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Repetitive mild traumatic brain injury, commonly experienced following sports injuries, results in various secondary injury processes and is increasingly recognised as a risk factor for the development of neurodegenerative conditions such as chronic traumatic encephalopathy, which is characterised by tau pathology. We aimed to characterise the underlying pathological mechanisms that might contribute to the onset of neurodegeneration and behavioural changes in the less-explored subacute (1-month) period following single or repetitive controlled cortical impact injury (five impacts, 48 h apart) in 12-week-old male and female C57Bl6 mice. We conducted motor and cognitive testing, extensively characterised the status of tau and its regulatory proteins via western blot and quantified neuronal populations using stereology. We report that r-mTBI resulted in neurobehavioural deficits, gait impairments and anxiety-like behaviour at 1 month post-injury, effects not seen following a single injury. R-mTBI caused a significant increase in amyloid precursor protein, an increased trend towards tau phosphorylation and significant changes in kinase/phosphatase proteins that may promote a downstream increase in tau phosphorylation, but no changes in synaptic or neuroinflammatory markers. Lastly, we report neuronal loss in various brain regions following both single and repeat injuries. We demonstrate herein that repeated impacts are required to promote the initiation of a cascade of biochemical events that are consistent with the onset of neurodegeneration subacutely post-injury. Identifying the timeframe in which these changes occur and the pathological mechanisms involved will be crucial for the development of future therapeutics to prevent the onset or mitigate the progression of neurodegeneration following r-mTBI.
Assuntos
Concussão Encefálica , Lesões Encefálicas Traumáticas , Animais , Masculino , Feminino , Camundongos , Proteínas tau/metabolismo , Precursor de Proteína beta-Amiloide , Concussão Encefálica/complicações , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Transtornos da Memória , Fatores de Transcrição , Lesões Encefálicas Traumáticas/complicaçõesRESUMO
BACKGROUND: Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury. FINDINGS: Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes. CONCLUSIONS: This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.
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Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/imunologia , Imunoglobulina G/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lisofosfolipídeos/imunologia , Adulto , Idoso de 80 Anos ou mais , Animais , Lesões Encefálicas/líquido cefalorraquidiano , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Escala de Coma de Glasgow , Humanos , Lisofosfolipídeos/líquido cefalorraquidiano , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Método Simples-Cego , Adulto JovemRESUMO
Objective:Breast cancer is a global public health issue. The disease can be diagnosed in both older and younger women, with the latter facing several dilemmas. Breastfeeding is of general concern to the scientific community as well as its connection with the prevention of breast cancer is being sought. The purpose of this review is to search for studies investigating the relationship between breast cancer and breastfeeding. Material and methods: The articles included in the present paper were searched in PubMed and Scopus databases according to PRISMA guidelines for systematic reviews. This systematic review sought primary studies investigating the relationship between breastfeeding and breast cancer and that were published in English between 2017-2022. Results:Seventeen articles that investigated the relationship of breast cancer with lactation duration, women's age, family history and lifestyle were included in the present review. Conclusion:It was found that, in most studies, breastfeeding could be evaluated as a protective factor of the disease. From all studied articles, the need for the design of additional studies investigating the relationship between breastfeeding and breast cancer emerges.
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The neurovascular unit provides a dynamic interface between the circulation and central nervous system. Disruption of neurovascular integrity occurs in numerous brain pathologies including neurotrauma and ischaemic stroke. Tissue plasminogen activator is a serine protease that converts plasminogen to plasmin, a protease that dissolves blood clots. Besides its role in fibrinolysis, tissue plasminogen activator is abundantly expressed in the brain where it mediates extracellular proteolysis. However, proteolytically active tissue plasminogen activator also promotes neurovascular disruption after ischaemic stroke; the molecular mechanisms of this process are still unclear. Tissue plasminogen activator is naturally inhibited by serine protease inhibitors (serpins): plasminogen activator inhibitor-1, neuroserpin or protease nexin-1 that results in the formation of serpin:protease complexes. Proteases and serpin:protease complexes are cleared through high-affinity binding to low-density lipoprotein receptors, but their binding to these receptors can also transmit extracellular signals across the plasma membrane. The matrix metalloproteinases are the second major proteolytic system in the mammalian brain, and like tissue plasminogen activators are pivotal to neurological function but can also degrade structures of the neurovascular unit after injury. Herein, we show that tissue plasminogen activator potentiates neurovascular damage in a dose-dependent manner in a mouse model of neurotrauma. Surprisingly, inhibition of activity following administration of plasminogen activator inhibitor-1 significantly increased cerebrovascular permeability. This led to our finding that formation of complexes between tissue plasminogen activator and plasminogen activator inhibitor-1 in the brain parenchyma facilitates post-traumatic cerebrovascular damage. We demonstrate that following trauma, the complex binds to low-density lipoprotein receptors, triggering the induction of matrix metalloproteinase-3. Accordingly, pharmacological inhibition of matrix metalloproteinase-3 attenuates neurovascular permeability and improves neurological function in injured mice. Our results are clinically relevant, because concentrations of tissue plasminogen activator: plasminogen activator inhibitor-1 complex and matrix metalloproteinase-3 are significantly elevated in cerebrospinal fluid of trauma patients and correlate with neurological outcome. In a separate study, we found that matrix metalloproteinase-3 and albumin, a marker of cerebrovascular damage, were significantly increased in brain tissue of patients with neurotrauma. Perturbation of neurovascular homeostasis causing oedema, inflammation and cell death is an important cause of acute and long-term neurological dysfunction after trauma. A role for the tissue plasminogen activator-matrix metalloproteinase axis in promoting neurovascular disruption after neurotrauma has not been described thus far. Targeting tissue plasminogen activator: plasminogen activator inhibitor-1 complex signalling or downstream matrix metalloproteinase-3 induction may provide viable therapeutic strategies to reduce cerebrovascular permeability after neurotrauma.
Assuntos
Lesões Encefálicas/fisiopatologia , Permeabilidade Capilar/fisiologia , Inibidor 1 de Ativador de Plasminogênio/fisiologia , Ativador de Plasminogênio Tecidual/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/metabolismo , Animais , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Lesões Encefálicas/líquido cefalorraquidiano , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Injeções Intraventriculares , Masculino , Inibidores de Metaloproteinases de Matriz/uso terapêutico , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/administração & dosagem , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Recuperação de Função Fisiológica/fisiologia , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/antagonistas & inibidores , Ativador de Plasminogênio Tecidual/metabolismoRESUMO
Repetitive mild traumatic brain injury (r-mTBI) has increasingly become recognised as a risk factor for the development of neurodegenerative diseases, many of which are characterised by tau pathology, metal dyshomeostasis and behavioural impairments. We aimed to characterise the status of tau and the involvement of iron dyshomeostasis in repetitive controlled cortical impact injury (5 impacts, 48 h apart) in 3-month-old C57Bl6 mice at the chronic (12-month) time point. We performed a battery of behavioural tests, characterised the status of neurodegeneration-associated proteins (tau and tau-regulatory proteins, amyloid precursor protein and iron-regulatory proteins) via western blot; and metal levels using bulk inductively coupled plasma-mass spectrometry (ICP-MS). We report significant changes in various ipsilateral iron-regulatory proteins following five but not a single injury, and significant increases in contralateral iron, zinc and copper levels following five impacts. There was no evidence of tau pathology or changes in tau-regulatory proteins following five impacts, although some changes were observed following a single injury. Five impacts resulted in significant gait deficits, mild anhedonia and mild cognitive deficits at 9-12 months post-injury, effects not seen following a single injury. To the best of our knowledge, we are the first to describe chronic changes in metals and iron-regulatory proteins in a mouse model of r-mTBI, providing a strong indication towards an overall increase in brain iron levels (and other metals) in the chronic phase following r-mTBI. These results bring to question the relevance of tau and highlight the involvement of iron dysregulation in the development and/or progression of neurodegeneration following injury, which may lead to new therapeutic approaches in the future.
Assuntos
Concussão Encefálica , Lesões Encefálicas Traumáticas , Camundongos , Animais , Concussão Encefálica/patologia , Camundongos Transgênicos , Ferro , Proteínas Reguladoras de Ferro , Camundongos Endogâmicos C57BL , Proteínas tau/metabolismo , Fatores de Transcrição , Modelos Animais de Doenças , Lesões Encefálicas Traumáticas/complicaçõesRESUMO
BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity in young adults. The role of iron in potentiating neurodegeneration following TBI has gained recent interest as iron deposition has been detected in the injured brain in the weeks to months post-TBI, in both the preclinical and clinical setting. A failure in iron homeostasis can lead to oxidative stress, inflammation and excitotoxicity; and whether this is a cause or consequence of the long-term effects of TBI remains unknown. EXPERIMENTAL APPROACH: We investigated the role of iron and the effect of therapeutic intervention using a brain-permeable iron chelator, deferiprone, in a controlled cortical impact mouse model of TBI. An extensive assessment of cognitive, motor and anxiety/depressive outcome measures were examined, and neuropathological and biochemical changes, over a 3-month period post-TBI. KEY RESULTS: Lesion volume was significantly reduced at 3 months, which was preceded by a reduction in astrogliosis, microglia/macrophages and preservation of neurons in the injured brain at 2 weeks and/or 1 month post-TBI in mice receiving oral deferiprone. Deferiprone treatment showed significant improvements in neurological severity scores, locomotor/gait performance and cognitive function, and attenuated anxiety-like symptoms post-TBI. Deferiprone reduced iron levels, lipid peroxidation/oxidative stress and altered expression of neurotrophins in the injured brain over this period. CONCLUSION AND IMPLICATIONS: Our findings support a detrimental role of iron in the injured brain and suggest that deferiprone (or similar iron chelators) may be promising therapeutic approaches to improve survival, functional outcomes and quality of life following TBI.
Assuntos
Lesões Encefálicas Traumáticas , Qualidade de Vida , Animais , Camundongos , Deferiprona/farmacologia , Deferiprona/uso terapêutico , Camundongos Endogâmicos C57BL , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , FerroRESUMO
Repetitive mild traumatic brain injury (r-mTBI), commonly experienced by athletes and military personnel, causes changes in multiple intracellular pathways, one of which involves the tau protein. Tau phosphorylation plays a role in several neurodegenerative conditions including chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder linked to repeated head trauma. There is now mounting evidence suggesting that tau phosphorylation may be regulated by metal ions (such as iron, zinc and copper), which themselves are implicated in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Recent work has also shown that a single TBI can result in age-dependent and region-specific modulation of metal ions. As such, this review explores the linkage among TBI, CTE, aging, and neurodegeneration, with a specific focus on the involvement of (and interaction between) tau pathology and metal dyshomeostasis. The authors highlight that metal dyshomeostasis has yet to be investigated in the context of repeat head trauma or CTE. Given the evidence that metal dyshomeostasis contributes to the onset and/or progression of neurodegeneration, and that CTE itself is a neurodegenerative condition, this brings to light an uncharted link that should be explored. The development of adequate models of r-mTBI and/or CTE will be crucial in deepening our understanding of the pathological mechanisms that drive the clinical manifestations in these conditions and also in the development of effective therapeutics targeted toward slowing progressive neurodegenerative disorders.
Assuntos
Doença de Alzheimer , Concussão Encefálica , Encefalopatia Traumática Crônica , Traumatismos Craniocerebrais , Doenças Neurodegenerativas , Doença de Alzheimer/complicações , Concussão Encefálica/complicações , Encefalopatia Traumática Crônica/patologia , Traumatismos Craniocerebrais/complicações , Humanos , Doenças Neurodegenerativas/etiologia , Proteínas tau/metabolismoRESUMO
Metal dyshomeostasis is a well-established consequence of neurodegenerative diseases and traumatic brain injury. While the significance of metals continues to be uncovered in many neurological disorders, their implication in repetitive mild traumatic brain injury remains uncharted. To address this gap, we characterized the spatial distribution of metal levels (iron, zinc, and copper) using laser ablation-inductively coupled plasma-mass spectrometry, the profile of metal-binding proteins via size exclusion chromatography-inductively coupled plasma-mass spectrometry and the expression of the major iron storing protein ferritin via western blotting. Using a mouse model of repetitive mild traumatic brain injury, 3-month-old male and female C57Bl6 mice received one or five impacts (48 h apart). At 1 month following 5× TBI (traumatic brain injury), iron and ferritin levels were significantly elevated in the contralateral cortex. There was a trend toward increased iron levels in the entire contralateral hemisphere and a reduction in contralateral cortical iron-binding proteins following 1× TBI. No major changes in zinc levels were seen in both hemispheres following 5× or 1× TBI, although there was a reduction in ipsilateral zinc-binding proteins following 5× TBI and a contralateral increase in zinc-binding proteins following 1× TBI. Copper levels were significantly increased in both hemispheres following 5× TBI, without changes in copper-binding proteins. This study shows for the first time that repetitive mild TBI (r-mTBI) leads to metal dyshomeostasis, highlighting its potential involvement in promoting neurodegeneration, which provides a rationale for examining the benefit of metal-targeting drugs, which have shown promising results in neurodegenerative conditions and single TBI, but have yet to be tested following r-mTBI.
Assuntos
Concussão Encefálica , Lesões Encefálicas Traumáticas , Metaloproteínas , Doenças Neurodegenerativas , Camundongos , Animais , Masculino , Feminino , Cobre/metabolismo , Metaloproteínas/metabolismo , Camundongos Endogâmicos C57BL , Lesões Encefálicas Traumáticas/metabolismo , Ferro/metabolismo , Zinco/metabolismo , Ferritinas , Modelos Animais de DoençasRESUMO
BACKGROUND: Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and its highest prevalence is observed in adolescents and young adults. This review examined studies that explore awareness about HPV among adolescents and young adults, as well as their attitudes and willingness towards the HPV vaccine. Besides, the impact of health professionals and health education interventions on HPV awareness and attitudes towards HPV vaccine is identified. OBJECTIVE: The aim of this review is, firstly, to systematically identify the studies that explore awareness about HPV among adolescents and young adults, as well as their attitudes and willingness towards the HPV vaccine. Secondly, the aim is to identify the impact of health professionals and health education interventions on HPV awareness and attitudes towards HPV vaccine among the same group. METHODS: The systematic review was conducted in the international databases PubMed, Scopus, and Google Scholar, between 2016-2019. RESULTS: The review revealed low to moderate levels of awareness and knowledge regarding HPV (10 studies), while a more favorable attitude towards the HPV vaccine (3 studies). The role of health professionals was ineffective (4 studies), while studies focused on the impact of health education interventions showed a positive impact on knowledge and awareness of HPV (4 studies). CONCLUSION: Continuous training of health personnel is necessary and new studies are needed to identify barriers to adolescents not being vaccinated.
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Research has highlighted the wide impact of intimate partner violence (IPV) and the public health role of community health professionals in detection of victimized women. The purpose of this study was to identify postpartum emotional and physical abuse and to validate the Greek version of the Women Abuse Screening Tool (WAST) along with its sensitivity and specificity. Five hundred seventy-nine mothers within 12 weeks postpartum were recruited from the perinatal care registers of the Maternity Departments of two public hospitals in Athens, Greece. Participants were randomly selected by clinic or shift. The WAST and the Partner Violence Screen (PVS) surveys were administered in random order to the mothers from September 2007 to January 2008. The WAST was compared with the PVS as a criterion standard. Agreement between the screening instruments was examined. The psychometric measurements that were performed included: two independent sample t tests, reliability coefficients, explanatory factor analysis using a Varimax rotation, and Principal Components Method. Confirmatory analysis-also called structural equation modeling-of principal components was conducted by Linear Structural Relations. A receiver operating characteristic (ROC) analysis was carried out to evaluate the global functioning of the scale. Two hundred four (35.6%) of the mothers screened were identified as experiencing IPV. Scores on the WAST correlated well with those on the PVS; the internal consistency of the WAST Greek version-tested using Cronbach's alpha coefficient-was found to be 0.926 and that of Guttman's split-half coefficient was 0.924. Our findings confirm the multidimensionality of the WAST, demonstrating a two-factor structure. The area under ROC curve (AUC) was found to be 0.824, and the logistic estimate for the threshold score of 0/1 fitted the model sensitivity at 99.7% and model specificity at 64.4%. Our data confirm the validity of the Greek version of the WAST in identifying IPV. The validated Greek WAST scale could be used for screening purposes in both clinical practice and research.
Assuntos
Período Pós-Parto/psicologia , Maus-Tratos Conjugais/diagnóstico , Adulto , Coleta de Dados , Violência Doméstica , Emoções , Feminino , Grécia , Hospitais Públicos , Humanos , Psicometria/instrumentação , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Tranexamic acid (TXA) is an anti-fibrinolytic agent used to reduce bleeding in various conditions including traumatic brain injury (TBI). As the fibrinolytic system also influences the central nervous system and the immune response, TXA may also modulate these parameters following TBI. OBJECTIVES: To determine the effect of TXA on blood-brain barrier (BBB) integrity and changes in immune and motor function in male and female mice subjected to TBI. METHODS: Wild-type and plasminogen deficient (plg-/-) mice were subjected to TBI then administered either TXA/vehicle. The degree of BBB breakdown, intracerebral hemorrhage (ICH), motor dysfunction, and changes in inflammatory subsets in blood and brain were determined. RESULTS AND CONCLUSIONS: Tranexamic acid significantly reduced BBB breakdown, and increased blood neutrophils in male mice 3 hours post-TBI. In contrast, TXA treatment of female mice increased BBB permeability and ICH but had no effect on blood neutrophils at the same time-point. TXA improved motor function in male mice but still increased BBB breakdown in female mice 24 hours post-TBI. Brain urokinase-type plasminogen activator (u-PA) antigen and activity levels were significantly higher in injured females compared to males. Because TXA can promote a pro-fibrinolytic effect via u-PA, these sex differences may be related to brain u-PA levels. TXA also increased monocyte subsets and dendritic cells in the injured brain of wild-type male mice 1 week post-TBI. Plg-/- mice of both sexes had reduced BBB damage and were protected from TBI irrespective of treatment indicating that TXA modulation of the BBB is plasmin-dependent. In conclusion, TXA is protective post-TBI but only in male mice.
Assuntos
Antifibrinolíticos , Lesões Encefálicas Traumáticas , Ácido Tranexâmico , Animais , Antifibrinolíticos/farmacologia , Barreira Hematoencefálica , Lesões Encefálicas Traumáticas/tratamento farmacológico , Feminino , Imunidade , Masculino , Camundongos , Permeabilidade , Ácido Tranexâmico/farmacologiaRESUMO
Traumatic brain injury (TBI) leaves many survivors with long-term disabilities. A prolonged immune response in the brain may cause neurodegeneration, resulting in chronic neurological disturbances. In this study, using a TBI mouse model, we correlate changes in the local immune response with neurodegeneration/neurological dysfunction over an 8-month period. Flow cytometric analysis reveals a protracted increase in effector/memory CD8+ T cells (expressing granzyme B) in the injured brain. This precedes interleukin-17+CD4+ T cell infiltration and is associated with progressive neurological/motor impairment, increased circulating brain-specific autoantibodies, and myelin-related pathology. Genetic deficiency or pharmacological depletion of CD8+ T cells, but not depletion of CD4+ T cells, improves neurological outcomes and produces a neuroprotective Th2/Th17 immunological shift, indicating a persistent detrimental role for cytotoxic T cells post-TBI. B cell deficiency results in severe neurological dysfunction and a heightened immune reaction. Targeting these adaptive immune cells offers a promising approach to improve recovery following TBI.
Assuntos
Lesões Encefálicas Traumáticas/imunologia , Encéfalo/patologia , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária/imunologia , Imunidade Adaptativa , Animais , Autoanticorpos/sangue , Linfócitos B/imunologia , Comportamento Animal , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/fisiopatologia , Linfócitos T CD4-Positivos/imunologia , DNA/imunologia , Marcha , Memória Imunológica , Depleção Linfocítica , Masculino , Camundongos Endogâmicos C57BL , Bainha de Mielina/imunologia , Medula Espinal/patologia , Células Th17/imunologia , Fatores de Tempo , Microglobulina beta-2/deficiência , Microglobulina beta-2/metabolismoRESUMO
The antifibrinolytic agent, tranexamic acid (TXA), an inhibitor of plasmin formation, currently is evaluated to reduce bleeding in various conditions, including traumatic brain injury (TBI). Because plasmin is implicated in inflammation and immunity, we investigated the effects of plasmin inhibition on the immune response after TBI in the presence or absence of induced pneumonia. Wild-type mice treated with vehicle or TXA or mice deficient in plasminogen (plg-/-) underwent TBI using the controlled cortical impact model. Mice were then subjected to Staphylococcus aureus induced pneumonia and the degree of immune competence determined. Significant baseline changes in the innate immune cell profile were seen in plg-/- mice with increases in spleen weight and white blood cell counts, and elevation in plasma interleukin-6 levels. The plg-/- mice subjected to TBI displayed no additional changes in these parameters at the 72 h or one week time point post-TBI. The plg-/- mice subjected to TBI did not exhibit any further increase in susceptibility to endogenous infection. Pneumonia was induced by intratracheal instillation of S. aureus. The TBI did not worsen pneumonia symptoms or delay recovery in plg-/- mice. Similarly, in wild type mice, treatment with TXA did not impact on the ability of mice to counteract pneumonia after TBI. Administration of TXA after TBI and subsequent pneumonia, however, altered the number and surface marker expression of several myeloid and lymphoid cell populations, consistent with enhanced immune activation at the 72 h time point. This investigation confirms the immune-modulatory properties of TXA, thereby highlighting its effects unrelated to inhibition of fibrinolysis.
Assuntos
Lesões Encefálicas Traumáticas/imunologia , Imunidade Celular/imunologia , Depuração Mucociliar/imunologia , Pneumonia Bacteriana/imunologia , Infecções Estafilocócicas/imunologia , Ácido Tranexâmico/uso terapêutico , Animais , Antifibrinolíticos/farmacologia , Antifibrinolíticos/uso terapêutico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/metabolismo , Modelos Animais de Doenças , Imunidade Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Depuração Mucociliar/efeitos dos fármacos , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/metabolismo , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus , Ácido Tranexâmico/farmacologiaRESUMO
BACKGROUND: Traumatic brain injury (TBI) is known to promote immunosuppression, making patients more susceptible to infection, yet potentially exerting protective effects by inhibiting central nervous system (CNS) reactivity. Plasmin, the effector protease of the fibrinolytic system, is now recognized for its involvement in modulating immune function. OBJECTIVE: To evaluate the effects of plasmin and tranexamic acid (TXA) on the immune response in wild-type and plasminogen-deficient (plg-/- ) mice subjected to TBI. METHODS: Leukocyte subsets in lymph nodes and the brain in mice post TBI were evaluated by flow cytometry and in blood with a hemocytometer. Immune responsiveness to CNS antigens was determined by Enzyme-linked Immunosorbent Spot (ELISpot) assay. Fibrinolysis was determined by thromboelastography and measuring D-dimer and plasmin-antiplasmin complex levels. RESULTS: Plg-/- mice, but not plg+/+ mice displayed increases in both the number and activation of various antigen-presenting cells and T cells in the cLN 1 week post TBI. Wild-type mice treated with TXA also displayed increased cellularity of the cLN 1 week post TBI together with increases in innate and adaptive immune cells. These changes occurred despite the absence of systemic hyperfibrinolysis or coagulopathy in this model of TBI. Importantly, neither plg deficiency nor TXA treatment enhanced the autoreactivity within the CNS. CONCLUSION: In the absence of systemic hyperfibrinolysis, plasmin deficiency or blockade with TXA increases migration and proliferation of conventional dendritic cells (cDCs) and various antigen-presenting cells and T cells in the draining cervical lymph node (cLN) post TBI. Tranexamic acid might also be clinically beneficial in modulating the inflammatory and immune response after TBI, but without promoting CNS autoreactivity.
Assuntos
Antifibrinolíticos/farmacologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Fibrinólise/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Ácido Tranexâmico/farmacologia , Animais , Encéfalo/imunologia , Encéfalo/patologia , Lesões Encefálicas Traumáticas/sangue , Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/patologia , Proliferação de Células/efeitos dos fármacos , Quimiotaxia de Leucócito/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Leucócitos/imunologia , Linfonodos/imunologia , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasminogênio/deficiência , Plasminogênio/genéticaRESUMO
Tranexamic acid (TXA) is an antifibrinolytic agent that blocks plasmin formation. Because plasmin is known to promote inflammatory and immunosuppressive responses, we explored the possibility that plasmin-mediated immunosuppression in patients undergoing cardiac surgery can be directly reversed by TXA and decrease postoperative infection rates. The modulatory effect of TXA on inflammatory cytokine levels and on innate immune cell activation were evaluated with multiplex enzyme-linked immunosorbent assay and flow cytometry, respectively. Postoperative infection rates were determined in patients undergoing cardiac surgery and randomized to TXA (ACTRN12605000557639; http://www.anzca.edu.au). We demonstrate that TXA-mediated plasmin blockade modulates the immune system and reduces surgery-induced immunosuppression in patients following cardiac surgery. TXA enhanced the expression of immune-activating markers while reducing the expression of immunosuppressive markers on multiple myeloid and lymphoid cell populations in peripheral blood. TXA administration significantly reduced postoperative infection rates, despite the fact that patients were being administered prophylactic antibiotics. This effect was independent of the effect of TXA at reducing blood loss. TXA was also shown to exert an immune-modulatory effect in healthy volunteers, further supporting the fibrin-independent effect of TXA on immune function and indicating that baseline plasmin levels contribute to the regulation of the immune system in the absence of any comorbidity or surgical trauma. Finally, the capacity of TXA to reduce infection rates, modulate the innate immune cell profile, and generate an antifibrinolytic effect overall was markedly reduced in patients with diabetes, demonstrating for the first time that the diabetic condition renders patients partially refractory to TXA.
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Antifibrinolíticos/uso terapêutico , Transmissão de Doença Infecciosa/estatística & dados numéricos , Ácido Tranexâmico/uso terapêutico , Adulto , Antifibrinolíticos/farmacologia , Humanos , Período Pós-Operatório , Estudos Prospectivos , Ácido Tranexâmico/farmacologia , VoluntáriosRESUMO
Traumatic brain injury (TBI) consists of acute and long-term pathophysiological sequelae that ultimately lead to cognitive and motor function deficits, with age being a critical risk factor for poorer prognosis. TBI has been recently linked to the development of neurodegenerative diseases later in life including Alzheimer's disease, Parkinson's disease, chronic traumatic encephalopathy, and multiple sclerosis. The accumulation of iron in the brain has been documented in a number of neurodegenerative diseases, and also in normal aging, and can contribute to neurotoxicity through a variety of mechanisms including the production of free radicals leading to oxidative stress, excitotoxicity and by promoting inflammatory reactions. A growing body of evidence similarly supports a deleterious role of iron in the pathogenesis of TBI. Iron deposition in the injured brain can occur via hemorrhage/microhemorrhages (heme-bound iron) or independently as labile iron (non-heme bound), which is considered to be more damaging to the brain. This review focusses on the role of iron in potentiating neurodegeneration in TBI, with insight into the intersection with neurodegenerative conditions. An important implication of this work is the potential for therapeutic approaches that target iron to attenuate the neuropathology/phenotype related to TBI and to also reduce the associated risk of developing neurodegenerative disease.
RESUMO
The highly conserved Grainyhead-like (Grhl) family of transcription factors, comprising three members in vertebrates (Grhl1-3), play critical regulatory roles during embryonic development, cellular proliferation, and apoptosis. Although loss of Grhl function leads to multiple neural abnormalities in numerous animal models, a comprehensive analysis of Grhl expression and function in the mammalian brain has not been reported. Here they show that only Grhl3 expression is detectable in the embryonic mouse brain; particularly within the habenula, an organ known to modulate repressive behaviors. Using both Grhl3-knockout mice (Grhl3-/- ), and brain-specific conditional deletion of Grhl3 in adult mice (Nestin-Cre/Grhl3flox/flox ), they performed histological expression analyses and behavioral tests to assess long-term effects of Grhl3 loss on motor co-ordination, spatial memory, anxiety, and stress. They found that complete deletion of Grhl3 did not lead to noticeable structural or cell-intrinsic defects in the embryonic brain; however, aged Grhl3 conditional knockout (cKO) mice showed enlarged lateral ventricles and displayed marked changes in motor function and behaviors suggestive of decreased fear and anxiety. They conclude that loss of Grhl3 in the brain leads to significant alterations in locomotor activity and decreased self-inhibition, and as such, these mice may serve as a novel model of human conditions of impulsive behavior or hyperactivity. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 775-788, 2017.
Assuntos
Envelhecimento , Ansiedade , Encéfalo/metabolismo , Proteínas de Ligação a DNA/deficiência , Locomoção/genética , Fatores de Transcrição/deficiência , Animais , Ansiedade/genética , Ansiedade/patologia , Ansiedade/fisiopatologia , Encéfalo/embriologia , Encéfalo/patologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Preferências Alimentares/psicologia , Marcha/genética , Antígeno Ki-67/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Nestina/genética , Sacarose/administração & dosagem , Edulcorantes/administração & dosagem , Natação/psicologia , Fatores de Transcrição/genéticaRESUMO
Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8- to 10-week-old male C57BL/6J WT and IFNAR1(-/-) mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1(-/-) mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1(-/-) mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNFα, IL-1ß and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI.
Assuntos
Lesões Encefálicas/metabolismo , Encefalite/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Interferon Tipo I/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Animais , Anticorpos Monoclonais/administração & dosagem , Astrócitos/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/complicações , Lesões Encefálicas/patologia , Encefalite/etiologia , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , RNA Mensageiro/metabolismo , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Transdução de SinaisRESUMO
The opening of the tight junctions in the blood-brain barrier (BBB) following traumatic brain injury (TBI) is hypothesized to be sufficient to enable accumulation of large drug carriers, such as stealth liposomes, in a similar manner to the extravasation seen in tumor tissue via the enhanced permeability and retention (EPR) effect. The controlled cortical impact model of TBI was used to evaluate liposome accumulation in mice. Dual-radiolabeled PEGylated liposomes were administered either immediately after induction of TBI or at increasing times post-TBI to mimic the likely clinical scenario. The accumulation of radiolabel in the brain tissue ipsilateral and contralateral to the site of trauma, as well as in other organs, was evaluated. Selective influx of liposomes occurred at 0-8 h after injury, while the barrier closed between 8 and 24 hr after injury, consistent with reports on albumin infiltration. Significantly enhanced accumulation of liposomes occurred in mice subjected to TBI compared to anaesthetized controls, and accumulation was greater in the injured versus the contralateral side of the brain. Thus, stealth liposomes show potential to enhance drug delivery to the site of brain injury with a wide range of encapsulated therapeutic candidates.
Assuntos
Barreira Hematoencefálica/patologia , Lesões Encefálicas/patologia , Encéfalo/metabolismo , Lipossomos/metabolismo , Lipossomos/farmacocinética , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Lesões Encefálicas/metabolismo , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Lipossomos/química , Masculino , Camundongos , Tamanho da Partícula , Permeabilidade , Cintilografia , Junções Íntimas/patologia , Trítio/química , Trítio/farmacocinéticaRESUMO
Purkinje neurons are a sensitive and specialised cell type important for fine motor movement and coordination. Purkinje cell damage manifests as motor incoordination and ataxia - a prominent feature of many human disorders including spinocerebellar ataxia and Huntington's disease. A correlation between Purkinje degeneration and excess cerebellar levels of tissue-type plasminogen activator (tPA) has been observed in multiple genetically-distinct models of ataxia. Here we show that Purkinje loss in a mouse model of Huntington's disease also correlates with a 200% increase in cerebellar tPA activity. That elevated tPA levels arise in a variety of ataxia models suggests that tPA is a common mediator of Purkinje damage. To address the specific contribution of tPA to cerebellar dysfunction we studied the T4 mice line that overexpresses murine tPA in postnatal neurons through the Thy1.2 gene promoter, which directs preferential expression to Purkinje cells within the cerebellum. Here we show that T4 mice develop signs of cerebellar damage within 10 weeks of birth including atrophy of Purkinje cell soma and dendrites, astrogliosis, reduced molecular layer volume and altered gait. In contrast, T4 mice displayed no evidence of microgliosis, nor any changes in interneuron density, nor alteration in the cerebellar granular neuron layer. Thus, excess tPA levels may be sufficient to cause targeted Purkinje cell degeneration and ataxia. We propose that elevated cerebellar tPA levels exert a common pathway of Purkinje cell damage. Therapeutically lowering cerebellar tPA levels may represent a novel means of preserving Purkinje cell integrity and motor coordination across a wide range of neurodegenerative diseases.