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Hernandez-Espinosa DR, Medina-Ruiz GI, Scrabis MG, Thathiah A, Aizenman E. Proinflammatory microglial activation impairs in vitro cortical tissue repair via zinc-dependent ADAM17 cleavage of the CSF-1 receptor. J Neurochem 2025; 169:e16239. [PMID: 39387604 PMCID: PMC11810582 DOI: 10.1111/jnc.16239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 08/25/2024] [Accepted: 09/19/2024] [Indexed: 10/15/2024]
Abstract
Infection and subsequent inflammatory processes negatively impact prognosis in individuals with traumatic brain injury (TBI). Tissue repair following TBI is tightly regulated by microglia, promoting or, importantly, preventing astrocyte-mediated repair processes, depending on the activation state of the neuroimmune cells. This study investigated the poorly understood mechanism linking proinflammatory microglia activation and astrocyte-mediated tissue repair using an in vitro mechanical injury model in mixed cortical cultures of rat neurons and glia. We hypothesized that proinflammatory activation disrupts the microglial response to colony-stimulating factor 1 (CSF-1), which stimulates microglia migration and proliferation, both essential for astrocyte-mediated tissue repair. Following mechanical damage, cultures were treated with lipopolysaccharide (LPS) and interferon-gamma (IFNγ) to induce a proinflammatory state. Immunocytochemical and biochemical analyses were used to evaluate glial repair. Proinflammatory activation dramatically impeded wound closure, reducing microglial levels via upregulation of the zinc-dependent disintegrin and metalloprotease 17 (ADAM17), leading to the cleavage of the CSF-1 receptor (CSF-1R). Indeed, pharmacological inhibition of ADAM17 effectively promoted wound closure during inflammation. Moreover, zinc chelation prevented ADAM17-mediated cleavage of CSF-1R and induced the release of trophic factors, dramatically improving tissue recovery. Our findings strongly identify ADAM17 as a primary regulator of CSF-1R-mediated signaling and establish a mechanism defining the association between pro-inflammatory microglial activation and tissue repair following injury.
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Affiliation(s)
- Diego R. Hernandez-Espinosa
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Gabriela I. Medina-Ruiz
- Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Mia G. Scrabis
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
- Present Address: Molecular Imaging Branch (MIB), National Institute of Mental Health (NIMH), National Institutes of Health, Bethesda, MD, USA
| | - Amantha Thathiah
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Elias Aizenman
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
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2
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Freire MAM, Rocha GS, Bittencourt LO, Falcao D, Lima RR, Cavalcanti JRLP. Cellular and Molecular Pathophysiology of Traumatic Brain Injury: What Have We Learned So Far? BIOLOGY 2023; 12:1139. [PMID: 37627023 PMCID: PMC10452099 DOI: 10.3390/biology12081139] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023]
Abstract
Traumatic brain injury (TBI) is one of the leading causes of long-lasting morbidity and mortality worldwide, being a devastating condition related to the impairment of the nervous system after an external traumatic event resulting in transitory or permanent functional disability, with a significant burden to the healthcare system. Harmful events underlying TBI can be classified into two sequential stages, primary and secondary, which are both associated with breakdown of the tissue homeostasis due to impairment of the blood-brain barrier, osmotic imbalance, inflammatory processes, oxidative stress, excitotoxicity, and apoptotic cell death, ultimately resulting in a loss of tissue functionality. The present study provides an updated review concerning the roles of brain edema, inflammation, excitotoxicity, and oxidative stress on brain changes resulting from a TBI. The proper characterization of the phenomena resulting from TBI can contribute to the improvement of care, rehabilitation and quality of life of the affected people.
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Affiliation(s)
- Marco Aurelio M. Freire
- Graduate Program in Physiological Sciences, University of the State of Rio Grande do Norte, Mossoró 59607-360, RN, Brazil
| | - Gabriel Sousa Rocha
- Graduate Program in Biochemistry and Molecular Biology, University of the State of Rio Grande do Norte, Mossoró 59607-360, RN, Brazil
| | - Leonardo Oliveira Bittencourt
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém 66075-900, PA, Brazil
| | - Daniel Falcao
- VCU Health Systems, Virginia Commonwealth University, 23219 Richmond, VA, USA
| | - Rafael Rodrigues Lima
- Laboratory of Functional and Structural Biology, Institute of Biological Sciences, Federal University of Pará, Belém 66075-900, PA, Brazil
| | - Jose Rodolfo Lopes P. Cavalcanti
- Graduate Program in Physiological Sciences, University of the State of Rio Grande do Norte, Mossoró 59607-360, RN, Brazil
- Graduate Program in Biochemistry and Molecular Biology, University of the State of Rio Grande do Norte, Mossoró 59607-360, RN, Brazil
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Barker S, Paul BD, Pieper AA. Increased Risk of Aging-Related Neurodegenerative Disease after Traumatic Brain Injury. Biomedicines 2023; 11:1154. [PMID: 37189772 PMCID: PMC10135798 DOI: 10.3390/biomedicines11041154] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/30/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
Traumatic brain injury (TBI) survivors frequently suffer from chronically progressive complications, including significantly increased risk of developing aging-related neurodegenerative disease. As advances in neurocritical care increase the number of TBI survivors, the impact and awareness of this problem are growing. The mechanisms by which TBI increases the risk of developing aging-related neurodegenerative disease, however, are not completely understood. As a result, there are no protective treatments for patients. Here, we review the current literature surrounding the epidemiology and potential mechanistic relationships between brain injury and aging-related neurodegenerative disease. In addition to increasing the risk for developing all forms of dementia, the most prominent aging-related neurodegenerative conditions that are accelerated by TBI are amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson's disease (PD), and Alzheimer's disease (AD), with ALS and FTD being the least well-established. Mechanistic links between TBI and all forms of dementia that are reviewed include oxidative stress, dysregulated proteostasis, and neuroinflammation. Disease-specific mechanistic links with TBI that are reviewed include TAR DNA binding protein 43 and motor cortex lesions in ALS and FTD; alpha-synuclein, dopaminergic cell death, and synergistic toxin exposure in PD; and brain insulin resistance, amyloid beta pathology, and tau pathology in AD. While compelling mechanistic links have been identified, significantly expanded investigation in the field is needed to develop therapies to protect TBI survivors from the increased risk of aging-related neurodegenerative disease.
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Affiliation(s)
- Sarah Barker
- Center for Brain Health Medicines, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA;
- Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106, USA
- Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA
- Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Bindu D. Paul
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA;
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA
- The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA
- Lieber Institute for Brain Development, Baltimore, MD 21205, USA
| | - Andrew A. Pieper
- Center for Brain Health Medicines, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA;
- Department of Psychiatry, Case Western Reserve University, Cleveland, OH 44106, USA
- Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA
- Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA
- Translational Therapeutics Core, Cleveland Alzheimer’s Disease Research Center, Cleveland, OH 44106, USA
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Liu Y, Yao X, Lv X, Qian J. The role of spectrin breakdown products in patients with traumatic brain injury: a systematic review and meta-analysis. Neurol Sci 2023; 44:1171-1183. [PMID: 36547778 DOI: 10.1007/s10072-022-06558-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 12/11/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Spectrin Breakdown Products (SBDPs) accumulate in the brain after traumatic brain injury (TBI) and are expected to become a potentially promising biomarker of TBI. OBJECTIVE This systematic review and meta-analysis were undertaken to evaluate the role of SBDPs in the diagnosis and prognosis of TBI. METHODS We systematically searched the following databases up to 31 October 2022: Ovid MEDLINE, PubMed, EMBASE, Cochrane Library, and Web of Science Database, and studies were only included if they had sufficient data on SBDP concentrations in TBI patients. We calculated the standardized mean differences (SMDs) and 95% confidence intervals (CIs) for continuous outcomes and assessed the potential publication bias by using Egger's test and funnel plots. The statistical analysis was conducted by RevMan 5.4 and Stata 17. RESULTS Of 1429 identified studies, 10 studies involving 417 participants were included in our systematic review and meta-analysis. The results demonstrated that serum and cerebrospinal fluid (CSF) SBDP concentrations were significantly increased in TBI compared to controls (SBDP120: SMD = 1.42, 95% CI = 0.71 ~ 2.12, P < 0.00001; SBDP145: SMD = 1.32, 95% CI = 0.78 ~ 1.86, P < 0.00001; SBDP150: SMD = 1.39, 95% CI = 0.97 ~ 1.80, P < 0.00001), and CSF SBDPs were significantly associated with poor functional outcomes (PFO) (SBDP145: SMD = 1.75, 95% CI = 1.37 ~ 2.13, P < 0.00001; SBDP150: SMD = 1.14, 95% CI = 0.75 ~ 1.52, P < 0.00001). In addition, CSF and serum SBDP145 are valuable in diagnosing TBI (AUC = 0.89, 95% CI = 0.80 ~ 0.99, P < 0.00001), and CSF SBDP145 also has diagnostic value for PFO (AUC = 0.80, 95% CI = 0.76 ~ 0.84, P < 0.00001). CONCLUSIONS The limited evidence supports that the SBDPs can be employed as potential biomarkers for the diagnosis and prognosis of TBI.
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Affiliation(s)
- Yang Liu
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Haidian District, No. 48 Xinxi Road, Beijing, 102211, China
| | - Xiaomeng Yao
- Viterbi School of Engineering, University of Southern California, Los Angeles, LA, USA
| | - Xianglin Lv
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Haidian District, No. 48 Xinxi Road, Beijing, 102211, China
| | - Jinghua Qian
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Haidian District, No. 48 Xinxi Road, Beijing, 102211, China.
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Traumatic Brain Injury Induces Microglial and Caspase3 Activation in the Retina. Int J Mol Sci 2023; 24:ijms24054451. [PMID: 36901880 PMCID: PMC10003323 DOI: 10.3390/ijms24054451] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/18/2023] [Accepted: 02/22/2023] [Indexed: 03/05/2023] Open
Abstract
Traumatic brain injury (TBI) is among the main causes of sudden death after head trauma. These injuries can result in severe degeneration and neuronal cell death in the CNS, including the retina, which is a crucial part of the brain responsible for perceiving and transmitting visual information. The long-term effects of mild-repetitive TBI (rmTBI) are far less studied thus far, even though damage induced by repetitive injuries occurring in the brain is more common, especially amongst athletes. rmTBI can also have a detrimental effect on the retina and the pathophysiology of these injuries is likely to differ from severe TBI (sTBI) retinal injury. Here, we show how rmTBI and sTBI can differentially affect the retina. Our results indicate an increase in the number of activated microglial cells and Caspase3-positive cells in the retina in both traumatic models, suggesting a rise in the level of inflammation and cell death after TBI. The pattern of microglial activation appears distributed and widespread but differs amongst the various retinal layers. sTBI induced microglial activation in both the superficial and deep retinal layers. In contrast to sTBI, no significant change occurred following the repetitive mild injury in the superficial layer, only the deep layer (spanning from the inner nuclear layer to the outer plexiform layer) shows microglial activation. This difference suggests that alternate response mechanisms play a role in the case of the different TBI incidents. The Caspase3 activation pattern showed a uniform increase in both the superficial and deep layers of the retina. This suggests a different action in the course of the disease in sTBI and rmTBI models and points to the need for new diagnostic procedures. Our present results suggest that the retina might serve as such a model of head injuries since the retinal tissue reacts to both forms of TBI and is the most accessible part of the human brain.
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Unnisa A, Greig NH, Kamal MA. Inhibition of Caspase 3 and Caspase 9 Mediated Apoptosis: A Multimodal Therapeutic Target in Traumatic Brain Injury. Curr Neuropharmacol 2023; 21:1001-1012. [PMID: 35339178 PMCID: PMC10227914 DOI: 10.2174/1570159x20666220327222921] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 02/17/2022] [Accepted: 03/23/2022] [Indexed: 02/08/2023] Open
Abstract
Traumatic brain injury (TBI) is one of the significant causes of death and morbidity, and it is hence a focus of translational research. Apoptosis plays an essential part in the pathophysiology of TBI, and its inhibition may help overcome TBI's negative consequences and improve functional recovery. Although physiological neuronal death is necessary for appropriate embryologic development and adult cell turnover, it can also drive neurodegeneration. Caspases are principal mediators of cell death due to apoptosis and are critical for the required cleavage of intracellular proteins of cells committed to die. Caspase-3 is the major executioner Caspase of apoptosis and is regulated by a range of cellular components during physiological and pathological conditions. Activation of Caspase-3 causes proteolyzation of DNA repair proteins, cytoskeletal proteins, and the inhibitor of Caspase-activated DNase (ICAD) during programmed cell death, resulting in morphological alterations and DNA damage that define apoptosis. Caspase-9 is an additional crucial part of the intrinsic pathway, activated in response to several stimuli. Caspases can be altered post-translationally or by modulatory elements interacting with the zymogenic or active form of a Caspase, preventing their activation. The necessity of Caspase-9 and -3 in diverse apoptotic situations suggests that mammalian cells have at least four distinct apoptotic pathways. Continued investigation of these processes is anticipated to disclose new Caspase regulatory mechanisms with consequences far beyond apoptotic cell death control. The present review discusses various Caspase-dependent apoptotic pathways and the treatment strategies to inhibit the Caspases potentially.
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Affiliation(s)
- Aziz Unnisa
- Department of Pharmacology, College of Pharmacy, University of Hail, Hail, KSA;
| | - Nigel H. Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Mohammad Amjad Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka, Bangladesh
- Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770; Novel Global Community Educational Foundation, NSW, Australia
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7
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Hakiminia B, Alikiaii B, Khorvash F, Mousavi S. Oxidative stress and mitochondrial dysfunction following traumatic brain injury: From mechanistic view to targeted therapeutic opportunities. Fundam Clin Pharmacol 2022; 36:612-662. [PMID: 35118714 DOI: 10.1111/fcp.12767] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 01/15/2022] [Accepted: 02/02/2022] [Indexed: 02/07/2023]
Abstract
Traumatic brain injury (TBI) is one of the most prevalent causes of permanent physical and cognitive disabilities. TBI pathology results from primary insults and a multi-mechanistic biochemical process, termed as secondary brain injury. Currently, there are no pharmacological agents for definitive treatment of patients with TBI. This article is presented with the purpose of reviewing molecular mechanisms of TBI pathology, as well as potential strategies and agents against pathological pathways. In this review article, materials were obtained by searching PubMed, Scopus, Elsevier, Web of Science, and Google Scholar. This search was considered without time limitation. Evidence indicates that oxidative stress and mitochondrial dysfunction are two key mediators of the secondary injury cascade in TBI pathology. TBI-induced oxidative damage results in the structural and functional impairments of cellular and subcellular components, such as mitochondria. Impairments of mitochondrial electron transfer chain and mitochondrial membrane potential result in a vicious cycle of free radical formation and cell apoptosis. The results of some preclinical and clinical studies, evaluating mitochondria-targeted therapies, such as mitochondria-targeted antioxidants and compounds with pleiotropic effects after TBI, are promising. As a proposed strategy in recent years, mitochondria-targeted multipotential therapy is a new hope, waiting to be confirmed. Moreover, based on the available findings, biologics, such as stem cell-based therapy and transplantation of mitochondria are novel potential strategies for the treatment of TBI; however, more studies are needed to clearly confirm the safety and efficacy of these strategies.
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Affiliation(s)
- Bahareh Hakiminia
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Babak Alikiaii
- Department of Anesthesiology and Intensive Care, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fariborz Khorvash
- Department of Neurology, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Sarah Mousavi
- Department of Clinical Pharmacy and Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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Mesenchymal Stem Cell Therapy: A Potential Treatment Targeting Pathological Manifestations of Traumatic Brain Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4645021. [PMID: 35757508 PMCID: PMC9217616 DOI: 10.1155/2022/4645021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 05/30/2022] [Indexed: 01/02/2023]
Abstract
Traumatic brain injury (TBI) makes up a large proportion of acute brain injuries and is a major cause of disability globally. Its complicated etiology and pathogenesis mainly include primary injury and secondary injury over time, which can cause cognitive deficits, physical disabilities, mood changes, and impaired verbal communication. Recently, mesenchymal stromal cell- (MSC-) based therapy has shown significant therapeutic potential to target TBI-induced pathological processes, such as oxidative stress, neuroinflammation, apoptosis, and mitochondrial dysfunction. In this review, we discuss the main pathological processes of TBI and summarize the underlying mechanisms of MSC-based TBI treatment. We also discuss research progress in the field of MSC therapy in TBI as well as major shortcomings and the great potential shown.
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Liao S, Luo Y, Chunchai T, Singhanat K, Arunsak B, Benjanuwattra J, Apaijai N, Chattipakorn N, Chattipakorn SC. An apoptosis inhibitor suppresses microglial and astrocytic activation after cardiac ischemia/reperfusion injury. Inflamm Res 2022; 71:861-872. [PMID: 35655102 DOI: 10.1007/s00011-022-01590-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 05/06/2022] [Accepted: 05/16/2022] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE Microglial hyperactivation and apoptosis were observed following myocardial infarction and ischemia reperfusion (I/R) injury. This study aimed to test the hypothesis that the apoptosis inhibitor, Z-VAD, attenuates microglial and astrocytic hyperactivation and brain inflammation in rats with cardiac I/R injury. MATERIALS AND METHODS Rats were subjected to either sham or cardiac I/R operation (30 min-ischemia followed by 120-min reperfusion), rats in the cardiac I/R group were given either normal saline solution or Z-VAD at 3.3 mg/kg via intravenous injection 15 min prior to cardiac ischemia. Left ventricular ejection fraction (% LVEF) was determined during the cardiac I/R protocol. The brain tissues were removed and used to determine brain apoptosis, brain inflammation, microglial and astrocyte morphology. RESULTS Cardiac dysfunction was observed in rats with cardiac I/R injury as indicated by decreased %LVEF. In the brain, we found brain apoptosis, brain inflammation, microglia hyperactivation, and reactive astrogliosis occurred following cardiac I/R injury. Pretreatment with Z-VAD effectively increased %LVEF, reduced brain apoptosis, attenuated brain inflammation by decreasing IL-1β mRNA levels, suppressed microglial and astrocytic hyperactivation and proliferation after cardiac I/R injury. CONCLUSION Z-VAD exerts neuroprotective effects against cardiac I/R injury not only targeting apoptosis but also microglial and astrocyte activation.
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Affiliation(s)
- Suchan Liao
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Ying Luo
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Titikorn Chunchai
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Kodchanan Singhanat
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Busarin Arunsak
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Juthipong Benjanuwattra
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nattayaporn Apaijai
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand.,Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand. .,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand. .,Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand.
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10
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Zhang A, Zhang Z, Liu Y, Lenahan C, Xu H, Jiang J, Yuan L, Wang L, Xu Y, Chen S, Fang Y, Zhang J. The Role of Caspase Family in Acute Brain Injury: The Potential Therapeutic Targets in the Future. Curr Neuropharmacol 2022; 20:1194-1211. [PMID: 34766893 PMCID: PMC9886824 DOI: 10.2174/1570159x19666211111121146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 11/22/2022] Open
Abstract
The caspase family is commonly involved in the pathophysiology of acute brain injury (ABI) through complex apoptotic, pyroptotic, and inflammatory pathways. Current translational strategies for caspase modulation in ABI primarily focus on caspase inhibitors. Because there are no caspase-inhibiting drugs approved for clinical use on the market, the development of caspase inhibitors remains an attractive challenge for researchers and clinicians. Therefore, we conducted the present review with the aim of providing a comprehensive introduction of caspases in ABI. In this review, we summarized the available evidence and potential mechanisms regarding the biological function of caspases. We also reviewed the therapeutic effects of caspase inhibitors on ABI and its subsequent complications. However, various important issues remain unclear, prompting further verification of the efficacy and safety regarding clinical application of caspase inhibitors. We believe that our work will be helpful to further understand the critical role of the caspase family and will provide novel therapeutic potential for ABI treatment.
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Affiliation(s)
- Anke Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; ,These authors contributed equally to this work.
| | - Zeyu Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; ,These authors contributed equally to this work.
| | - Yibo Liu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; ,These authors contributed equally to this work.
| | - Cameron Lenahan
- Burrell College of Osteopathic Medicine, Las Cruces, New Mexico, USA;
| | - Houshi Xu
- Department of Neurosurgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;
| | | | | | | | - Yuanzhi Xu
- Department of Neurosurgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;
| | - Sheng Chen
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China;
| | - Yuanjian Fang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; ,Address correspondence to these authors at the Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; E-mail:
| | - Jianmin Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; ,Address correspondence to these authors at the Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; E-mail:
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11
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Sharma S, Tiarks G, Haight J, Bassuk AG. Neuropathophysiological Mechanisms and Treatment Strategies for Post-traumatic Epilepsy. Front Mol Neurosci 2021; 14:612073. [PMID: 33708071 PMCID: PMC7940684 DOI: 10.3389/fnmol.2021.612073] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/26/2021] [Indexed: 12/11/2022] Open
Abstract
Traumatic brain injury (TBI) is a leading cause of death in young adults and a risk factor for acquired epilepsy. Severe TBI, after a period of time, causes numerous neuropsychiatric and neurodegenerative problems with varying comorbidities; and brain homeostasis may never be restored. As a consequence of disrupted equilibrium, neuropathological changes such as circuit remodeling, reorganization of neural networks, changes in structural and functional plasticity, predisposition to synchronized activity, and post-translational modification of synaptic proteins may begin to dominate the brain. These pathological changes, over the course of time, contribute to conditions like Alzheimer disease, dementia, anxiety disorders, and post-traumatic epilepsy (PTE). PTE is one of the most common, devastating complications of TBI; and of those affected by a severe TBI, more than 50% develop PTE. The etiopathology and mechanisms of PTE are either unknown or poorly understood, which makes treatment challenging. Although anti-epileptic drugs (AEDs) are used as preventive strategies to manage TBI, control acute seizures and prevent development of PTE, their efficacy in PTE remains controversial. In this review, we discuss novel mechanisms and risk factors underlying PTE. We also discuss dysfunctions of neurovascular unit, cell-specific neuroinflammatory mediators and immune response factors that are vital for epileptogenesis after TBI. Finally, we describe current and novel treatments and management strategies for preventing PTE.
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Affiliation(s)
- Shaunik Sharma
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
| | - Grant Tiarks
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
| | - Joseph Haight
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
| | - Alexander G Bassuk
- Medical Laboratories, Department of Pediatrics, University of Iowa, Iowa City, IA, United States
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Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions. Biomedicines 2020; 8:biomedicines8100389. [PMID: 33003373 PMCID: PMC7601301 DOI: 10.3390/biomedicines8100389] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 09/25/2020] [Accepted: 09/26/2020] [Indexed: 12/15/2022] Open
Abstract
Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.
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Abstract
Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide. Although TBI leads to mechanical damage during initial impact, secondary damage also occurs as results from delayed neurochemical process and intracellular signaling pathways. Accumulated animal and human studies demonstrated that apoptotic mechanism contributes to overall pathology of TBI. Apoptotic cell death has been identified within contusional brain lesion at acute phase of TBI and in region remote from the site directly injured in days to weeks after trauma. TBI is also dynamic conditions that cause neuronal decline overtime and is likely due to neurodegenerative mechanisms years after trauma. Current studies have even suggested association of neuronal damage through apoptotic pathway with mild TBI, which contributes chronic persistent neurological symptoms and cognitive deficits. Thus, a better understanding of the acute and chronic consequences of apoptosis following TBI is required. The purpose of this review is to describe (1) neuronal apoptotic pathway following TBI, (2) contribution of apoptosis to acute and chronic phase of TBI, and (3) current treatment targeting on apoptotic pathway.
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Affiliation(s)
- Yosuke Akamatsu
- Division of Neurosurgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Department of Neurosurgery, Iwate Medical University, Morioka, Japan
| | - Khalid A Hanafy
- Department of Neurology, Harvard Medical School, Boston, MA, USA.
- Division of Neurointensive Care, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle Rm 639, Boston, MA, 02115, USA.
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Jing Y, Yang DX, Wang W, Yuan F, Chen H, Ding J, Geng Z, Tian HL. Aloin Protects Against Blood-Brain Barrier Damage After Traumatic Brain Injury in Mice. Neurosci Bull 2020; 36:625-638. [PMID: 32100248 DOI: 10.1007/s12264-020-00471-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 12/06/2019] [Indexed: 12/13/2022] Open
Abstract
Aloin is a small-molecule drug well known for its protective actions in various models of damage. Traumatic brain injury (TBI)-induced cerebral edema from secondary damage caused by disruption of the blood-brain barrier (BBB) often leads to an adverse prognosis. Since the role of aloin in maintaining the integrity of the BBB after TBI remains unclear, we explored the protective effects of aloin on the BBB using in vivo and in vitro TBI models. Adult male C57BL/6 mice underwent controlled cortical impact injury, and mouse brain capillary endothelial bEnd.3 cells underwent biaxial stretch injury, then both received aloin treatment. In the animal experiments, we found 20 mg/kg aloin to be the optimum concentration to decrease cerebral edema, decrease disruption of the BBB, and improve neurobehavioral performance after cortical impact injury. In the cellular studies, the optimum concentration of 40 μg/mL aloin reduced apoptosis and reversed the loss of tight junctions by reducing the reactive oxygen species levels and changes in mitochondrial membrane potential after stretch injury. The mechanisms may be that aloin downregulates the phosphorylation of p38 mitogen-activated protein kinase, the activation of p65 nuclear factor-kappa B, and the ratios of B cell lymphoma (Bcl)-2-associated X protein/Bcl-2 and cleaved caspase-3/caspase-3. We conclude that aloin exhibits these protective effects on the BBB after TBI through its anti-oxidative stress and anti-apoptotic properties in mouse brain capillary endothelial cells. Aloin may thus be a promising therapeutic drug for TBI.
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Affiliation(s)
- Yao Jing
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Dian-Xu Yang
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Wei Wang
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Fang Yuan
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Hao Chen
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Jun Ding
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Zhi Geng
- Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| | - Heng-Li Tian
- Department of Neurosurgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
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Sahab Negah S, Oliazadeh P, Jahanbazi Jahan-Abad A, Eshaghabadi A, Samini F, Ghasemi S, Asghari A, Gorji A. Transplantation of human meningioma stem cells loaded on a self-assembling peptide nanoscaffold containing IKVAV improves traumatic brain injury in rats. Acta Biomater 2019; 92:132-144. [PMID: 31075516 DOI: 10.1016/j.actbio.2019.05.010] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/02/2019] [Accepted: 05/06/2019] [Indexed: 12/20/2022]
Abstract
Traumatic brain injury (TBI) can result in permanent brain function impairment due to the poor regenerative ability of neural tissue. Tissue engineering has appeared as a promising approach to promote nerve regeneration and to ameliorate brain damage. The present study was designed to investigate the effect of transplantation of the human meningioma stem-like cells (hMgSCs) seeded in a promising three-dimensional scaffold (RADA4GGSIKVAV; R-GSIK) on the functional recovery of the brain and neuroinflammatory responses following TBI in rats. After induction of TBI, hMgSCs seeded in R-GSIK was transplanted within the injury site and its effect was compared to several control groups. Application of hMgSCs with R-GSIK improved functional recovery after TBI. A significant higher number of hMgSCs was observed in the brain when transplanted with R-GSIK scaffold compared to the control groups. Application of hMgSCs seeded in R-GSIK significantly decreased the lesion volume, reactive gliosis, and apoptosis at the injury site. Furthermore, treatment with hMgSCs seeded in R-GSIK significantly inhibited the expression of Toll-like receptor 4 and its downstream signaling molecules, including interleukin-1β and tumor necrosis factor. These data revealed the potential for hMgSCs seeded in R-GSIK to improve the functional recovery of the brain after TBI; possibly via amelioration of inflammatory responses. STATEMENT OF SIGNIFICANCE: Tissue engineered scaffolds that mimic the natural extracellular matrix of the brain may modulate stem cell fate and contribute to tissue repair following traumatic brain injury (TBI). Among several scaffolds, self-assembly peptide nanofiber scaffolds markedly promotes cellular behaviors, including cell survival and differentiation. We developed a novel three-dimensional scaffold (RADA16GGSIKVAV; R-GSIK). Transplantation of the human meningioma stem-like cells seeded in R-GSIK in an animal model of TBI significantly improved functional recovery of the brain, possibly via enhancement of stem cell survival as well as reduction of the lesion volume, inflammatory process, and reactive gliosis at the injury site. R-GSIK is a suitable microenvironment for human stem cells and could be a potential biomaterial for the reconstruction of the injured brain after TBI.
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Glotfelty EJ, Delgado TE, Tovar-y-Romo LB, Luo Y, Hoffer BJ, Olson L, Karlsson TE, Mattson MP, Harvey BK, Tweedie D, Li Y, Greig NH. Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury. ACS Pharmacol Transl Sci 2019; 2:66-91. [PMID: 31396586 PMCID: PMC6687335 DOI: 10.1021/acsptsci.9b00003] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Indexed: 12/17/2022]
Abstract
Traumatic brain injury (TBI) is becoming an increasing public health issue. With an annually estimated 1.7 million TBIs in the United States (U.S) and nearly 70 million worldwide, the injury, isolated or compounded with others, is a major cause of short- and long-term disability and mortality. This, along with no specific treatment, has made exploration of TBI therapies a priority of the health system. Age and sex differences create a spectrum of vulnerability to TBI, with highest prevalence among younger and older populations. Increased public interest in the long-term effects and prevention of TBI have recently reached peaks, with media attention bringing heightened awareness to sport and war related head injuries. Along with short-term issues, TBI can increase the likelihood for development of long-term neurodegenerative disorders. A growing body of literature supports the use of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor (R) agonists, along with unimolecular combinations of these therapies, for their potent neurotrophic/neuroprotective activities across a variety of cellular and animal models of chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and acute cerebrovascular disorders (stroke). Mild or moderate TBI shares many of the hallmarks of these conditions; recent work provides evidence that use of these compounds is an effective strategy for its treatment. Safety and efficacy of many incretin-based therapies (GLP-1 and GIP) have been demonstrated in humans for the treatment of type 2 diabetes mellitus (T2DM), making these compounds ideal for rapid evaluation in clinical trials of mild and moderate TBI.
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Affiliation(s)
- Elliot J. Glotfelty
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
- Department
of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Thomas E. Delgado
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
| | - Luis B. Tovar-y-Romo
- Division
of Neuroscience, Institute of Cellular Physiology, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Yu Luo
- Department
of Molecular Genetics, University of Cincinnati, Cincinnati, Ohio 45221, United States
| | - Barry J. Hoffer
- Department
of Neurosurgery, Case Western Reserve University
School of Medicine, Cleveland, Ohio 44106, United States
| | - Lars Olson
- Department
of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | | | - Mark P. Mattson
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
| | - Brandon K. Harvey
- Molecular
Mechanisms of Cellular Stress and Inflammation Unit, Integrative Neuroscience
Department, National Institute on Drug Abuse,
National Institutes of Health, Baltimore, Maryland 21224, United States
| | - David Tweedie
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
| | - Yazhou Li
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
| | - Nigel H. Greig
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
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Xing G, Ren M, Verma A. Divergent Induction of Branched-Chain Aminotransferases and Phosphorylation of Branched Chain Keto-Acid Dehydrogenase Is a Potential Mechanism Coupling Branched-Chain Keto-Acid-Mediated-Astrocyte Activation to Branched-Chain Amino Acid Depletion-Mediated Cognitive Deficit after Traumatic Brain Injury. J Neurotrauma 2018; 35:2482-2494. [PMID: 29764289 PMCID: PMC6196747 DOI: 10.1089/neu.2017.5496] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Deficient branched-chain amino acids (BCAAs) are implicated in cognitive dysfunction after traumatic brain injury (TBI). The mechanism remains unknown. BCAAs are catabolized by neuron-specific cytosolic and astrocyte-specific mitochondrial branched-chain aminotransferases (BCATc, BCATm) to generate glutamate and branched-chain keto-acids (BCKAs) that are metabolized by the mitochondrial branched-chain keto-acid dehydrogenase (BCKD) whose activity is regulated by its phosphorylation state. BCKD phosphorylation by BCKD kinase (BCKDK) inactivates BCKD and cause neurocognitive dysfunction, whereas dephosphorylation by specific phosphatase restores BCKD activity. Real-time polymerase chain reaction showed rapidly and significantly decreased BCATc messenger RNA (mRNA) levels, but significantly increased BCATm mRNA level post-CCI (controlled cortical impact). BCKD and BCKDK mRNA decreased significantly immediately after CCI-induced TBI (CCI) in the rat. Phosphorylated BCKD proteins (pBCKD) increased significantly in the ipsilateral-CCI hemisphere. Immunohistochemistry revealed significantly increased pBCKD proteins in ipsilateral astrocytes post-CCI. BCKD protein expression is higher in primarily cultured cortical neurons than in astrocytes, whereas pBCKD protein level is higher in astrocytes than in cortical neurons. Transforming growth factor beta treatment (10 μg/mL for 48 h) significantly increased pBCKD protein expression in astrocytes, whereas glutamate treatment (25 μM for 24 h) significantly decreased pBCKD protein in neurons. Because increased pBCKD would lead to increased BCKA accumulation, BCKA-mediated astrocyte activation, cell death, and cognitive dysfunction as found in maple syrup urine disease; thus, TBI may potentially induce cognitive deficit through diverting BCAA from glutamate production in neurons to BCKA production in astrocytes through the pBCKD-dependent mechanism.
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Affiliation(s)
- Guoqiang Xing
- Department of Radiology and Imaging, Institute of Rehabilitation and Development of Brain Function, The Second Clinical Medical College of North Sichuan Medical College, Nanchong Central Hospital, Nanchong, China
| | - Ming Ren
- Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China
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Chronic Upregulation of Cleaved-Caspase-3 Associated with Chronic Myelin Pathology and Microvascular Reorganization in the Thalamus after Traumatic Brain Injury in Rats. Int J Mol Sci 2018; 19:ijms19103151. [PMID: 30322151 PMCID: PMC6214127 DOI: 10.3390/ijms19103151] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 10/06/2018] [Accepted: 10/09/2018] [Indexed: 12/14/2022] Open
Abstract
Traumatic brain injury (TBI) is associated with long-term disabilities and devastating chronic neurological complications including problems with cognition, motor function, sensory processing, as well as behavioral deficits and mental health problems such as anxiety, depression, personality change and social unsuitability. Clinical data suggest that disruption of the thalamo-cortical system including anatomical and metabolic changes in the thalamus following TBI might be responsible for some chronic neurological deficits following brain trauma. Detailed mechanisms of these pathological processes are not completely understood. The goal of this study was to evaluate changes in the thalamus following TBI focusing on cleaved-caspase-3, a specific effector of caspase pathway activation and myelin and microvascular pathologies using immuno- and histochemistry at different time points from 24 h to 3 months after controlled cortical impact (CCI) in adult Sprague-Dawley rats. Significant increases in cleaved-caspase-3 immunoreactivity in the thalamus were observed starting one month and persisting for at least three months following experimental TBI. Further, the study demonstrated an association of cleaved-caspase-3 with the demyelination of neuronal processes and tissue degeneration in the gray matter in the thalamus, as reflected in alterations of myelinated fiber integrity (luxol fast blue) and decreases in myelin basic protein (MBP) immunoreactivity. The immunofluorescent counterstaining of cleaved-caspase-3 with endothelial barrier antigen (EBA), a marker of blood-brain barrier, revealed limited direct and indirect associations of cleaved caspase-3 with blood-brain barrier damage. These results demonstrate for the first time a significant chronic upregulation of cleaved-caspase-3 in selected thalamic regions associated with cortical regions directly affected by CCI injury. Further, our study is also the first to report that significant upregulation of cleaved-caspase-3 in selected ipsilateral thalamic regions is associated with microvascular reorganization reflected in the significant increases in the number of microvessels with blood-brain barrier alterations detected by EBA staining. These findings provide new insights into potential mechanisms of TBI cell death involving chronic activation of caspase-3 associated with disrupted cortico-thalamic and thalamo-cortical connectivity. Moreover, this study offers the initial evidence that this upregulation of activated caspase-3, delayed degeneration of myelinated nerve fibers and microvascular reorganization with impaired blood-brain barrier integrity in the thalamus might represent reciprocal pathological processes affecting neuronal networks and brain function at the chronic stages of TBI.
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Neuroprotective Effects of Platonin, a Therapeutic Immunomodulating Medicine, on Traumatic Brain Injury in Mice after Controlled Cortical Impact. Int J Mol Sci 2018; 19:ijms19041100. [PMID: 29642394 PMCID: PMC5979356 DOI: 10.3390/ijms19041100] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/02/2018] [Accepted: 04/03/2018] [Indexed: 11/23/2022] Open
Abstract
Traumatic brain injury (TBI) is one of the leading causes of mortality worldwide and leads to persistent cognitive, sensory, motor dysfunction, and emotional disorders. TBI-caused primary injury results in structural damage to brain tissues. Following the primary injury, secondary injuries which are accompanied by neuroinflammation, microglial activation, and additional cell death subsequently occur. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers, and some types of acute inflammation. In the present study, the neuroprotective effects of platonin against TBI were explored in a controlled cortical impact (CCI) injury model in mice. Treatment with platonin (200 µg/kg) significantly reduced the neurological severity score, general locomotor activity, and anxiety-related behavior, and improved the rotarod performance of CCI-injured mice. In addition, platonin reduced lesion volumes, the expression of cleaved caspase-3, and microglial activation in TBI-insulted brains. Platonin also suppressed messenger (m)RNA levels of caspase-3, caspase-1, cyclooxygenase-2, tumor necrosis factor-α, interleukin-6, and interleukin-1β. On the other hand, free radical production after TBI was obviously attenuated in platonin-treated mice. Treatment with platonin exhibited prominent neuroprotective properties against TBI in a CCI mouse model through its anti-inflammatory, anti-apoptotic, and anti-free radical capabilities. This evidence collectively indicates that platonin may be a potential therapeutic medicine for use with TBIs.
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Kim W, Ma L, Lomoio S, Willen R, Lombardo S, Dong J, Haydon PG, Tesco G. BACE1 elevation engendered by GGA3 deletion increases β-amyloid pathology in association with APP elevation and decreased CHL1 processing in 5XFAD mice. Mol Neurodegener 2018; 13:6. [PMID: 29391027 PMCID: PMC5796504 DOI: 10.1186/s13024-018-0239-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 01/24/2018] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in the production of amyloid beta (Aβ), the toxic peptide that accumulates in the brains of Alzheimer's disease (AD) patients. Our previous studies have shown that the clathrin adaptor Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) plays a key role in the trafficking of BACE1 to lysosomes, where it is normally degraded. GGA3 depletion results in BACE1 stabilization both in vitro and in vivo. Moreover, levels of GGA3 are reduced and inversely related to BACE1 levels in post-mortem brains of AD patients. METHOD In order to assess the effect of GGA3 deletion on AD-like phenotypes, we crossed GGA3 -/- mice with 5XFAD mice. BACE1-mediated processing of APP and the cell adhesion molecule L1 like protein (CHL1) was measured as well as levels of Aβ42 and amyloid burden. RESULTS In 5XFAD mice, we found that hippocampal and cortical levels of GGA3 decreased while BACE1 levels increased with age, similar to what is observed in human AD brains. GGA3 deletion prevented age-dependent elevation of BACE1 in GGA3KO;5XFAD mice. We also found that GGA3 deletion resulted in increased hippocampal levels of Aβ42 and amyloid burden in 5XFAD mice at 12 months of age. While levels of BACE1 did not change with age and gender in GGAKO;5XFAD mice, amyloid precursor protein (APP) levels increased with age and were higher in female mice. Moreover, elevation of APP was associated with a decreased BACE1-mediated processing of CHL1 not only in 12 months old 5XFAD mice but also in human brains from subjects affected by Down syndrome, most likely due to substrate competition. CONCLUSION This study demonstrates that GGA3 depletion is a leading candidate mechanism underlying elevation of BACE1 in AD. Furthermore, our findings suggest that BACE1 inhibition could exacerbate mechanism-based side effects in conditions associated with APP elevation (e.g. Down syndrome) owing to impairment of BACE1-mediated processing of CHL1. Therefore, therapeutic approaches aimed to restore GGA3 function and to prevent the down stream effects of its depletion (e.g. BACE1 elevation) represent an attractive alternative to BACE inhibition for the prevention/treatment of AD.
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Affiliation(s)
- WonHee Kim
- Alzheimer’s Disease Research Laboratory, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
- Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
| | - Liang Ma
- Alzheimer’s Disease Research Laboratory, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
- Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
| | - Selene Lomoio
- Alzheimer’s Disease Research Laboratory, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
- Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
| | - Rachel Willen
- Alzheimer’s Disease Research Laboratory, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
- Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
| | - Sylvia Lombardo
- Alzheimer’s Disease Research Laboratory, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
- Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
| | - Jinghui Dong
- Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
| | - Philip G. Haydon
- Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
| | - Giuseppina Tesco
- Alzheimer’s Disease Research Laboratory, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
- Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111 USA
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Glushakova OY, Glushakov AO, Borlongan CV, Valadka AB, Hayes RL, Glushakov AV. Role of Caspase-3-Mediated Apoptosis in Chronic Caspase-3-Cleaved Tau Accumulation and Blood–Brain Barrier Damage in the Corpus Callosum after Traumatic Brain Injury in Rats. J Neurotrauma 2018. [DOI: 10.1089/neu.2017.4999] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Olena Y. Glushakova
- Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia
| | - Andriy O. Glushakov
- Department of Neurosurgery, University of South Florida College of Medicine, Tampa, Florida
| | - Cesar V. Borlongan
- Department of Neurosurgery, University of South Florida College of Medicine, Tampa, Florida
| | - Alex B. Valadka
- Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia
| | - Ronald L. Hayes
- Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia
- Banyan Biomarkers, Inc., Alachua, Florida
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Liu YL, Xu ZM, Yang GY, Yang DX, Ding J, Chen H, Yuan F, Tian HL. Sesamin alleviates blood-brain barrier disruption in mice with experimental traumatic brain injury. Acta Pharmacol Sin 2017; 38:1445-1455. [PMID: 28770828 DOI: 10.1038/aps.2017.103] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 03/12/2017] [Indexed: 12/16/2022]
Abstract
Sesamin, a major lignan of sesame oil, was reported to have neuroprotective effects in several brain injury models. However, its protective action in maintaining blood-brain barrier (BBB) integrity has not been studied. In this study we investigated the effects of sesamin on the BBB in a mouse model of traumatic brain injury (TBI) and explored the underlying mechanisms. Adult male C57BL/6 mice were subjected to a controlled cortical impact (CCI) injury and then received sesamin (30 mg·kg-1·d-1, ip). The mice were euthanized on the 1st and 3rd days after CCI injury and samples were collected for analysis. Sesamin treatment significantly attenuated CCI-induced brain edema on the 1st and 3rd days after the injury, evidenced by the decreases in water content, tissue hemoglobin levels, Evans blue extravasation and AQP4 expression levels in the ipsilateral cortical tissue compared with the vehicle-treated group. Furthermore, sesamin treatment significantly alleviated CCI-induced loss of the tight junction proteins ZO-1 and occludin in the brain tissues. The neuroprotective mechanisms of sesamin were further explored in cultured mouse brain microvascular bEnd.3 cells subjected to biaxial stretch injury (SI). Pretreatment with sesamin (50 μmol/L) significantly alleviated SI-induced loss of ZO-1 in bEnd.3 cells. Furthermore, we revealed that pretreatment with sesamin significantly attenuated SI-induced oxidative stress and early-stage apoptosis in bEnd.3 cells by decreasing the activation of ERK, p-38 and caspase-3. In conclusion, sesamin alleviates BBB disruption at least partly through its anti-oxidative and anti-apoptotic effects on endothelial cells in CCI injury. These findings suggest that sesamin may be a promising potential therapeutic intervention for preventing disruption of the BBB after TBI.
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Glushakova OY, Glushakov AA, Wijesinghe DS, Valadka AB, Hayes RL, Glushakov AV. Prospective clinical biomarkers of caspase-mediated apoptosis associated with neuronal and neurovascular damage following stroke and other severe brain injuries: Implications for chronic neurodegeneration. Brain Circ 2017; 3:87-108. [PMID: 30276309 PMCID: PMC6126261 DOI: 10.4103/bc.bc_27_16] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 04/10/2017] [Accepted: 04/17/2017] [Indexed: 12/11/2022] Open
Abstract
Acute brain injuries, including ischemic and hemorrhagic stroke, as well as traumatic brain injury (TBI), are major worldwide health concerns with very limited options for effective diagnosis and treatment. Stroke and TBI pose an increased risk for the development of chronic neurodegenerative diseases, notably chronic traumatic encephalopathy, Alzheimer's disease, and Parkinson's disease. The existence of premorbid neurodegenerative diseases can exacerbate the severity and prognosis of acute brain injuries. Apoptosis involving caspase-3 is one of the most common mechanisms involved in the etiopathology of both acute and chronic neurological and neurodegenerative diseases, suggesting a relationship between these disorders. Over the past two decades, several clinical biomarkers of apoptosis have been identified in cerebrospinal fluid and peripheral blood following ischemic stroke, intracerebral and subarachnoid hemorrhage, and TBI. These biomarkers include selected caspases, notably caspase-3 and its specific cleavage products such as caspase-cleaved cytokeratin-18, caspase-cleaved tau, and a caspase-specific 120 kDa αII-spectrin breakdown product. The levels of these biomarkers might be a valuable tool for the identification of pathological pathways such as apoptosis and inflammation involved in injury progression, assessment of injury severity, and prediction of clinical outcomes. This review focuses on clinical studies involving biomarkers of caspase-3-mediated pathways, following stroke and TBI. The review further examines their prospective diagnostic utility, as well as clinical utility for improved personalized treatment of stroke and TBI patients and the development of prophylactic treatment chronic neurodegenerative disease.
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Affiliation(s)
- Olena Y Glushakova
- Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA
| | - Andriy A Glushakov
- Department of Neurosurgery, University of South Florida College of Medicine, Tampa, FL, USA
| | - Dayanjan S Wijesinghe
- Department of Pharmacotherapy and Outcomes Sciences, Laboratory of Pharmacometabolomics and Companion Diagnostics, Virginia Commonwealth University, Richmond, VA, USA
| | - Alex B Valadka
- Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA
| | - Ronald L Hayes
- Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA
- Banyan Biomarkers, Inc., Alachua, 32615, USA
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Muneer PMA, Conte AA, Haldar D, Long M, Patel RK, Santhakumar V, Overall CM, Pfister BJ. Traumatic brain injury induced matrix metalloproteinase2 cleaves CXCL12α (stromal cell derived factor 1α) and causes neurodegeneration. Brain Behav Immun 2017; 59:190-199. [PMID: 27614125 DOI: 10.1016/j.bbi.2016.09.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Revised: 08/26/2016] [Accepted: 09/06/2016] [Indexed: 12/15/2022] Open
Abstract
Traumatic brain injury (TBI), even at mild levels, can activate matrix metalloproteinases (MMPs) and the induction of neuroinflammation that can result in blood brain barrier breakdown and neurodegeneration. MMP2 has a significant role in neuroinflammation and neurodegeneration by modulating the chemokine CXCL12α (stromal cell derived factor SDF-1α) signaling pathway and the induction of apoptosis. SDF-1α is responsible for cell proliferation and differentiation throughout the nervous system and is also implicated in various neurodegenerative illnesses. We hypothesized that TBI leads to MMP2 activation and cleavage of the N-terminal 4 amino acid residues of CXCL12α with generation of the highly neurotoxic fragment SDF-1(5-67). Using an in vitro stretch-injury model of rat neuronal cultures and the in vivo fluid percussion injury (FPI) model in rats, we found that oxidative stress has a significant role in the activation of MMP2. This is initiated by the induction of free radical generating enzyme NADPH oxidase 1 (NOX1). Induction of NOX1 correlated well with the signatures of oxidative stress marker, 4HNE in the injured neuronal cultures and cerebral cortex of rats. Further, using MMP2 siRNA and pharmacological MMP2 inhibitor, ARP100, we established the neurodegenerative role of MMP2 in cleaving SDF-1α to a neurotoxic fragment SDF-1(5-67). By immunofluorescence, western blotting and TUNEL experiments, we show the cleaved form of SDF leads to apoptotic cell death in neurons. This work identifies a new potential therapeutic target to reduce the complications of brain damage in TBI.
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Affiliation(s)
- P M Abdul Muneer
- Laboratory of CNS Injury and Repair, Neuroscience Institute, JFK Medical Center, 65 James St, Edison, NJ 08820, United States; Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States.
| | - Adriano Andrea Conte
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States
| | - Debanjan Haldar
- Laboratory of CNS Injury and Repair, Neuroscience Institute, JFK Medical Center, 65 James St, Edison, NJ 08820, United States; Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States
| | - Mathew Long
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States
| | - Rachel K Patel
- Laboratory of CNS Injury and Repair, Neuroscience Institute, JFK Medical Center, 65 James St, Edison, NJ 08820, United States; Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States
| | - Vijayalakshmi Santhakumar
- Department of Pharmacology, Physiology and Neuroscience, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Christopher M Overall
- Departments of Biochemistry and Molecular Biology, and Oral Biological and Medical Sciences, University of British Columbia, 2199 Westbrook Mall, Vancouver, British Columbia V6T 1Z3, Canada
| | - Bryan J Pfister
- Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States.
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Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein. Proc Natl Acad Sci U S A 2016; 113:9587-92. [PMID: 27482083 DOI: 10.1073/pnas.1610099113] [Citation(s) in RCA: 204] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.
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Shahim P, Linemann T, Inekci D, Karsdal MA, Blennow K, Tegner Y, Zetterberg H, Henriksen K. Serum Tau Fragments Predict Return to Play in Concussed Professional Ice Hockey Players. J Neurotrauma 2016; 33:1995-1999. [PMID: 25621407 DOI: 10.1089/neu.2014.3741] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The diagnosis of sports-related concussion is mainly based on subjective clinical symptoms and neuropsychological tests. Therefore, reliable brain injury biomarkers to assess when it is safe to return to play are highly desirable. The overall objective of this study was to evaluate the utility of two newly described tau fragments for diagnosis and prognosis of sports-related concussions. This multi-center prospective cohort study involved all 12 teams of the top professional ice hockey league in Sweden. A total of 288 players consented to participate in the study. Thirty-five players sustained concussions, of whom 28 underwent repeated blood samplings at 1, 12, 36, and 144 h after the trauma, or when the player returned to play (7 to >90 days). There was no significant increase in the levels of Tau-A in post-concussion samples compared with preseason values. However, serum levels of Tau-C were significantly higher in post-concussion samples compared with preseason. Further, levels of Tau-A correlated with the duration of post-concussive symptoms. Tau-A in serum, which is newly discovered biomarker, could be used to predict when it is safe to return to play after a sports-related concussion.
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Affiliation(s)
- Pashtun Shahim
- 1 Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology , the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
| | - Thomas Linemann
- 2 Biomarkers & Research , Nordic Bioscience, Herlev, Denmark
| | - Dilek Inekci
- 2 Biomarkers & Research , Nordic Bioscience, Herlev, Denmark
| | | | - Kaj Blennow
- 1 Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology , the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
| | - Yelverton Tegner
- 3 Division of Medical Sciences, Department of Health Sciences, Luleå University of Technology , Luleå, Sweden
| | - Henrik Zetterberg
- 1 Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology , the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden .,4 UCL Institute of Neurology , Queen Square, London, United Kingdom
| | - Kim Henriksen
- 2 Biomarkers & Research , Nordic Bioscience, Herlev, Denmark
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Ekmark-Lewén S, Flygt J, Fridgeirsdottir GA, Kiwanuka O, Hånell A, Meyerson BJ, Mir AK, Gram H, Lewén A, Clausen F, Hillered L, Marklund N. Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β. Eur J Neurosci 2016; 43:1016-33. [PMID: 27091435 DOI: 10.1111/ejn.13190] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 01/06/2016] [Accepted: 01/26/2016] [Indexed: 12/15/2022]
Abstract
Widespread traumatic axonal injury (TAI) results in brain network dysfunction, which commonly leads to persisting cognitive and behavioural impairments following traumatic brain injury (TBI). TBI induces a complex neuroinflammatory response, frequently located at sites of axonal pathology. The role of the pro-inflammatory cytokine interleukin (IL)-1β has not been established in TAI. An IL-1β-neutralizing or a control antibody was administered intraperitoneally at 30 min following central fluid percussion injury (cFPI), a mouse model of widespread TAI. Mice subjected to moderate cFPI (n = 41) were compared with sham-injured controls (n = 20) and untreated, naive mice (n = 9). The anti-IL-1β antibody reached the target brain regions in adequate therapeutic concentrations (up to ~30 μg/brain tissue) at 24 h post-injury in both cFPI (n = 5) and sham-injured (n = 3) mice, with lower concentrations at 72 h post-injury (up to ~18 μg/g brain tissue in three cFPI mice). Functional outcome was analysed with the multivariate concentric square field (MCSF) test at 2 and 9 days post-injury, and the Morris water maze (MWM) at 14-21 days post-injury. Following TAI, the IL-1β-neutralizing antibody resulted in an improved behavioural outcome, including normalized behavioural profiles in the MCSF test. The performance in the MWM probe (memory) trial was improved, although not in the learning trials. The IL-1β-neutralizing treatment did not influence cerebral ventricle size or the number of microglia/macrophages. These findings support the hypothesis that IL-1β is an important contributor to the processes causing complex cognitive and behavioural disturbances following TAI.
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Affiliation(s)
- Sara Ekmark-Lewén
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden
| | - Johanna Flygt
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden
| | | | - Olivia Kiwanuka
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden
| | - Anders Hånell
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden
| | - Bengt J Meyerson
- Department of Neuroscience, Pharmacology, Biomedical Centre, Uppsala University, Uppsala, Sweden
| | - Anis K Mir
- Novartis Institutes of Biomedical Research, Basel, Switzerland
| | - Hermann Gram
- Novartis Institutes of Biomedical Research, Basel, Switzerland
| | - Anders Lewén
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden
| | - Fredrik Clausen
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden
| | - Lars Hillered
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden
| | - Niklas Marklund
- Department of Neuroscience, Neurosurgery, Uppsala University, Uppsala, Sweden.,Department of Neurosurgery, Uppsala University Hospital, Ing 85, 2 tr, SE-756 55, Uppsala, Sweden
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Xu L. Animal model of repetitive mild traumatic brain injury for human traumatic axonal injury and chronic traumatic encephalopathy. Neural Regen Res 2016; 10:1731-2. [PMID: 26807094 PMCID: PMC4705771 DOI: 10.4103/1673-5374.165319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Leyan Xu
- Division of Neuropathology, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Analysis of the Oxidative Stress Status in Nonspecific Vaginitis and Its Role in Vaginal Epithelial Cells Apoptosis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:795656. [PMID: 26558281 PMCID: PMC4628999 DOI: 10.1155/2015/795656] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 08/20/2015] [Accepted: 09/01/2015] [Indexed: 11/18/2022]
Abstract
Nonspecific vaginitis (NSV), also named bacterial vaginosis, is one of the most common genital system diseases in women during their reproductive years. The specific pathogenic mechanism of NSV is not clear yet. Upon the balance alteration, large amount of reactive oxidant species (ROS) is generated and accumulated in the genital tract, and thus resulting in oxidative stress, which has been reported to be an important trigger of mitochondrial pathway cell apoptosis. In this study, the antioxidant secretion level and antioxidant enzyme activity in the vaginal discharge were evaluated to analyze the oxidative status in the vaginal tract of NSV patients. The effect of oxidative stress on the vaginal mucosa epithelial cell apoptosis was then studied. The role of oxidative stress on NSV development was uncovered; thus open new direction for the prevention and treatment of NSV by providing antiradical agents was revealed.
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Temporal pattern of neurodegeneration, programmed cell death, and neuroplastic responses in the thalamus after lateral fluid percussion brain injury in the rat. J Neuropathol Exp Neurol 2015; 74:512-26. [PMID: 25933386 DOI: 10.1097/nen.0000000000000194] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The effects of traumatic brain injury (TBI) on the thalamus are not well characterized. We analyzed neuronal degeneration and loss, apoptosis, programmed cell death-executing pathways, and neuroplastic responses in the rat thalamus during the first week after lateral fluid percussion injury (LFPI). The most prominent neurodegenerative and neuroplastic changes were observed in the region containing the posterior thalamic nuclear group and ventral posteromedial and posterolateral thalamic nuclei ipsilateral to the LFPI. There was progressive neurodegeneration in these regions, with maximal neuronal loss on Day 7. Increases in numbers of apoptotic cells were detected on Day 1 and were enhanced on Days 3 and 7 after TBI. There was unchanged expression of active caspase-3 at all postinjury time points, but there was increased expression of apoptosis-inducing factor (AIF) on Day 7. The AIF nuclear translocation was detected on Day 1 and was maximal on Day 7. Total thalamic synaptophysin expression was unchanged, but immunostaining intensities were increased at all time points after TBI. Decreased growth-associated protein-43 expression and signal intensity were observed on Day 1. Our results suggest that progressive neuronal damage and loss, AIF signaling pathway-dependent programmed cell death, and limited neuroplastic changes occur in the rat thalamus during the first week after LFPI induction.
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31
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Boone DR, Micci MA, Taglialatela IG, Hellmich JL, Weisz HA, Bi M, Prough DS, DeWitt DS, Hellmich HL. Pathway-focused PCR array profiling of enriched populations of laser capture microdissected hippocampal cells after traumatic brain injury. PLoS One 2015; 10:e0127287. [PMID: 26016641 PMCID: PMC4446038 DOI: 10.1371/journal.pone.0127287] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 04/13/2015] [Indexed: 12/22/2022] Open
Abstract
Cognitive deficits in survivors of traumatic brain injury (TBI) are associated with irreversible neurodegeneration in brain regions such as the hippocampus. Comparative gene expression analysis of dying and surviving neurons could provide insight into potential therapeutic targets. We used two pathway-specific PCR arrays (RT2 Profiler Apoptosis and Neurotrophins & Receptors PCR arrays) to identify and validate TBI-induced gene expression in dying (Fluoro-Jade-positive) or surviving (Fluoro-Jade- negative) pyramidal neurons obtained by laser capture microdissection (LCM). In the Apoptosis PCR array, dying neurons showed significant increases in expression of genes associated with cell death, inflammation, and endoplasmic reticulum (ER) stress compared with adjacent, surviving neurons. Pro-survival genes with pleiotropic functions were also significantly increased in dying neurons compared to surviving neurons, suggesting that even irreversibly injured neurons are able to mount a protective response. In the Neurotrophins & Receptors PCR array, which consists of genes that are normally expected to be expressed in both groups of hippocampal neurons, only a few genes were expressed at significantly different levels between dying and surviving neurons. Immunohistochemical analysis of selected, differentially expressed proteins supported the gene expression data. This is the first demonstration of pathway-focused PCR array profiling of identified populations of dying and surviving neurons in the brain after TBI. Combining precise laser microdissection of identifiable cells with pathway-focused PCR array analysis is a practical, low-cost alternative to microarrays that provided insight into neuroprotective signals that could be therapeutically targeted to ameliorate TBI-induced neurodegeneration.
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Affiliation(s)
- Deborah R. Boone
- Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555–0830, United States of America
| | - Maria-Adelaide Micci
- Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555–0830, United States of America
| | - Isabella G. Taglialatela
- Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555–0830, United States of America
| | - Judy L. Hellmich
- Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555–0830, United States of America
| | - Harris A. Weisz
- Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555–0830, United States of America
| | - Min Bi
- Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555–0830, United States of America
| | - Donald S. Prough
- Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555–0830, United States of America
| | - Douglas S. DeWitt
- Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555–0830, United States of America
| | - Helen L. Hellmich
- Department of Anesthesiology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555–0830, United States of America
- * E-mail:
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32
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A potent inhibition of oxidative stress induced gene expression in neural cells by sustained ferulic acid release from chitosan based hydrogel. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2015; 49:691-699. [DOI: 10.1016/j.msec.2015.01.030] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Revised: 11/19/2014] [Accepted: 01/06/2015] [Indexed: 11/22/2022]
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Kochanek PM, Jackson TC, Ferguson NM, Carlson SW, Simon DW, Brockman EC, Ji J, Bayir H, Poloyac SM, Wagner AK, Kline AE, Empey PE, Clark RS, Jackson EK, Dixon CE. Emerging therapies in traumatic brain injury. Semin Neurol 2015; 35:83-100. [PMID: 25714870 PMCID: PMC4356170 DOI: 10.1055/s-0035-1544237] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Despite decades of basic and clinical research, treatments to improve outcomes after traumatic brain injury (TBI) are limited. However, based on the recent recognition of the prevalence of mild TBI, and its potential link to neurodegenerative disease, many new and exciting secondary injury mechanisms have been identified and several new therapies are being evaluated targeting both classic and novel paradigms. This includes a robust increase in both preclinical and clinical investigations. Using a mechanism-based approach the authors define the targets and emerging therapies for TBI. They address putative new therapies for TBI across both the spectrum of injury severity and the continuum of care, from the field to rehabilitation. They discussTBI therapy using 11 categories, namely, (1) excitotoxicity and neuronal death, (2) brain edema, (3) mitochondria and oxidative stress, (4) axonal injury, (5) inflammation, (6) ischemia and cerebral blood flow dysregulation, (7) cognitive enhancement, (8) augmentation of endogenous neuroprotection, (9) cellular therapies, (10) combination therapy, and (11) TBI resuscitation. The current golden age of TBI research represents a special opportunity for the development of breakthroughs in the field.
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Affiliation(s)
- Patrick M. Kochanek
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departments of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Travis C. Jackson
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departments of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Nikki Miller Ferguson
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departments of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Shaun W. Carlson
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departmentol Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Dennis W. Simon
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departments of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Erik C. Brockman
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departments of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jing Ji
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departments of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Hülya Bayir
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departments of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Environmental and Occupational Health, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Samuel M. Poloyac
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Environmental and Occupational Health, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Amy K. Wagner
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Anthony E. Kline
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Philip E. Empey
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Environmental and Occupational Health, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Robert S.B. Clark
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departments of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Edwin K. Jackson
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - C. Edward Dixon
- Safar Center for Resuscitation Research, University of Pittburgh School of Medicine, Pittsburgh, Pennsylvania
- Departmentol Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Abstract
Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite extensive preclinical research supporting the effectiveness of neuroprotective therapies for brain trauma, there have been no successful randomized controlled clinical trials to date. TBI results in delayed secondary tissue injury due to neurochemical, metabolic and cellular changes; modulating such effects has provided the basis for neuroprotective interventions. To establish more effective neuroprotective treatments for TBI it is essential to better understand the complex cellular and molecular events that contribute to secondary injury. Here we critically review relevant research related to causes and modulation of delayed tissue damage, with particular emphasis on cell death mechanisms and post-traumatic neuroinflammation. We discuss the concept of utilizing multipotential drugs that target multiple secondary injury pathways, rather than more specific "laser"-targeted strategies that have uniformly failed in clinical trials. Moreover, we assess data supporting use of neuroprotective drugs that are currently being evaluated in human clinical trials for TBI, as well as promising emerging experimental multipotential drug treatment strategies. Finally, we describe key challenges and provide suggestions to improve the likelihood of successful clinical translation.
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Affiliation(s)
- David J Loane
- Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bogdan A Stoica
- Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alan I Faden
- Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD, USA.
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Bramlett HM, Dietrich WD. Long-Term Consequences of Traumatic Brain Injury: Current Status of Potential Mechanisms of Injury and Neurological Outcomes. J Neurotrauma 2014; 32:1834-48. [PMID: 25158206 DOI: 10.1089/neu.2014.3352] [Citation(s) in RCA: 337] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Traumatic brain injury (TBI) is a significant clinical problem with few therapeutic interventions successfully translated to the clinic. Increased importance on the progressive, long-term consequences of TBI have been emphasized, both in the experimental and clinical literature. Thus, there is a need for a better understanding of the chronic consequences of TBI, with the ultimate goal of developing novel therapeutic interventions to treat the devastating consequences of brain injury. In models of mild, moderate, and severe TBI, histopathological and behavioral studies have emphasized the progressive nature of the initial traumatic insult and the involvement of multiple pathophysiological mechanisms, including sustained injury cascades leading to prolonged motor and cognitive deficits. Recently, the increased incidence in age-dependent neurodegenerative diseases in this patient population has also been emphasized. Pathomechanisms felt to be active in the acute and long-term consequences of TBI include excitotoxicity, apoptosis, inflammatory events, seizures, demyelination, white matter pathology, as well as decreased neurogenesis. The current article will review many of these pathophysiological mechanisms that may be important targets for limiting the chronic consequences of TBI.
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Affiliation(s)
- Helen M Bramlett
- The Miami Project to Cure Paralysis/Department of Neurological Surgery, University of Miami Miller School of Medicine , Miami, Florida
| | - W Dalton Dietrich
- The Miami Project to Cure Paralysis/Department of Neurological Surgery, University of Miami Miller School of Medicine , Miami, Florida
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Steuer E, Schaefer ML, Belluscio L. Using the olfactory system as an in vivo model to study traumatic brain injury and repair. J Neurotrauma 2014; 31:1277-91. [PMID: 24694002 DOI: 10.1089/neu.2013.3296] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Loss of olfactory function is an early indicator of traumatic brain injury (TBI). The regenerative capacity and well-defined neural maps of the mammalian olfactory system enable investigations into the degeneration and recovery of neural circuits after injury. Here, we introduce a unique olfactory-based model of TBI that reproduces many hallmarks associated with human brain trauma. We performed a unilateral penetrating impact to the mouse olfactory bulb and observed a significant loss of olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) ipsilateral to the injury, but not contralateral. By comparison, we detected the injury markers p75(NTR), β-APP, and activated caspase-3 in both the ipsi- and contralateral OE. In the olfactory bulb (OB), we observed a graded cell loss, with ipsilateral showing a greater reduction than contralateral and both significantly less than sham. Similar to OE, injury markers in the OB were primarily detected on the ipsilateral side, but also observed contralaterally. Behavioral experiments measured 4 days after impact also demonstrated loss of olfactory function, yet following a 30-day recovery period, we observed a significant improvement in olfactory function and partial recovery of olfactory circuitry, despite the persistence of TBI markers. Interestingly, by using the M71-IRES-tauLacZ reporter line to track OSN organization, we further determined that inducing neural activity during the recovery period with intense odor conditioning did not enhance the recovery process. Together, these data establish the mouse olfactory system as a new model to study TBI, serving as a platform to understand neural disruption and the potential for circuit restoration.
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Affiliation(s)
- Elizabeth Steuer
- 1 Developmental Neural Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health , Bethesda, Maryland
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Apoptosis Induction by the Total Flavonoids from Arachniodes exilis in HepG2 Cells through Reactive Oxygen Species-Mediated Mitochondrial Dysfunction Involving MAPK Activation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 2014:906941. [PMID: 24976852 PMCID: PMC4058121 DOI: 10.1155/2014/906941] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Revised: 05/02/2014] [Accepted: 05/08/2014] [Indexed: 02/06/2023]
Abstract
Arachniodes exilis is used as a folk medicine in China and proved to have antibacterial, anti-inflammatory, and sedative activities. In the present study, the antitumor effect of the total flavonoids of A. exilis (TFAE) against HepG2 cells was evaluated. The results showed that TFAE inhibited the growth of HepG2 cells in a dosage- and time-dependent manner. Flow cytometry and Hoechst 33342 fluorescence staining results showed that TFAE could significantly increase the apoptosis ratio of HepG2 cells, which is accompanied with increased intracellular reactive oxygen species (ROS) production and decreased mitochondrial membrane potential (ΔΨm). Western blotting indicated that TFAE downregulated the ratio of Bcl-2/Bax, increased cytochrome c release, and activated the caspases-3 and -9. Further analysis showed that TFAE stimulated the mitogen-activated protein kinase (MAPK). However, treatment with NAC (reactive oxygen species scavenger) and MAPK-specific inhibitors (SP600125 and SB203580) could reverse the changes of these apoptotic-related proteins. These results suggested that TFAE possessed potential anticancer activity in HepG2 cells through ROS-mediated mitochondrial dysfunction involving MAPK pathway.
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Kabadi SV, Faden AI. Neuroprotective strategies for traumatic brain injury: improving clinical translation. Int J Mol Sci 2014; 15:1216-36. [PMID: 24445258 PMCID: PMC3907865 DOI: 10.3390/ijms15011216] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 01/07/2014] [Accepted: 01/13/2014] [Indexed: 01/15/2023] Open
Abstract
Traumatic brain injury (TBI) induces secondary biochemical changes that contribute to delayed neuroinflammation, neuronal cell death, and neurological dysfunction. Attenuating such secondary injury has provided the conceptual basis for neuroprotective treatments. Despite strong experimental data, more than 30 clinical trials of neuroprotection in TBI patients have failed. In part, these failures likely reflect methodological differences between the clinical and animal studies, as well as inadequate pre-clinical evaluation and/or trial design problems. However, recent changes in experimental approach and advances in clinical trial methodology have raised the potential for successful clinical translation. Here we critically analyze the current limitations and translational opportunities for developing successful neuroprotective therapies for TBI.
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Affiliation(s)
- Shruti V Kabadi
- Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Alan I Faden
- Department of Anesthesiology, Center for Shock, Trauma and Anesthesiology Research (STAR), National Study Center for Trauma and EMS, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Interleukin-10 mediates the neuroprotection of hyperbaric oxygen therapy against traumatic brain injury in mice. Neuroscience 2013; 266:235-43. [PMID: 24291771 DOI: 10.1016/j.neuroscience.2013.11.036] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2013] [Revised: 11/20/2013] [Accepted: 11/20/2013] [Indexed: 01/01/2023]
Abstract
The aim of present study was to elucidate the role of Interleukin-10 (IL-10) in the neuroprotection of hyperbaric oxygen (HBO) against traumatic brain injury (TBI) in mice. The TBI in mice was induced by controlled cortical impact (CCI). HBO was given for 1h at 2.0 absolute atmosphere (ATA) in 100% O2. HBO enhanced the serumal and cerebral IL-10 protein levels in both sham-operated and TBI mice. HBO therapy after TBI reduced lesion volume, attenuated cerebral edema, improved neurological status including motor and cognitive function, inhibited apoptosis evidenced by decreased ratio of cleaved caspase-3 (C3) to pro-C3 and Bax expression and increased bcl-2 expression, and attenuated inflammation marked by reduced expression of IL-1β, IL-6, macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1) and activity of matrix metalloproteinase-9 (MMP9). In addition, HBO after TBI improved the blood-brain barrier, and upregulated the expression of tight junction proteins including zonula occludens-1 (ZO-1) and claudin-5. IL-10 deficiency aggravated TBI-induced damage in the brain and abrogated the beneficial effects of HBO on neuroinflammation, apoptosis, and edema after TBI. IL-10 deficiency itself had no significant effect on brain water content and neurological status. In conclusion, IL-10 played an important role in the neuroprotection of HBO therapy against TBI in mice.
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40
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Walker KR, Tesco G. Molecular mechanisms of cognitive dysfunction following traumatic brain injury. Front Aging Neurosci 2013; 5:29. [PMID: 23847533 PMCID: PMC3705200 DOI: 10.3389/fnagi.2013.00029] [Citation(s) in RCA: 179] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Accepted: 06/18/2013] [Indexed: 12/12/2022] Open
Abstract
Traumatic brain injury (TBI) results in significant disability due to cognitive deficits particularly in attention, learning and memory, and higher-order executive functions. The role of TBI in chronic neurodegeneration and the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and most recently chronic traumatic encephalopathy (CTE) is of particular importance. However, despite significant effort very few therapeutic options exist to prevent or reverse cognitive impairment following TBI. In this review, we present experimental evidence of the known secondary injury mechanisms which contribute to neuronal cell loss, axonal injury, and synaptic dysfunction and hence cognitive impairment both acutely and chronically following TBI. In particular we focus on the mechanisms linking TBI to the development of two forms of dementia: AD and CTE. We provide evidence of potential molecular mechanisms involved in modulating Aβ and Tau following TBI and provide evidence of the role of these mechanisms in AD pathology. Additionally we propose a mechanism by which Aβ generated as a direct result of TBI is capable of exacerbating secondary injury mechanisms thereby establishing a neurotoxic cascade that leads to chronic neurodegeneration.
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Affiliation(s)
- Kendall R Walker
- Alzheimer's Disease Research Laboratory, Department of Neuroscience, Tufts University School of Medicine Boston, MA, USA
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41
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Cai Q, Huang H, Qian D, Chen K, Luo J, Tian Y, Lin T, Lin T. 13-methyltetradecanoic acid exhibits anti-tumor activity on T-cell lymphomas in vitro and in vivo by down-regulating p-AKT and activating caspase-3. PLoS One 2013; 8:e65308. [PMID: 23762338 PMCID: PMC3676434 DOI: 10.1371/journal.pone.0065308] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2012] [Accepted: 04/29/2013] [Indexed: 12/11/2022] Open
Abstract
13-Methyltetradecanoic acid (13-MTD), a saturated branched-chain fatty acid purified from soy fermentation products, induces apoptosis in human cancer cells. We investigated the inhibitory effects and mechanism of action of 13-MTD on T-cell non-Hodgkin’s lymphoma (T-NHL) cell lines both in vitro and in vivo. Growth inhibition in response to 13-MTD was evaluated by the cell counting kit-8 (CCK-8) assay in three T-NHL cell lines (Jurkat, Hut78, EL4 cells). Flow cytometry analyses were used to monitor the cell cycle and apoptosis. Proteins involved in 13-MTD-induced apoptosis were examined in Jurkat cells by western blotting. We found that 13-MTD inhibited proliferation and induced the apoptosis of T-NHL cell lines. 13-MTD treatment also induced a concentration-dependent arrest of Jurkat cells in the G1-phase. During 13-MTD-induced apoptosis in Jurkat cells, the cleavage of caspase-3 and poly ADP-ribose polymerase (PARP, a caspase enzymolysis product) were detected after incubation for 2 h, and increased after extending the incubation time. However, there was no change in the expression of Bcl-2 or c-myc proteins. The appearance of apoptotic Jurkat cells was accompanied by the inhibition of AKT and nuclear factor-kappa B (NF-κB) phosphorylation. In addition, 13-MTD could also effectively inhibit the growth of T-NHL tumors in vivo in a xenograft model. The tumor inhibition rate in the experimental group was 40%. These data indicate that 13-MTD inhibits proliferation and induces apoptosis through the down-regulation of AKT phosphorylation followed by caspase activation, which may provide a new approach for treating T-cell lymphomas.
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Affiliation(s)
- Qingqing Cai
- Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, P. R. China
- State Key Laboratory of Oncology in Southern China, Guangzhou, P. R. China
| | - Huiqiang Huang
- Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, P. R. China
- State Key Laboratory of Oncology in Southern China, Guangzhou, P. R. China
| | - Dong Qian
- State Key Laboratory of Oncology in Southern China, Guangzhou, P. R. China
| | - Kailin Chen
- Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, P. R. China
- State Key Laboratory of Oncology in Southern China, Guangzhou, P. R. China
| | - Junhua Luo
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P. R. China
- Lin Bai-xin Medical Research Center, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ying Tian
- State Key Laboratory of Oncology in Southern China, Guangzhou, P. R. China
| | - Tianxin Lin
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, P. R. China
- Lin Bai-xin Medical Research Center, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
- * E-mail: (Tongyu Lin); (Tianxin Lin)
| | - Tongyu Lin
- Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, P. R. China
- State Key Laboratory of Oncology in Southern China, Guangzhou, P. R. China
- * E-mail: (Tongyu Lin); (Tianxin Lin)
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Cheng G, Kong RH, Zhang LM, Zhang JN. Mitochondria in traumatic brain injury and mitochondrial-targeted multipotential therapeutic strategies. Br J Pharmacol 2013; 167:699-719. [PMID: 23003569 DOI: 10.1111/j.1476-5381.2012.02025.x] [Citation(s) in RCA: 256] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Traumatic brain injury (TBI) is a major health and socioeconomic problem throughout the world. It is a complicated pathological process that consists of primary insults and a secondary insult characterized by a set of biochemical cascades. The imbalance between a higher energy demand for repair of cell damage and decreased energy production led by mitochondrial dysfunction aggravates cell damage. At the cellular level, the main cause of the secondary deleterious cascades is cell damage that is centred in the mitochondria. Excitotoxicity, Ca(2+) overload, reactive oxygen species (ROS), Bcl-2 family, caspases and apoptosis inducing factor (AIF) are the main participants in mitochondria-centred cell damage following TBI. Some preclinical and clinical results of mitochondria-targeted therapy show promise. Mitochondria- targeted multipotential therapeutic strategies offer new hope for the successful treatment of TBI and other acute brain injuries.
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Affiliation(s)
- Gang Cheng
- Neurosurgical Department, PLA Navy General Hospital, Beijing, China
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Abstract
Traumatic brain injury (TBI) is one of the most robust environmental risk factors for Alzheimer's disease (AD). Compelling evidence is accumulating that a single event of TBI is associated with increased levels of Aβ. However, the underlying molecular mechanisms remain unknown. We report here that the BACE1 interacting protein, GGA3, is depleted while BACE1 levels increase in the acute phase after injury (48 h) in a mouse model of TBI. We further demonstrated the role of GGA3 in the regulation of BACE1 in vivo by showing that BACE1 levels are increased in the brain of GGA3-null mice. We next found that head trauma potentiates BACE1 elevation in GGA3-null mice in the acute phase after TBI, and discovered that GGA1, a GGA3 homolog, is a novel caspase-3 substrate depleted at 48 h after TBI. Moreover, GGA1 silencing potentiates BACE1 elevation induced by GGA3 deletion in neurons in vitro, indicating that GGA1 and GGA3 synergistically regulate BACE1. Accordingly, we found that levels of both GGA1 and GGA3 are depleted while BACE1 levels are increased in a series of postmortem AD brains. Finally, we show that GGA3 haploinsufficiency results in sustained elevation of BACE1 and Aβ levels while GGA1 levels are restored in the subacute phase (7 d) after injury. In conclusion, our data indicate that depletion of GGA1 and GGA3 engender a rapid and robust elevation of BACE1 in the acute phase after injury. However, the efficient disposal of the acutely accumulated BACE1 solely depends on GGA3 levels in the subacute phase of injury.
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Kanbak G, Kartkaya K, Ozcelik E, Guvenal AB, Kabay SC, Arslan G, Durmaz R. The neuroprotective effect of acute moderate alcohol consumption on caspase-3 mediated neuroapoptosis in traumatic brain injury: the role of lysosomal cathepsin L and nitric oxide. Gene 2012; 512:492-5. [PMID: 23099040 DOI: 10.1016/j.gene.2012.10.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 06/25/2012] [Accepted: 10/10/2012] [Indexed: 11/19/2022]
Abstract
Our aim in this study was to investigate the effect of moderate acute alcohol administration on cysteine protease mediated neuronal apoptosis and nitric oxide production in the traumatic brain injury. A total of 29 adult Sprague-Dawley male rats weighing 250-300 g were used. The rats were allocated into four groups. The first group was the control (sham-operated) group in which only a craniotomy was performed, the others were alcohol, trauma and trauma+alcohol groups. Caspase-3 enzyme activity in the trauma group increased significantly in comparison with the control group. The alcohol given group showed a decreased caspase-3 enzyme activity compared to the trauma group. The level of caspase-3 enzyme activity in the alcohol+trauma group decreased in comparison to the trauma group. SF/FEL ratio of cathepsin-L enzyme activity in the trauma group was significantly higher than in the control group. Our results indicate that moderate alcohol consumption may have protective effects on apoptotic cell death after traumatic brain injury. Protective effects of moderate ethanol consumption might be related to inhibition of lysosomal protease release and nitric oxide production.
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Affiliation(s)
- Gungor Kanbak
- Eskisehir Osmangazi University, The Medical School, Department of Biochemistry, Turkey
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45
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Schoch KM, Madathil SK, Saatman KE. Genetic manipulation of cell death and neuroplasticity pathways in traumatic brain injury. Neurotherapeutics 2012; 9:323-37. [PMID: 22362424 PMCID: PMC3337028 DOI: 10.1007/s13311-012-0107-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Traumatic brain injury (TBI) initiates a complex cascade of secondary neurodegenerative mechanisms contributing to cell dysfunction and necrotic and apoptotic cell death. The injured brain responds by activating endogenous reparative processes to counter the neurodegeneration or remodel the brain to enhance functional recovery. A vast array of genetically altered mice provide a unique opportunity to target single genes or proteins to better understand their role in cell death and endogenous repair after TBI. Among the earliest targets for transgenic and knockout studies in TBI have been programmed cell death mediators, such as the Bcl-2 family of proteins, caspases, and caspase-independent pathways. In addition, the role of cell cycle regulatory elements in the posttraumatic cell death pathway has been explored in mouse models. As interest grows in neuroplasticity in TBI, the use of transgenic and knockout mice in studies focused on gliogenesis, neurogenesis, and the balance of growth-promoting and growth-inhibiting molecules has increased in recent years. With proper consideration of potential effects of constitutive gene alteration, traditional transgenic and knockout models can provide valuable insights into TBI pathobiology. Through increasing sophistication of conditional and cell-type specific genetic manipulations, TBI studies in genetically altered mice will be increasingly useful for identification and validation of novel therapeutic targets.
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Affiliation(s)
- Kathleen M. Schoch
- Spinal Cord and Brain Injury Research Center and Department of Physiology, University of Kentucky College of Medicine, B473 Biomedical and Biological Sciences Research Building (BBSRB), 741 South Limestone Street, Lexington, KY 40536 USA
| | - Sindhu K. Madathil
- Spinal Cord and Brain Injury Research Center and Department of Physiology, University of Kentucky College of Medicine, B473 Biomedical and Biological Sciences Research Building (BBSRB), 741 South Limestone Street, Lexington, KY 40536 USA
| | - Kathryn E. Saatman
- Spinal Cord and Brain Injury Research Center and Department of Physiology, University of Kentucky College of Medicine, B473 Biomedical and Biological Sciences Research Building (BBSRB), 741 South Limestone Street, Lexington, KY 40536 USA
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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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Piao CS, Loane DJ, Stoica BA, Li S, Hanscom M, Cabatbat R, Blomgren K, Faden AI. Combined inhibition of cell death induced by apoptosis inducing factor and caspases provides additive neuroprotection in experimental traumatic brain injury. Neurobiol Dis 2012; 46:745-58. [PMID: 22426396 DOI: 10.1016/j.nbd.2012.03.018] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Revised: 01/31/2012] [Accepted: 03/01/2012] [Indexed: 12/20/2022] Open
Abstract
Neuronal programmed cell death (PCD) contributes to delayed tissue damage after traumatic brain injury (TBI). Both caspase-dependent and caspase-independent mechanisms have been implicated, with the latter including apoptosis inducing factor (AIF). The peptidyl-proplyl isomerase Cyclophilin A (CypA) transports AIF from the cytosol to the nucleus, a key step for AIF-dependent cell death. We compared the effects of single versus combined inhibition of caspase and AIF pathways in a mouse controlled cortical impact (CCI) model, by examining the effects of CypA gene knockout (CypA(-/-)), caspase inhibition with a pan-caspase inhibitor (boc-aspartyl(OMe)-fluoromethylketone, BAF), or combined modulation. TBI caused caspase activation as well as translocation of AIF to the nucleus. Markers of caspase activation including caspase-specific fodrin cleavage fragments and number of FLIVO-positive cells were reduced in BAF-treated CypA(+/+) mice, whereas markers of AIF activation including AIF/H2AX interaction and AIF translocation to the nucleus were attenuated in CypA(-/-) mice. Each single intervention, (CypA(-/-) or BAF-treated CypA(+/+)) reduced the number of apoptotic cells (TUNEL-positive) in the cortex and improved long-term sensorimotor function; CypA(-/-) also attenuated microglial activation after injury. Importantly, BAF-treated CypA(-/-) mice, showed greater effects than either intervention alone on multiple outcomes including: reduction in TUNEL-positive cells, decrease in neuroinflammation, improved motor and cognitive recovery, and attenuation of lesion volume and neuronal loss in the hippocampus. Using two in vitro neuronal cell death models known to induce AIF-mediated PCD, we also showed that neurons from CypA(-/-) animals were protected and that effects were unrelated to caspase activation. These data indicate that AIF-mediated and caspase-dependent pathways contribute independently and in parallel to secondary injury after TBI, and suggest that combined therapeutic strategies directed at multiple PCD pathways may provide superior neuroprotection than those directed at single mechanisms.
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Affiliation(s)
- Chun-Shu Piao
- Center for Shock, Trauma and Anesthesiology Research and Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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48
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Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease? Nat Rev Neurosci 2011; 11:361-70. [PMID: 20216546 DOI: 10.1038/nrn2808] [Citation(s) in RCA: 438] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Traumatic brain injury (TBI) has devastating acute effects and in many cases seems to initiate long-term neurodegeneration. Indeed, an epidemiological association between TBI and the development of Alzheimer's disease (AD) later in life has been demonstrated, and it has been shown that amyloid-β (Aβ) plaques — one of the hallmarks of AD — may be found in patients within hours following TBI. Here, we explore the mechanistic underpinnings of the link between TBI and AD, focusing on the hypothesis that rapid Aβ plaque formation may result from the accumulation of amyloid precursor protein in damaged axons and a disturbed balance between Aβ genesis and catabolism following TBI.
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Cheng Liu M, Kobeissy F, Zheng W, Zhang Z, Hayes RL, Wang KKW. Dual vulnerability of tau to calpains and caspase-3 proteolysis under neurotoxic and neurodegenerative conditions. ASN Neuro 2011; 3:e00051. [PMID: 21359008 PMCID: PMC3040574 DOI: 10.1042/an20100012] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Revised: 08/31/2010] [Accepted: 09/22/2010] [Indexed: 12/21/2022] Open
Abstract
Axonally specific microtubule-associated protein tau is an important component of neurofibrillary tangles found in AD (Alzheimer's disease) and other tauopathy diseases such as CTE (chronic traumatic encephalopathy). Such tau aggregate is found to be hyperphosphorylated and often proteolytically fragmented. Similarly, tau is degraded following TBI (traumatic brain injury). In the present study, we examined the dual vulnerability of tau to calpain and caspase-3 under neurotoxic and neurodegenerative conditions. We first identified three novel calpain cleavage sites in rat tau (four-repeat isoform) as Ser130↓Lys131, Gly157↓Ala158 and Arg380↓Glu381. Fragment-specific antibodies to target the major calpain-mediated TauBDP-35K (35 kDa tau-breakdown product) and the caspase-mediated TauBDP-45K respectively were developed. In rat cerebrocortical cultures treated with excitotoxin [NMDA (N-methyl-D-aspartate)], tau is significantly degraded into multiple fragments, including a dominant signal of calpain-mediated TauBDP-35K with minimal caspase-mediated TauBDP-45K. Following apoptosis-inducing EDTA treatment, tau was truncated only to TauBDP-48K/45K-exclusively by caspase. Cultures treated with another apoptosis inducer STS (staurosporine), dual fragmentation by calpain (TauBDP-35K) and caspase-3 (TauBDP-45K) was observed. Tau was also fragmented in injured rat cortex following TBI in vivo to BDPs of 45-42 kDa (minor), 35 kDa and 15 kDa, followed by TauBDP-25K. Calpain-mediated TauBDP-35K-specific antibody confirmed robust signals in the injured cortex, while caspase-mediated TauBDP-45K-specific antibody only detected faint signals. Furthermore, intravenous administration of a calpain-specific inhibitor SNJ-1945 strongly suppressed the TauBDP-35K formation. Taken together, these results suggest that tau protein is dually vulnerable to calpain and caspase-3 proteolysis under different neurotoxic and injury conditions.
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Key Words
- AD, Alzheimer's disease
- CCI, controlled cortical impact
- CSF, colony-stimulating factor
- CTE, chronic traumatic encephalopathy
- DMEM, Dulbecco's modified Eagle's medium
- DTT, dithiothreitol
- NMDA, N-methyl-d-aspartate
- STS, staurosporine
- TAI, traumatic axonal injury
- TBI, traumatic brain injury
- TBST, TBS and 0.05% Tween-2
- TauBDP-35K, 35 kDa tau-breakdown product
- cell death
- neurodegeneration
- protease
- tau protein
- tauopathy
- traumatic brain injury (TBI)
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Affiliation(s)
- Ming Cheng Liu
- *Center of Innovative Research, Banyan Biomarkers Inc., 12085 Research Drive, Alachua, FL 32615, U.S.A
| | - Firas Kobeissy
- *Center of Innovative Research, Banyan Biomarkers Inc., 12085 Research Drive, Alachua, FL 32615, U.S.A
- †Department of Psychiatry, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, U.S.A
| | - Wenrong Zheng
- *Center of Innovative Research, Banyan Biomarkers Inc., 12085 Research Drive, Alachua, FL 32615, U.S.A
| | - Zhiqun Zhang
- *Center of Innovative Research, Banyan Biomarkers Inc., 12085 Research Drive, Alachua, FL 32615, U.S.A
| | - Ronald L Hayes
- *Center of Innovative Research, Banyan Biomarkers Inc., 12085 Research Drive, Alachua, FL 32615, U.S.A
- ‡Department of Anesthesiology, University of Florida, Gainesville, FL 32610, U.S.A
| | - Kevin KW Wang
- *Center of Innovative Research, Banyan Biomarkers Inc., 12085 Research Drive, Alachua, FL 32615, U.S.A
- †Department of Psychiatry, McKnight Brain Institute, University of Florida, Gainesville, FL 32610, U.S.A
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Tay LL, Tremblay RG, Hulse J, Zurakowski B, Thompson M, Bani-Yaghoub M. Detection of acute brain injury by Raman spectral signature. Analyst 2011; 136:1620-6. [DOI: 10.1039/c0an00897d] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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