesthesiology and Intensive Care, Karolinska Institutet, Stockholm, Sweden
| | - Bo-Michael Bellander
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Neurosurgery, Karolinska University Hospital, Stockholm, Sweden
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18
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Abbasi M, Sajjadi M, Fathi M, Maghsoudi M. Serum S100B Protein as an Outcome Prediction Tool in Emergency Department Patients with Traumatic Brain Injury. Turk J Emerg Med 2016; 14:147-52. [PMID: 27437512 PMCID: PMC4909959 DOI: 10.5505/1304.7361.2014.74317] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2014] [Accepted: 10/10/2014] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVES Traumatic brain injury is a common cause of death and disability worldwide. Early recognition of patients with brain cellular damage allows for early rehabilitation and patient outcome improvement. METHODS In this prospective study, the clinical conditions of patients with mild to moderate traumatic brain injury (TBI) were assessed, and patient serum S100B levels were measured. Patients were followed up one month later and evaluated for level of consciousness, presence or absence of post-traumatic headache, and daily activity performance (using the Barthel scale). Student's t-test and the chi-square test were used for data analysis, which was performed using SPSS software. RESULTS The mean serum S100B value was significantly lower for patients with minor TBI than for patients with moderate TBI (23.1±14.2 ng/dl and 134.0±245.0 ng/dl, respectively). Patients with normal CT scans also had statistically significantly lower serum S100B levels than patients with abnormal CT findings. The mean S100B value was statistically significantly higher for patients with suspected diffused axonal injury (632.18±516.1 ng/dl) than for patients with other abnormal CT findings (p=0.000): 24.97±22.9 ng/dl in patients with normal CT results; 41.56±25.7 ng/dl in patients with skull bone fracture; 57.38 ±28.9 ng/dl in patients with intracranial hemorrhage; and 76.23±38.3 ng/dl in patients with fracture plus intracranial hemorrhage). CONCLUSIONS Serum S100B levels increase in patients with minor to moderate TBIs, especially in those with diffused axonal injury. However, serum S100B values cannot accurately predict one-month neuropsychological outcomes and performance.
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Changyaleket B, Xu H, Vetri F, Valyi-Nagy T, Paisansathan C, Chong ZZ, Pelligrino DA, Testai FD. Intracerebroventricular application of S100B selectively impairs pial arteriolar dilating function in rats. Brain Res 2016; 1634:171-178. [PMID: 26773687 DOI: 10.1016/j.brainres.2015.12.061] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 12/22/2015] [Accepted: 12/29/2015] [Indexed: 10/22/2022]
Abstract
S100B is an astrocyte-derived protein that can act through the receptor for advanced glycation endproducts (RAGE) to mediate either "trophic" or "toxic" responses. Its levels increase in many neurological conditions with associated microvascular dysregulation, such as subarachnoid hemorrhage (SAH) and traumatic brain injury. The role of S100B in the pathogenesis of microvasculopathy has not been addressed. This study was designed to examine whether S100B alters pial arteriolar vasodilating function. Rats were randomized to receive (1) artificial cerebrospinal fluid (aCSF), (2) exogenous S100B, and (3) exogenous S100B+the decoy soluble RAGE (sRAGE). S100B was infused intracerebroventricularly (icv) using an osmotic pump and its levels in the CSF were adjusted to achieve a concentration similar to what we observed in SAH. After 48 h of continuous icv infusion, a cranial window/intravital microscopy was applied to animals for evaluation of pial arteriolar dilating responses to sciatic nerve stimulation (SNS), hypercapnia, and topical suffusion of vasodilators including acetylcholine (ACh), s-nitroso-N-acetyl penicillamine (SNAP), or adenosine (ADO). Pial arteriolar dilating responses were calculated as the percentage change of arteriolar diameter in relation to baseline. The continuous S100B infusion for 48 h was associated with reduced responses to the neuronal-dependent vasodilator SNS (p<0.05) and the endothelial-dependent vasodilator ACh (p<0.05), compared to controls. The inhibitory effects of S100B were prevented by sRAGE. On the other hand, S100B did not alter the responses elicited by vascular smooth muscle cell-dependent vasodilators, namely hypercapnia, SNAP, or ADO. These findings indicate that S100B regulates neuronal and endothelial dependent cerebral arteriolar dilation and suggest that this phenomenon is mediated through RAGE-associated pathways.
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Affiliation(s)
- Benjarat Changyaleket
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, United States
| | - Haoliang Xu
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, United States; Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States.
| | - Francesco Vetri
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, United States
| | - Tibor Valyi-Nagy
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, United States
| | | | - Zhao Zhong Chong
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, United States
| | - Dale A Pelligrino
- Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, United States
| | - Fernando D Testai
- Department of Neurology and Rehabilitation, University of Illinois at Chicago, Chicago, IL, United States
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Schulte S, Podlog LW, Hamson-Utley JJ, Strathmann FG, Strüder HK. A systematic review of the biomarker S100B: implications for sport-related concussion management. J Athl Train 2015; 49:830-50. [PMID: 25299445 DOI: 10.4085/1062-6050-49.3.33] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Elevated levels of the astroglial protein S100B have been shown to predict sport-related concussion. However, S100B levels within an athlete can vary depending on the type of physical activity (PA) engaged in and the methodologic approach used to measure them. Thus, appropriate reference values in the diagnosis of concussed athletes remain undefined. The purpose of our systematic literature review was to provide an overview of the current literature examining S100B measurement in the context of PA. The overall goal is to improve the use of the biomarker S100B in the context of sport-related concussion management. DATA SOURCES PubMed, SciVerse Scopus, SPORTDiscus, CINAHL, and Cochrane. STUDY SELECTION We selected articles that contained (1) research studies focusing exclusively on humans in which (2) either PA was used as an intervention or the test participants or athletes were involved in PA and (3) S100B was measured as a dependent variable. DATA EXTRACTION We identified 24 articles. Study variations included the mode of PA used as an intervention, sample types, sample-processing procedures, and analytic techniques. DATA SYNTHESIS Given the nonuniformity of the analytical methods used and the data samples collected, as well as differences in the types of PA investigated, we were not able to determine a single consistent reference value of S100B in the context of PA. Thus, a clear distinction between a concussed athlete and a healthy athlete based solely on the existing S100B cutoff value of 0.1 μg/L remains unclear. However, because of its high sensitivity and excellent negative predictive value, S100B measurement seems to have the potential to be a diagnostic adjunct for concussion in sports settings. We recommend that the interpretation of S100B values be based on congruent study designs to ensure measurement reliability and validity.
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Affiliation(s)
- Stefanie Schulte
- Department of Exercise and Sport Science, University of Utah, Salt Lake City
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21
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Krohn M, Dreßler J, Bauer M, Schober K, Franke H, Ondruschka B. Immunohistochemical investigation of S100 and NSE in cases of traumatic brain injury and its application for survival time determination. J Neurotrauma 2015; 32:430-40. [PMID: 25211554 DOI: 10.1089/neu.2014.3524] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The availability of markers able to provide insight into protein changes in the central nervous system after fatal traumatic brain injury (TBI) is limited. The present study reports on the semi-quantitative assessments of the immunopositive neuroglial cells (both astrocytes and oligodendrocytes) and neurons for S100 protein (S100), as well as neuronal specific enolase (NSE), in the cerebral cortex, hippocampus, and cerebellum with regard to survival time and cause of death. Brain tissues of 47 autopsy cases with TBI (survival times ranged between several minutes and 34 d) and 10 age- and gender-matched controls (natural deaths) were examined. TBI cases were grouped according to their survival time in acute death after brain injury (ABI, n = 25), subacute death after brain injury (SBI, n = 18) and delayed death after brain injury (DBI, n = 4). There were no significant changes in the percentages of S100-stained astrocytes between TBI and control cases. The percentages of S100-positive oligodendrocytes in the pericontusional zone (PCZ) in cases with SBI were significantly lower than in controls (p < 0.05) and in the ABI group (p < 0.05). In the hippocampus, S100-positive oligodendrocytes were significantly lower in cases with ABI and SBI (both, p < 0.05), compared with controls. It is of particular interest that there were also S100-positive neurons in the PCZ and hippocampus in TBI cases after more than 2 h survival but not in ABI cases or controls. The percentages of NSE-positive neurons in the hippocampus were likewise significantly lower in cases with ABI, compared with controls (p < 0.05) but increased in cases with SBI in PCZ (p < 0.05). In conclusion, the present findings emphasize that S100 and NSE-immunopositivity might be useful for detecting the cause and process of death due to TBI. Further, S100-positivity in neurons may be helpful to estimate the survival time of fatal injuries in legal medicine.
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Affiliation(s)
- Michael Krohn
- 1 Institute of Legal Medicine, University of Leipzig , Germany
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Abstract
The S100 protein family consists of 24 members functionally distributed into three main subgroups: those that only exert intracellular regulatory effects, those with intracellular and extracellular functions and those which mainly exert extracellular regulatory effects. S100 proteins are only expressed in vertebrates and show cell-specific expression patterns. In some instances, a particular S100 protein can be induced in pathological circumstances in a cell type that does not express it in normal physiological conditions. Within cells, S100 proteins are involved in aspects of regulation of proliferation, differentiation, apoptosis, Ca2+ homeostasis, energy metabolism, inflammation and migration/invasion through interactions with a variety of target proteins including enzymes, cytoskeletal subunits, receptors, transcription factors and nucleic acids. Some S100 proteins are secreted or released and regulate cell functions in an autocrine and paracrine manner via activation of surface receptors (e.g. the receptor for advanced glycation end-products and toll-like receptor 4), G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans. Extracellular S100A4 and S100B also interact with epidermal growth factor and basic fibroblast growth factor, respectively, thereby enhancing the activity of the corresponding receptors. Thus, extracellular S100 proteins exert regulatory activities on monocytes/macrophages/microglia, neutrophils, lymphocytes, mast cells, articular chondrocytes, endothelial and vascular smooth muscle cells, neurons, astrocytes, Schwann cells, epithelial cells, myoblasts and cardiomyocytes, thereby participating in innate and adaptive immune responses, cell migration and chemotaxis, tissue development and repair, and leukocyte and tumor cell invasion.
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Affiliation(s)
- R Donato
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
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Sorci G, Riuzzi F, Arcuri C, Tubaro C, Bianchi R, Giambanco I, Donato R. S100B protein in tissue development, repair and regeneration. World J Biol Chem 2013; 4:1-12. [PMID: 23580916 PMCID: PMC3622753 DOI: 10.4331/wjbc.v4.i1.1] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 03/01/2013] [Indexed: 02/05/2023] Open
Abstract
The Ca2+-binding protein of the EF-hand type, S100B, exerts both intracellular and extracellular regulatory activities. As an intracellular regulator, S100B is involved in the regulation of energy metabolism, transcription, protein phosphorylation, cell proliferation, survival, differentiation and motility, and Ca2+ homeostasis, by interacting with a wide array of proteins (i.e., enzymes, enzyme substrates, cytoskeletal subunits, scaffold/adaptor proteins, transcription factors, ubiquitin E3 ligases, ion channels) in a restricted number of cell types. As an extracellular signal, S100B engages the pattern recognition receptor, receptor for advanced glycation end-products (RAGE), on immune cells as well as on neuronal, astrocytic and microglial cells, vascular smooth muscle cells, skeletal myoblasts and cardiomyocytes. However, RAGE may not be the sole receptor activated by S100B, the protein being able to enhance bFGF-FGFR1 signaling by interacting with FGFR1-bound bFGF in particular cell types. Moreover, extracellular effects of S100B vary depending on its local concentration. Increasing evidence suggests that at the concentration found in extracellular fluids in normal physiological conditions and locally upon acute tissue injury, which is up to a few nM levels, S100B exerts trophic effects in the central and peripheral nervous system and in skeletal muscle tissue thus participating in tissue homeostasis. The present commentary summarizes results implicating intracellular and extracellular S100B in tissue development, repair and regeneration.
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Abstract
Recent advances in medicine, intensive care and diagnostic imaging modalities have led to a pronounced reduction in deaths and disability resulting from traumatic brain injury. However, there are not sufficient findings to evaluate and quantify the severity of the initial and secondary processes destructive and therefore there are not effective therapeutic measures to effectively predict the outcome. For this reason, in recent decades, researchers and clinicians have focused on specific markers of cellular brain injury to improve the diagnosis and the evaluation of outcome. Many proteins synthesized in the astroglia cells or in the neurons, such as neuron-specific enolase, S100 calcium binding protein B, myelin basic protein, creatine kinase brain isoenzyme, glial fibrillary acidic protein, plasma desoxyribonucleic acid, brain-derived neurotrophic factor, and ubiquitin carboxy-terminal hydrolase-L1, have been proposed as potential markers for cell damage in central nervous system. Usually, the levels of these proteins increase following brain injury and are found in increasing concentrations in the cerebrospinal fluid depending on the injury magnitude, and can also be found in blood stream because of a compromised blood-brain barrier. In this review, we examine the various factors that must be taken into account in the search for a reliable non-invasive biomarkers in traumatic brain injury and their role in the diagnosis and outcome evaluation.
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Lange SC, Bak LK, Waagepetersen HS, Schousboe A, Norenberg MD. Primary cultures of astrocytes: their value in understanding astrocytes in health and disease. Neurochem Res 2012; 37:2569-88. [PMID: 22926576 DOI: 10.1007/s11064-012-0868-0] [Citation(s) in RCA: 133] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Revised: 08/01/2012] [Accepted: 08/01/2012] [Indexed: 12/26/2022]
Abstract
During the past few decades of astrocyte research it has become increasingly clear that astrocytes have taken a central position in all central nervous system activities. Much of our new understanding of astrocytes has been derived from studies conducted with primary cultures of astrocytes. Such cultures have been an invaluable tool for studying roles of astrocytes in physiological and pathological states. Many central astrocytic functions in metabolism, amino acid neurotransmission and calcium signaling were discovered using this tissue culture preparation and most of these observations were subsequently found in vivo. Nevertheless, primary cultures of astrocytes are an in vitro model that does not fully mimic the complex events occurring in vivo. Here we present an overview of the numerous contributions generated by the use of primary astrocyte cultures to uncover the diverse functions of astrocytes. Many of these discoveries would not have been possible to achieve without the use of astrocyte cultures. Additionally, we address and discuss the concerns that have been raised regarding the use of primary cultures of astrocytes as an experimental model system.
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Affiliation(s)
- Sofie C Lange
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark
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Abstract
In vitro models of traumatic brain injury (TBI) are helping elucidate the pathobiological mechanisms responsible for dysfunction and delayed cell death after mechanical stimulation of the brain. Researchers have identified compounds that have the potential to break the chain of molecular events set in motion by traumatic injury. Ultimately, the utility of in vitro models in identifying novel therapeutics will be determined by how closely the in vitro cascades recapitulate the sequence of cellular events that play out in vivo after TBI. Herein, the major in vitro models are reviewed, and a discussion of the physical injury mechanisms and culture preparations is employed. A comparison between the efficacy of compounds tested in vitro and in vivo is presented as a critical evaluation of the fidelity of in vitro models to the complex pathobiology that is TBI. We conclude that in vitro models were greater than 88% predictive of in vivo results.
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Affiliation(s)
- Barclay Morrison
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
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Abstract
Protocols are presented describing a unique in vitro injury model and how to culture and mature mouse, rat, and human astrocytes for its use. This injury model produces widespread injury and astrocyte reactivity that enable quantitative measurements of morphological, biochemical, and functional changes in rodent and human reactive astrocytes. To investigate structural and molecular mechanisms of reactivity in vitro, cultured astrocytes need to be purified and then in vitro "matured" to reach a highly differentiated state. This is achieved by culturing astrocytes on deformable collagen-coated membranes in the presence of adult-derived horse serum (HS), followed by its stepwise withdrawal. These in vitro matured, process-bearing, quiescent astrocytes are then subjected to mechanical stretch injury by an abrupt pressure pulse from a pressure control device that briefly deforms the culture well bottom. This inflicts a measured reproducible, widespread strain that induces reactivity and injury in rodent and human astrocytes. Cross-species comparisons are possible because mouse, rat, and human astrocytes are grown using essentially the same in vitro treatment regimen. Human astrocytes from fetal cerebral cortex are compared to those derived from cortical biopsies of epilepsy patients (ages 1-12 years old), with regard to growth, purity, and differentiation. This opens a unique opportunity for future studies on glial biology, maturation, and pathology of human astrocytes. Prototypical astrocyte proteins including GFAP, S100, aquaporin4, glutamate transporters, and tenascin are expressed in mouse, rat, and human in vitro matured astrocyte. Upon pressure-stretching, rodent and human astrocytes undergo dynamic morphological, gene expression, and protein changes that are characteristic for trauma-induced reactive astrogliosis.
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Affiliation(s)
- Ina-Beate Wanner
- Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA.
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Lu J, Ng KC, Ling G, Wu J, Poon DJF, Kan EM, Tan MH, Wu YJ, Li P, Moochhala S, Yap E, Lee LKH, Teo M, Yeh IB, Sergio DMB, Chua F, Kumar SD, Ling EA. Effect of blast exposure on the brain structure and cognition in Macaca fascicularis. J Neurotrauma 2011; 29:1434-54. [PMID: 21639720 DOI: 10.1089/neu.2010.1591] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Blast injury to the brain is one of the major causes of death and can also significantly affect cognition and physical and psychological skills in survivors of blast. The complex mechanisms via which blast injury causes impairment of cognition and other symptoms are poorly understood. In this study, we investigated the effects of varying degrees of primary blast overpressure (BOP; 80 and 200 kPa) on the pathophysiological and magnetic resonance imaging (MRI) changes and neurocognitive performance as assessed by the monkey Cambridge Neuropsychological Test Automated Battery (mCANTAB) in non-human primates (NHP). The study aimed to examine the effects of neurobehavioral and histopathological changes in NHP. MRI and histopathology revealed ultrastructural changes in the brain, notably in the Purkinje neurons in the cerebellum and pyramidal neurons in the hippocampus, which were most vulnerable to the blast. The results correlated well with the behavioral changes and changes in motor coordination and working memory of the affected monkeys. In addition, there was white matter damage affecting myelinated axons, astrocytic hypertrophy, and increased aquaporin-4 (AQP-4) expression in astrocytes, suggesting cerebral edema. Increased apoptosis appeared to involve astrocytes and oligodendrocytes in the animals following blast exposure. The small sample size could have contributed to the non-significant outcome in cognitive performance post-blast and limited quantitative analyses. Nevertheless, the study has provided initial descriptive changes for establishing a primary BOP threshold for brain injury to serve as a useful platform for future investigations that aim to estimate brain injury potential and set safe limits of exposure.
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Affiliation(s)
- Jia Lu
- Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore 117510.
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Ralay Ranaivo H, Zunich SM, Choi N, Hodge JN, Wainwright MS. Mild stretch-induced injury increases susceptibility to interleukin-1β-induced release of matrix metalloproteinase-9 from astrocytes. J Neurotrauma 2011; 28:1757-66. [PMID: 21732764 DOI: 10.1089/neu.2011.1799] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Traumatic brain injury (TBI) results in the activation of glia and the release of proinflammatory cytokines, including interleukin (IL)-1β. The response of astrocytes to mild TBI has not been well studied. We used an in vitro model of cell stretch to investigate the effects of mild mechanical insult on astrocyte injury (lactate dehydrogenase and propidium iodide), and on mediators of inflammation including IL-1β, the chemokine CX3CL1, and nitrite. Here, we tested the hypothesis that a mild mechanical insult would increase susceptibility of astrocytes to delayed exposure to IL-1β, including enhanced release of the matrix metalloproteinease-9 (MMP-9). We investigated the role of the mitogen protein-activated kinase (MAPK) pathway in these responses. Cells subjected to a mild stretch show an increase in activation of the ERK1/2 and JNK pathways, and an increase in lactate dehydrogenase (LDH), but no change in the levels of inflammatory mediators. An early increase in LDH was dependent on ERK activation. Exposure to IL-1β, or to stretch alone, did not increase MMP-9. In contrast, the combination of mild stretch followed by IL-1β resulted in greater activation of the ERK pathway compared to either stimulus alone, and also resulted in an increase in the production of MMP-9 by astrocytes. Inhibition of the ERK pathway suppressed the increase in MMP-9 induced by the combination of stretch and IL-1β treatment. These results suggest that a primary mild mechanical injury renders astrocytes more susceptible to a secondary exposure to a proinflammatory cytokine such as IL-1β via the activation of the ERK pathway, and suggest a mechanism by which a mild head injury may confer increased susceptibility to neurologic injury caused by a subsequent insult.
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Affiliation(s)
- Hantamalala Ralay Ranaivo
- Department of Pediatrics, Division of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
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Dangerous attraction: phagocyte recruitment and danger signals of apoptotic and necrotic cells. Apoptosis 2010; 15:1007-28. [PMID: 20157780 DOI: 10.1007/s10495-010-0472-1] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Tissue homeostasis in metazoa requires the rapid and efficient clearance of dying cells by professional or semi-professional phagocytes. Impairment of this finely regulated, fundamental process has been implicated in the development of autoimmune diseases, such as systemic lupus erythematosus. Various studies have provided us a detailed understanding of the interaction between dying cells and phagocytes as well as the current concept that apoptotic cell removal leads to a non- or anti-inflammatory response, whereas necrotic cell removal stimulates a pro-inflammatory reaction. In contrast, our knowledge about the soluble factors released from dying cells is rather limited, although meanwhile it is generally accepted that not only the dying cell itself but also the substances liberated during cell death contribute to the process of corpse clearance and the subsequent immune response. This review article is intended as an up-to-date survey over attraction and danger signals of apoptotic, primary and secondary necrotic cells, their function as chemoattractants in phagocyte recruitment, additional effects on the immune system, and the receptors, which are engaged in this scenario.
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Sorci G, Bianchi R, Riuzzi F, Tubaro C, Arcuri C, Giambanco I, Donato R. S100B Protein, A Damage-Associated Molecular Pattern Protein in the Brain and Heart, and Beyond. Cardiovasc Psychiatry Neurol 2010; 2010:656481. [PMID: 20827421 PMCID: PMC2933911 DOI: 10.1155/2010/656481] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Accepted: 06/08/2010] [Indexed: 12/15/2022] Open
Abstract
S100B belongs to a multigenic family of Ca(2+)-binding proteins of the EF-hand type and is expressed in high abundance in the brain. S100B interacts with target proteins within cells thereby altering their functions once secreted/released with the multiligand receptor RAGE. As an intracellular regulator, S100B affects protein phosphorylation, energy metabolism, the dynamics of cytoskeleton constituents (and hence, of cell shape and migration), Ca(2+) homeostasis, and cell proliferation and differentiation. As an extracellular signal, at low, physiological concentrations, S100B protects neurons against apoptosis, stimulates neurite outgrowth and astrocyte proliferation, and negatively regulates astrocytic and microglial responses to neurotoxic agents, while at high doses S100B causes neuronal death and exhibits properties of a damage-associated molecular pattern protein. S100B also exerts effects outside the brain; as an intracellular regulator, S100B inhibits the postinfarction hypertrophic response in cardiomyocytes, while as an extracellular signal, (high) S100B causes cardiomyocyte death, activates endothelial cells, and stimulates vascular smooth muscle cell proliferation.
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Affiliation(s)
- Guglielmo Sorci
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Roberta Bianchi
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Francesca Riuzzi
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Claudia Tubaro
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Cataldo Arcuri
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Ileana Giambanco
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
| | - Rosario Donato
- Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy
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The Passage of S100B from Brain to Blood Is Not Specifically Related to the Blood-Brain Barrier Integrity. Cardiovasc Psychiatry Neurol 2010; 2010:801295. [PMID: 20671945 PMCID: PMC2910463 DOI: 10.1155/2010/801295] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2010] [Revised: 05/12/2010] [Accepted: 05/24/2010] [Indexed: 01/25/2023] Open
Abstract
Following brain injury, S100B is released from damaged astrocytes but also yields repair mechanisms. We measured S100B in the cerebrospinal fluid (CSF) and serum (Cobas e411 electrochemiluminescence assay, Roche) longitudinally in a large cohort of patients treated with a ventricular drainage following traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH). Statistical analysis was performed with SPSS software applying the Mann-Whitney rank sum test or chi-test where appropriate. S100B in CSF and serum was significantly increased following TBI (n = 71) and SAH (n = 185) for at least one week following injury. High S100B levels in CSF and serum were inconsistent associated with outcome. The passage of S100B from CSF to blood (100∗serumS100B/CSFS100B) was significantly decreased although the albumin quotient suggested an “open” blood-CSF barrier. Events possibly interfering with the BBB did not affect the S100B passage (P = .591). In conclusion, we could not confirm S100B measurements to reliably predict outcome, and a compromised blood-CSF barrier did not affect the passage of S100B from CSF to serum.
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Kleindienst A, Meissner S, Eyupoglu IY, Parsch H, Schmidt C, Buchfelder M. Dynamics of S100B release into serum and cerebrospinal fluid following acute brain injury. ACTA NEUROCHIRURGICA. SUPPLEMENT 2010; 106:247-50. [PMID: 19812958 DOI: 10.1007/978-3-211-98811-4_46] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
High S100B serum levels are considered to reflect brain injury severity. However, the dynamics of S100B passage from the cerebral compartment into the blood remain unclear. We examined the temporal profile of S100B release into the cerebrospinal fluid (CSF) and blood in acute brain injury.In patients treated with ventricular drainage (subarachnoid hemorrhage, SAH, n = 23; traumatic brain injury, TBI, n = 19), we measured S100B levels in the serum and CSF. The Glasgow Coma Score (GCS) was assessed daily. Statistical analysis was performed by the Mann-Whitney rank sum test for group differences and by the Pearson correlation.In normal controls (n = 6), S100B levels in the serum (0.05 +/- 0.01 microg/L) comprised around 10% of the CSF concentration (0.66 +/- 0.08 microg/L). Following brain injury, S100B levels were significantly increased in the serum (p < 0.05 in SAH day 2-5, TBI day 1-8) and excessively increased in the CSF (p < 0.05 in SAH and TBI day 1-10). For the individual patient, there was no consistent correlation between S100B levels in serum or CSF and GCS. We therefore calculated the ratio of S100B serum/CSF. Following brain injury, the S100B passage from the CSF to the blood was significantly impaired. Further, higher ratios were correlated with better neurological function (p = 0.002).Because stimulated active S100B release may serve as a repair mechanism, a higher S100B serum/CSF ratio may contribute to neurological recovery.
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Affiliation(s)
- A Kleindienst
- Department of Neurosurgery, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
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35
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Mechanism of S100b release from rat cortical slices determined under basal and stimulated conditions. Neurochem Res 2009; 35:429-36. [PMID: 19823932 DOI: 10.1007/s11064-009-0075-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2009] [Indexed: 10/20/2022]
Abstract
Incubation of rat cortical slices in a medium that was not containing oxygen and glucose (oxygen-glucose deprivation, OGD) caused a 200% increase in the release of S100B. However, when slices were transferred to a medium containing oxygen and glucose (reoxygenation conditions, or REO), S100B release reached 500% of its control value. Neither inhibition of nitric oxide (NO) synthase by L-NAME nor addition of the NO donors sodium nitroprussid (SNP) or hydroxylamine (HA) to the medium altered basal S100B release. Similarly, the presence of SNP, HA or NO precursor L: -arginine in the medium, or inhibition of NO synthase by L-NAME also failed to alter OGD- and REO-induced S100B outputs. Moreover, individual inhibition of PKC, PLA(2) or PLC all failed to attenuate the S100B release determined under control condition or enhanced by either OGD or REO. Blockade of calcium channels with verapamil, chelating the Ca(+2) ions with BAPTA or blockade of sodium channels with tetrodotoxin (TTX) did not alter OGD- and REO-induced S100B release. In contrast to the pharmacologic manipulations mentioned above, glutamate and alpha-ketoglutarate added at high concentrations to the medium prevented both OGD- and REO-induced S100B outputs. These results indicate that neither NO nor the activation of PKC, PLA(2) or PLC seem to be involved in basal or OGD- and REO-induced S100B outputs. Additionally, calcium and sodium currents that are sensitive to verapamil and TTX, respectively, are unlikely to contribute to the enhanced S100B release observed under these conditions.
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Donato R, Sorci G, Riuzzi F, Arcuri C, Bianchi R, Brozzi F, Tubaro C, Giambanco I. S100B's double life: intracellular regulator and extracellular signal. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2008; 1793:1008-22. [PMID: 19110011 DOI: 10.1016/j.bbamcr.2008.11.009] [Citation(s) in RCA: 546] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2008] [Revised: 11/12/2008] [Accepted: 11/21/2008] [Indexed: 12/22/2022]
Abstract
The Ca2+-binding protein of the EF-hand type, S100B, exerts both intracellular and extracellular functions. Recent studies have provided more detailed information concerning the mechanism(s) of action of S100B as an intracellular regulator and an extracellular signal. Indeed, intracellular S100B acts as a stimulator of cell proliferation and migration and an inhibitor of apoptosis and differentiation, which might have important implications during brain, cartilage and skeletal muscle development and repair, activation of astrocytes in the course of brain damage and neurodegenerative processes, and of cardiomyocyte remodeling after infarction, as well as in melanomagenesis and gliomagenesis. As an extracellular factor, S100B engages RAGE (receptor for advanced glycation end products) in a variety of cell types with different outcomes (i.e. beneficial or detrimental, pro-proliferative or pro-differentiative) depending on the concentration attained by the protein, the cell type and the microenvironment. Yet, RAGE might not be the sole S100B receptor, and S100B's ability to engage RAGE might be regulated by its interaction with other extracellular factors. Future studies using S100B transgenic and S100B null mice might shed more light on the functional role(s) of the protein.
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Affiliation(s)
- Rosario Donato
- Department of Experimental Medicine and Biochemical Sciences, Section Anatomy, University of Perugia, Via del Giochetto C.P. 81 Succ. 3, 06122 Perugia, Italy.
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Mostert JP, Koch MW, Heerings M, Heersema DJ, De Keyser J. Therapeutic potential of fluoxetine in neurological disorders. CNS Neurosci Ther 2008; 14:153-64. [PMID: 18482027 DOI: 10.1111/j.1527-3458.2008.00040.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
The selective serotonin reuptake inhibitor (SSRI) fluoxetine, which is registered for a variety of psychiatric disorders, has been found to stimulate the cAMP-responsive element binding protein (CREB), increase the production of brain-derived neurotrophic factor (BNDF) and the neurotrophic peptide S100beta, enhance glycogenolysis in astrocytes, block voltage-gated calcium and sodium channels, and decrease the conductance of mitochondrial voltage-dependent anion channels (VDACs). These mechanisms of actions suggest that fluoxetine may also have potential for the treatment of a number of neurological disorders. We performed a Pubmed search to review what is known about possible therapeutic effects of fluoxetine in animal models and patients with neurological disorders. Beneficial effects of fluoxetine have been noted in animal models of stroke, multiple sclerosis, and epilepsy. Fluoxetine was reported to improve neurological manifestations in patients with Alzheimer's disease, stroke, Huntington's disease, multiple sclerosis, traumatic brain injury, and epilepsy. Clinical studies so far were small and often poorly designed. Results were inconclusive and contradictory. However, the available preclinical data justify further clinical trials to determine the therapeutic potential of fluoxetine in neurological disorders.
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Affiliation(s)
- Jop P Mostert
- Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
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38
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Serum S100B but not NSE Levels are Increased in Morbidly Obese Individuals Affected by Obstructive Sleep Apnea–Hypopnea Syndrome. Obes Surg 2008; 18:993-9. [DOI: 10.1007/s11695-007-9386-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Accepted: 11/28/2007] [Indexed: 02/01/2023]
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Cao F, Yang XF, Liu WG, Hu WW, Li G, Zheng XJ, Shen F, Zhao XQ, Lv ST. Elevation of neuron-specific enolase and S-100beta protein level in experimental acute spinal cord injury. J Clin Neurosci 2008; 15:541-4. [PMID: 18343116 DOI: 10.1016/j.jocn.2007.05.014] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2006] [Revised: 05/02/2007] [Accepted: 05/23/2007] [Indexed: 11/19/2022]
Abstract
We evaluated the protein levels of neuron-specific enolase (NSE) and S-100beta in serum and cerebrospinal fluid (CSF) in an animal model of acute spinal cord injury and ascertained their relevance. Spinal cord injury was induced at the T8 level in rats. Enzyme-linked immunosorbent assay was used to measure the protein levels of NSE and S-100beta in both serum and CSF at different time points (30 min, 2 h, 6 h, 12 h and 24 h after induction of spinal cord injury). There existed a significant correlation between neurological deficits and the severity of spinal cord injury (p<0.05). Compared with the control group, the protein levels of NSE and S-100beta in serum and CSF significantly increased from 2 h after injury (p<0.05) and reached a maximum at 6 h. Within a certain time window, the protein levels of NSE and S-100beta in serum and CSF were closely related to the severity of injury level (p<0.05). The protein levels of NSE and S-100beta in serum and CSF significantly increased after experimental spinal cord injury in a time-dependent manner and thus may be considered specific biomarkers for acute spinal cord injury.
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Affiliation(s)
- Fei Cao
- Department of Neurosurgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, China
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Vicente E, Tramontina F, Leite MC, Nardin P, Silva M, Karkow AR, Adolf R, Lucion AB, Netto CA, Gottfried C, Gonçalves CA. S100B levels in the cerebrospinal fluid of rats are sex and anaesthetic dependent. Clin Exp Pharmacol Physiol 2007; 34:1126-30. [PMID: 17880365 DOI: 10.1111/j.1440-1681.2007.04687.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
1. S100B is a calcium-binding protein that acts as a neurotrophic cytokine and is expressed in the central nervous system, predominantly by astrocytes. At nanomolar concentrations, S100B stimulates neurite outgrowth and glial glutamate uptake, as well as protecting neurons against glutamate excitoxicity. 2. Peripheral S100B concentrations, particularly in the serum and cerebrospinal fluid (CSF), have been used as a parameter of glial activation or death in several physiological and pathological conditions. 3. In the present study, we investigated the effect of anaesthetics (thiopental, ketamine and halothane) on CSF concentrations of S100B, as well as a possible sex dependence, because several studies have suggested astrocytes as putative targets for oestrogen. 4. Higher levels of CSF S100B were found when rats were anaesthetized with thiopental; these levels, independently of anaesthetic, were sex dependent. Conversely, no effect of anaesthetic or sex was observed on serum concentrations of S100B. 5. The increase in CSF concentrations of S100B induced by thiopental was confirmed in non-anaesthetized neonatal rats and cortical astrocyte cultures. 6. Assuming CSF S100B as a marker of development, glial activation or even brain damage, investigations regarding the sex dependence of its concentration may be useful in gaining an understanding of sex variations in the behaviour and the pathological course of, as well as susceptibility to, many brain disorders. The findings of the present study reinforce the sex effect on synaptic plasticity and suggest a sex dependence of neural communication mediated by extracellular S100B without restricting the influence of astrocytes on the developmental phase.
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Affiliation(s)
- Evelin Vicente
- Post Graduate Program in Neuroscience, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
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Spaethling JM, Geddes-Klein DM, Miller WJ, von Reyn CR, Singh P, Mesfin M, Bernstein SJ, Meaney DF. Linking impact to cellular and molecular sequelae of CNS injury: modeling in vivo complexity with in vitro simplicity. PROGRESS IN BRAIN RESEARCH 2007; 161:27-39. [PMID: 17618968 DOI: 10.1016/s0079-6123(06)61003-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/07/2023]
Abstract
Traumatic brain injury (TBI) represents one of most common disorders to the central nervous system (CNS). Despite significant efforts, though, an effective clinical treatment for TBI is not yet available. The complexity of human TBI is modeled with a broad group of experimental models, with each model matching some aspect of the human condition. In the past 15 years, these in vivo models were complemented with a group of in vitro models, with these in vitro models allowing investigators to more precisely identify the mechanism(s) of TBI, the different intracellular events that occur in acute period following injury, and the possible treatment of this injury in vitro. In this paper, we review the available in vitro models to study TBI, discuss their biomechanical basis for human TBI, and review the findings from these in vitro models. Finally, we synthesize the current knowledge and point out possible future directions for this group of models, especially in the effort toward developing new therapies for the traumatically brain injured patient.
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Affiliation(s)
- Jennifer M Spaethling
- Department of Bioengineering, University of Pennsylvania, 3320 Smith Walk, Philadelphia, PA 19104-6392, USA
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Diehl LA, Silveira PP, Leite MC, Crema LM, Portella AK, Billodre MN, Nunes E, Henriques TP, Fidelix-da-Silva LB, Heis MD, Gonçalves CA, Quillfeldt JA, Dalmaz C. Long lasting sex-specific effects upon behavior and S100b levels after maternal separation and exposure to a model of post-traumatic stress disorder in rats. Brain Res 2007; 1144:107-16. [PMID: 17335785 DOI: 10.1016/j.brainres.2007.01.084] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2006] [Revised: 01/05/2007] [Accepted: 01/23/2007] [Indexed: 12/21/2022]
Abstract
This study was undertaken to verify if repeated long-term separation from dams would affect the development of parameters related to post-traumatic stress disorder (PTSD) after animals are subjected to inescapable shock when adults. Wistar rats were subjected to repeated maternal separation during post-natal days 1-10. When adults, rats from both sexes were submitted to a PTSD model consisting of exposure to inescapable footshock, followed by situational reminders. We observed long-lasting effects of both interventions. Exposure to shock increased fear conditioning. Anxiety-like behavior was increased and exploratory activity decreased by both treatments, and these effects were more robust in males. Additionally, basal corticosterone in plasma was decreased, paralleling effects observed in PTSD patients. Levels of S100B protein in serum and cerebrospinal fluid (CSF) were measured. Levels in serum correlated with the effects observed in anxiety-like behavior, increasing in males exposed to shock, and presenting no effect in females. S100B in CSF was increased in females submitted to maternal separation during the neonatal period. These results suggest that, in rats, an early stress experience such as maternal separation may aggravate some effects of exposure to a stressor during adult age, and that this effect is sex-specific. Additionally, data suggest that the increased S100B levels, observed in serum, have an extracerebral origin, possibly mediated by an increase in the noradrenergic tonus. Increased S100B in brain could be related to its neurotrophic actions.
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Affiliation(s)
- Luisa Amalia Diehl
- Departamento de Bioquímica, ICBS, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600, Anexo, Lab. 11. 90035-003 - Porto Alegre, RS, Brazil
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Ellis EF, Willoughby KA, Sparks SA, Chen T. S100B protein is released from rat neonatal neurons, astrocytes, and microglia by in vitro trauma and anti-S100 increases trauma-induced delayed neuronal injury and negates the protective effect of exogenous S100B on neurons. J Neurochem 2007; 101:1463-70. [PMID: 17403138 DOI: 10.1111/j.1471-4159.2007.04515.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
S100B protein is found in brain, has been used as a marker for brain injury and is neurotrophic. Using a well-characterized in vitro model of brain cell trauma, we have previously shown that strain injury causes S100B release from neonatal rat neuronal plus glial cultures and that exogenous S100B reduces delayed post-traumatic neuronal damage even when given at 6 or 24 h post-trauma. The purpose of the current studies was to measure post-traumatic S100B release by specific brain cell types and to examine the effect of an antibody to S100 on post-traumatic delayed (48 h) neuronal injury and the protective effect of exogenous S100B. Neonatal rat cortical cells grown on a deformable elastic membrane were subjected to a strain (stretch) injury produced by a 50 ms displacement of the membrane. S100B was measured with an ELISA kit. Trauma released S100B from pure cultures of astrocytes, microglia, and neurons. Anti-S100 reduced released S100B to below detectable levels, increased delayed neuronal injury in traumatized cells and negated the protective effect of exogenous S100B on injured cells. Heat denatured anti-S100 did not exacerbate injury. These studies provide further evidence for a protective role for S100B following neuronal trauma.
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Affiliation(s)
- Earl F Ellis
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0613, USA.
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Floyd CL, Lyeth BG. Astroglia: important mediators of traumatic brain injury. PROGRESS IN BRAIN RESEARCH 2007; 161:61-79. [PMID: 17618970 DOI: 10.1016/s0079-6123(06)61005-4] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Traumatic brain injury (TBI) research to date has focused almost exclusively on the pathophysiology of injured neurons with very little attention paid to non-neuronal cells. However in the past decade, exciting discoveries have challenged this century-old view of passive glial cells and have led to a reinterpretation of the role of glial cells in central nervous system (CNS) biology and pathology. In this chapter we review several lines of evidence, indicating that glial cells, particularly astrocytes, are active partners to neurons in the brain, and summarize recent findings that detail the significance of astrocyte pathology in traumatic brain injury.
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Affiliation(s)
- Candace L Floyd
- Department of Physical Medicine and Rehabilitation, Center for Glial Biology in Medicine, 547 Spain Rehabilitation Center, University of Alabama at Birmingham, Birmingham, AL 35249, USA.
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Gautschi OP, Toffoli AM, Joesbury KA, Skirving AP, Filgueira L, Zellweger R. Osteoinductive Effect of Cerebrospinal Fluid from Brain-Injured Patients. J Neurotrauma 2007; 24:154-62. [PMID: 17263679 DOI: 10.1089/neu.2006.0166] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Patients with traumatic brain injury (TBI) are predisposed to heterotopic ossification, which is believed to be due to osteoinductive factors released at the site of the brain injury. To date, little is known about the presence of such factors in human cerebrospinal fluid (CSF). This study investigated whether CSF of TBI patients is osteoinductive. In addition, known osteoinductive factors--such as bone morphogenetic protein (BMP)-2, BMP-4, and BMP-7, and S100B--were measured in CSF. Eighty-four consecutive patients were classified according to brain pathology: TBI (n = 11), non-traumatic brain pathology (NTBP) (n = 26), and no brain pathology (control group) (n = 47). The osteoinductive effect of CSF was measured repeatedly in proliferation assays using a fetal human osteoblast cell line. The mean proliferation rate (normalized to the internal negative control) of the TBI, NTBP, and control groups was 138.2% (SD 13.1), 110.0% (SD 22.1), and 118.8% (SD 16.9), respectively. The potentially confounding effect of age was investigated further by restricting the selection of patients for analysis to that of the oldest patient in the TBI group and use of multiple regression analysis. After implementation of both, it was shown that age is highly unlikely to account for the higher rates of proliferation observed among the TBI patients in this study. Of note, the TBI group had a significantly higher mean proliferation rate than the NTBP (p = 0.001) and the control group (p = 0.006). S100B and BMP-2, -4, or -7 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). There was no correlation between proliferation rates and S100B (r = 0.023). Only three of 36 CSF samples had measurable levels of BMP-2 and -7, and none had detectable concentrations of BMP-4. Consequently, it is unlikely that S100B or BMP-2, -4, or -7 are the putative osteoinductive factors. The results indicate that CSF from TBI patients has an osteoinductive effect in vitro. However, the osteoinductive factor has still to be characterized.
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Affiliation(s)
- Oliver P Gautschi
- Department of Orthopaedic and Trauma Surgery, Royal Perth Hospital, Wellington Street, Perth, 6000 WA, Australia.
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Kleindienst A, Hesse F, Bullock MR, Buchfelder M. The neurotrophic protein S100B: value as a marker of brain damage and possible therapeutic implications. PROGRESS IN BRAIN RESEARCH 2007; 161:317-25. [PMID: 17618987 DOI: 10.1016/s0079-6123(06)61022-4] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
We provide a critical analysis of the value of S100B as a marker of brain damage and possible therapeutic implications. The early assessment of the injury severity and the consequent prognosis are of major concern for physicians treating patients suffering from traumatic brain injury (TBI). A reliable indicator to accurately determine the extent of the brain damage has to meet certain requirements: (i) to originate in the central nervous system (CNS) with no contribution from extracerebral sources; (ii) a passive release from damaged neurons and/or glial cells without any stimulated active release; (iii) a lack of specific effects on neurons and/or glial cells interfering with the initial injury; (iv) an unlimited passage through the blood-brain barrier (BBB). The measurement of putative biochemical markers, such as the S100B protein, has been proposed in this role. Over the past decade, numerous studies have reported a positive correlation of S100B serum levels with a poor outcome following TBI. However, some studies raise doubt whether the serum measurement of S100B is a valid biochemical marker of brain damage. We summarize the specific properties of S100B and analyze whether they support or counteract the necessary requirements to designate this protein as an indicator of brain damage. Finally, we report recent experimental findings suggesting a possible therapeutic potential of S100B.
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Affiliation(s)
- Andrea Kleindienst
- Department of Neurosurgery, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany.
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Kleindienst A, Ross Bullock M. A Critical Analysis of the Role of the Neurotrophic Protein S100B in Acute Brain Injury. J Neurotrauma 2006; 23:1185-200. [PMID: 16928177 DOI: 10.1089/neu.2006.23.1185] [Citation(s) in RCA: 123] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We provide a critical analysis of the relevance of S100B in acute brain injury emphazising the beneficial effect of its biological properties. S100B is a calcium-binding protein, primarily produced by glial cells, and exerts auto- and paracrine functions. Numerous reports indicate, that S100B is released after brain insults and serum levels are positively correlated with the degree of injury and negatively correlated with outcome. However, new data suggest that the currently held view, that serum measurement of S100B is a valid "biomarker" of brain damage in traumatic brain injury (TBI), does not acknowlege the multifaceted release pattern and effect of the blood-brain barrier disruption upon S100B levels in serum. In fact, serum and brain S100B levels are poorly correlated, with serum levels dependent primarily on the integrity of the blood-brain barrier, and not the level of S100B in the brain. The time profile of S100B release following experimental TBI, both in vitro and in vivo, suggests a role of S100B in delayed reparative processes. Further, recent findings provide evidence, that S100B may decrease neuronal injury and/or contribute to repair following TBI. Hence, S100B, far from being a negative determinant of outcome, as suggested previously in the human TBI and ischemia literature, is of potential therapeutic value that could improve outcome in patients who sustain various forms of acute brain damage.
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Affiliation(s)
- Andrea Kleindienst
- Department of Neurosurgery, Georg August University, Göttingen, Germany.
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Edwards MM, Robinson SR. TNF alpha affects the expression of GFAP and S100B: implications for Alzheimer's disease. J Neural Transm (Vienna) 2006; 113:1709-15. [PMID: 16736247 DOI: 10.1007/s00702-006-0479-5] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2005] [Accepted: 03/12/2006] [Indexed: 11/30/2022]
Abstract
Neurodegenerative disorders such as Alzheimer's disease are characterized by increased intracellular and extracellular concentrations of the astrocytic proteins glial fibrillary acidic protein (GFAP) and S100B. The present study examined the potential contribution of tumor necrosis factor alpha (TNFalpha) to these changes by measuring astrocyte viability along with the intracellular and extracellular expression of GFAP and S100B following exposure to this cytokine. Although TNFalpha did not affect astrocyte viability, the extracellular levels of both proteins were increased three-fold with associated reductions in immunocytochemical labeling.
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Affiliation(s)
- M M Edwards
- School of Psychology, Psychiatry and Psychological Medicine, Monash University, Clayton, Victoria, Australia
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Büyükuysal RL. Protein S100B release from rat brain slices during and after ischemia: comparison with lactate dehydrogenase leakage. Neurochem Int 2005; 47:580-8. [PMID: 16194580 DOI: 10.1016/j.neuint.2005.06.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2005] [Revised: 06/20/2005] [Accepted: 06/22/2005] [Indexed: 10/25/2022]
Abstract
One hour of ischemia significantly increased protein S100B release from rat brain slices without altering lactate dehydrogenase leakage. Reoxygenation of the ischemic slices, however, increased the levels of these biochemical markers in the medium. Although removal of extracellular Ca(+2) ions from the medium did not alter the basal lactate dehydrogenase leakage from cortical slices, an excessive increase in basal protein S100B release was seen under this condition. Ischemia and/or reoxygenation induced enhancements in these markers were attenuated by removal of Ca(+2) ions from the medium. Ischemia significantly increased glutamate release, but neither ischemia nor reoxygenation induced rises in protein S100B and lactate dehydrogenase levels were altered by glutamate receptor antagonists. Rising the glutamate levels in the medium by each ouabain or exogenous glutamate, moreover, failed in exerting an ischemia like effect on protein S100B and LDH outputs. In contrast, exogenous glutamate added into the medium protected the slices against reoxygenation induced increments in protein S100B and lactate dehydrogenase levels. These results indicate that protein S100B has a greater sensitivity against ischemia than lactate dehydrogenase in in vitro brain slice preparations. Since neither exogenous glutamate nor enhancements of the extracellular glutamate levels by ouabain had an ischemia like effect, and since glutamate receptor antagonists were also unsuccessful, it seems unlikely that ischemia-induced increase in glutamate release is directly involved in protein S100B release or lactate dehydrogenase leakage determined in the present study.
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Affiliation(s)
- Rifat Levent Büyükuysal
- Uludağ University, Medical School, Department of Pharmacology and Clinical Pharmacology, 16059 Bursa, Turkey.
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