RESUMEN
The postmortem diagnosis of diffuse traumatic axonal injury (dTAI) relies on ß-amyloid precursor protein (ß-APP) immunohistochemistry. Most reports of factors associating with dTAI are decades old. We compared background characteristics and neuropathology findings of today's Finnish medico-legal autopsy cases with and without ß-APP-positive dTAI (dTAI+ and dTAI-, respectively). The cases had suffered a head injury prior to death and underwent a full neuropathological examination including ß-APP stain. Background and circumstantial data as well as neuropathology findings were collected from police documents, medical records, and autopsy and neuropathology reports. Prevalence ratios were calculated for each factor to facilitate comparisons between the dTAI+ and dTAI- groups. The dataset comprised 57 cases (66.7% males), with 17 classified as dTAI+ and 40 as dTAI-. Based on prevalence ratios, the factors that had at least two-fold prevalence among dTAI+ cases compared to dTAI- cases were: an unknown injury mechanism; concurrent epidural or subdural haemorrhage; and an accidental manner of death. In contrast, the factors that had at least two-fold prevalence among dTAI- cases compared to dTAI+ cases were: a short postinjury survival (<30 min); concurrent intracerebral/ventricular haemorrhage or contusion; vermal atrophy; and a natural or homicidal manner of death. This study revealed differences in circumstantial features and neuropathology findings between dTAI+ and dTAI- cases in today's medico-legal autopsy material. Data on typical case profiles may help estimate the prior probability of dTAI not only in medico-legal autopsies but also among living patients with head injuries.
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Precursor de Proteína beta-Amiloide , Autopsia , Lesión Axonal Difusa , Humanos , Precursor de Proteína beta-Amiloide/metabolismo , Masculino , Lesión Axonal Difusa/patología , Lesión Axonal Difusa/metabolismo , Femenino , Persona de Mediana Edad , Adulto , Anciano , Patologia Forense , Anciano de 80 o más Años , Finlandia/epidemiología , InmunohistoquímicaRESUMEN
Diffuse axonal injury (DAI), one of the most common and devastating type of traumatic brain injury, is the result of the shear force on axons due to severe rotational acceleration and deceleration. Neurogranin (NRGN) is a postsynaptic protein secreted by excitatory neurons, and synaptic dysfunction can alter extracellular NRGN levels. In this study, we examined NRGN levels in serum and cerebrospinal fluid (CSF) after experimental DAI in terms of their diagnostic value. Experimental DAI was induced using the Marmarou technique in male Wistar albino rats. Serum and CSF NRGN levels of the sham group, onehour, sixhour, 24hour, and 72hour postDAI groups were measured by ELISA method. DAI was verified by staining with hematoxylineosin and ßamyloid precursor protein in the rat brain samples. While no histopathological and immunohistochemical changes were observed in the early hours of the postDAI groups, the staining of the ßAPP visibly increased over time, with positivity being most frequent and intense in the 72hour group. It was found that serum NRGN levels were significantly lower in the 6hour group than in the sham group. The serum NRGN levels in the 24hour group were significantly higher than those in the sham group. This study showed a dichotomy of postDAI serum NRGN levels in consecutive time periods. NRGN levels in CSF were higher in the onehour group than in the sham group and returned to baseline by 72 hours, although not significantly. Our study provides an impression of serum and CSF NRGN levels in a rat DAI model in consecutive time periods. Further studies are needed to understand the diagnostic value of NRGN.
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Lesión Axonal Difusa , Neurogranina , Ratas , Masculino , Animales , Neurogranina/metabolismo , Ratas Wistar , Lesión Axonal Difusa/metabolismo , Lesión Axonal Difusa/patología , Neuronas/metabolismo , Axones/metabolismoRESUMEN
INTRODUCTION: Diffuse axonal injury (DAI), with high mortality and morbidity both in children and adults, is one of the most severe pathological consequences of traumatic brain injury. Currently, clinical diagnosis, disease assessment, disability identification, and postmortem diagnosis of DAI is mainly limited by the absent of specific molecular biomarkers. AREAS COVERED: In this review, we first introduce the pathophysiology of DAI, summarized the reported biomarkers in previous animal and human studies, and then the molecular biomarkers such as ß-Amyloid precursor protein, neurofilaments, S-100ß, myelin basic protein, tau protein, neuron-specific enolase, Peripherin and Hemopexin for DAI diagnosis is summarized. Finally, we put forward valuable views on the future research direction of diagnostic biomarkers of DAI. EXPERT OPINION: In recent years, the advanced technology has ultimately changed the research of DAI, and the numbers of potential molecular biomarkers was introduced in related studies. We summarized the latest updated information in such studies to provide references for future research and explore the potential pathophysiological mechanism on diffuse axonal injury.
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Lesiones Traumáticas del Encéfalo , Lesión Axonal Difusa , Adulto , Animales , Niño , Humanos , Encéfalo/metabolismo , Lesión Axonal Difusa/diagnóstico , Lesión Axonal Difusa/metabolismo , Lesión Axonal Difusa/patología , Lesiones Traumáticas del Encéfalo/metabolismo , Biomarcadores/metabolismo , ProteómicaRESUMEN
Traumatic axonal injury (TAI) accounts for a large proportion of the mortality of traumatic brain injury (TBI). The diagnosis of TAI is currently of limited use for medicolegal purposes. It is known that axons in TAI are diffusely damaged by secondary processes other than direct head injury. However, the physiopathological mechanism of TAI is still elusive. The present study used RGD peptide, an antagonist of the mechanotransduction protein integrin, to explore the role of integrin-transmitted mechanical signalling in the pathogenesis of rat TAI. The rats were subjected to a linearly accelerating load, and changes in beta-amyloid precursor protein (ß-APP) expression, skeleton ultrastructure, skeleton protein neurofilament light (NF-L), and α-tubulin in the brainstem were observed, indicating that RGD could relieve the severity of axonal injury in TAI rats. In addition, the expression of ß-integrin was stronger and centralized in the brainstem of the deceased died from TAI compared to other nonviolent causes. This study examined the pathophysiology and biomechanics of TAI and assessed the role of integrin in the injury of microtubules and neurofilaments in TAI. Thus, we propose that integrin-mediated cytoskeletal injury plays an important role in TAI and that integrin has the potential as a biomarker for TAI.
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Lesiones Encefálicas , Lesión Axonal Difusa , Ratas , Animales , Ratas Sprague-Dawley , Lesiones Encefálicas/patología , Mecanotransducción Celular , Inmunohistoquímica , Axones/metabolismo , Axones/patología , Biomarcadores/metabolismo , Lesión Axonal Difusa/etiología , Lesión Axonal Difusa/metabolismo , Lesión Axonal Difusa/patologíaRESUMEN
Diffuse axonal injury (DAI) represents a frequent traumatic brain injury (TBI) type, significantly contributing to the dismal neurological prognosis and high mortality in TBI patients. The increase in mortality can be associated with delayed and nonspecific initial symptoms in DAI patients. Additionally, the existing approaches for diagnosis and monitoring are either low sensitivity or high cost. Therefore, novel, reliable, and objective diagnostic markers should be developed to diagnose and monitor DAI prognosis. Urine is an optimal sample to detect biomarkers for DAI noninvasively. Therefore, the DAI rat model was established in this work. Meanwhile, the ultraperformance liquid chromatography quadrupole-time-of-flight hybrid mass spectrometry- (UPLC/Q-TOF MS-) untargeted metabolomics approach was utilized to identify the features of urine metabolomics to diagnose DAI. This work included 57 metabolites with significant alterations and 21 abnormal metabolic pathways from the injury groups. Three metabolites, viz., urea, butyric acid, and taurine, were identified as possible biomarkers to diagnose DAI based on the great fold changes (FCs) and biological functions during DAI. The present study detected several novel biomarkers for noninvasively diagnosing and monitoring DAI and helped understand the DAI-associated metabolic events.
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Lesiones Traumáticas del Encéfalo , Lesión Axonal Difusa , Animales , Biomarcadores/metabolismo , Lesiones Traumáticas del Encéfalo/diagnóstico , Ácido Butírico , Lesión Axonal Difusa/diagnóstico , Lesión Axonal Difusa/metabolismo , Metabolómica , Ratas , Taurina , UreaRESUMEN
BACKGROUND: Ketogenic diet (KD) has been identified as a potential therapy to enhance recovery after traumatic brain injury (TBI). Diffuse axonal injury (DAI) is a common type of traumatic brain injury that is characterized by delayed axonal disconnection. Previous studies showed that demyelination resulting from oligodendrocyte damage contributes to axonal degeneration in DAI. AIM: The present study tests a hypothesis that ketone bodies from the ketogenic diet confers protection for myelin and attenuates degeneration of demyelinated axon in DAI. METHODS: A modified Marmarou's model of DAI was induced in adult rats. The DAI rats were fed with KD and analyzed with western blot, transmission electron microscope, ELISA test and immunohistochemistry. Meanwhile, a co-culture of primary oligodendrocytes and neurons was treated with ketone body ß-hydroxybutryate (ßHB) to test for its effects on the myelin-axon unit. RESULTS: Here we report that rats fed with KD showed an increased fatty acid metabolism and ketonemia. This dietary intervention significantly reduced demyelination and attenuated axonal damage in rats following DAI, likely through inhibition of DAI-induced excessive mitochondrial fission and promoting mitochondrial fusion. In an in vitro model of myelination, the ketone body ßHB increased myelination significantly and reduced axonal degeneration induced by glucose deprivation (GD). ßHB robustly increased cell viability, inhibited GD-induced collapse of mitochondrial membrane potential and attenuated death of oligodendrocytes. CONCLUSION: Ketone bodies protect myelin-forming oligodendrocytes and reduce axonal damage. Ketogenic diet maybe a promising therapy for DAI.
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Lesiones Traumáticas del Encéfalo , Enfermedades Desmielinizantes , Dieta Cetogénica , Lesión Axonal Difusa , Animales , Axones/metabolismo , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/prevención & control , Lesión Axonal Difusa/metabolismo , Modelos Animales de Enfermedad , Cuerpos Cetónicos , Cetonas , Vaina de Mielina , RatasRESUMEN
Traumatic brain injury (TBI) is a condition burdened by an extremely high rate of morbidity and mortality and can result in an overall disability rate as high as 50% in affected individuals. Therefore, the importance of identifying clinical prognostic factors for diffuse axonal injury (DAI) in (TBI) is commonly recognized as critical. The aim of the present review paper is to evaluate the most recent contributions from the relevant literature in order to understand how each single prognostic factor determinates the severity of the clinical syndrome associated with DAI. The main clinical factors with an important impact on prognosis in case of DAI are glycemia, early GCS, the peripheral oxygen saturation, blood pressure, and time to recover consciousness. In addition, the severity of the lesion, classified on the ground of the cerebral anatomical structures involved after the trauma, has a strong correlation with survival after DAI. In conclusion, modern findings concerning the role of reactive oxygen species (ROS) and oxidative stress in DAI suggest that biomarkers such as GFAP, pNF-H, NF-L, microtubule associated protein tau, Aß42, S-100ß, NSE, AQP4, Drp-1, and NCX represent a possible critical target for future pharmaceutical treatments to prevent the damages caused by DAI.
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Biomarcadores/metabolismo , Lesiones Traumáticas del Encéfalo/complicaciones , Lesión Axonal Difusa/patología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Lesión Axonal Difusa/etiología , Lesión Axonal Difusa/metabolismo , Humanos , PronósticoRESUMEN
OBJECTIVE: We have previously demonstrated that inflammation induced by toll-like receptors (TLRs) 2/4 exert cerebral deleterious effects after diffuse axonal injury (DAI); however, the underlying mechanisms are not fully understood. Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine involved in inflammatory responses. The purpose of this study was to investigate the role of MIF in inflammation induced by TLRs in the cortices of DAI rats. METHODS: The rat DAI model was established by head rotational acceleration and confirmed by ß-APP, HE, and silver staining. MIF protein expression at 3 h, 6 h, 12 h, 1 d, and 3 d after DAI was measured by western blot. The localization of MIF was measured by immunofluorescence. MIF antagonist ISO-1 was intracerebroventricularly injected to inhibit MIF. Neuronal and axonal injury and glial responses were assessed by TUNEL, immunohistochemistry, and TEM. Expression of TLR2, TLR4, ERK, phospho-ERK, NF-κB, and phospho-NF-κB was examined by western blot. The level of IL-1ß, IL-6, and TNF-α was measured by ELISA. RESULTS: MIF expression was significantly increased, peaking at 1 day after DAI, and MIF was mainly localized in microglial cells and neurons. ISO-1 suppressed neuronal apoptosis, axonal injury, and glial responses and decreased the expression of downstream signaling molecules related to TLR2/4, including ERK, phospho-ERK, NF-κB, phospho-NF-κB, IL-1ß, IL-6, and TNF-α. CONCLUSION: MIF was involved in the neuronal and axonal damage through a TLR-related pathway following DAI.
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Lesión Axonal Difusa/metabolismo , Inflamación/metabolismo , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/metabolismo , Factores Inhibidores de la Migración de Macrófagos/antagonistas & inhibidores , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Receptores Toll-Like/metabolismo , Animales , Apoptosis/fisiología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Microglía/metabolismo , FN-kappa B/metabolismo , Neuroglía/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/fisiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Blood-brain barrier (BBB) disruption exacerbates diffuse axonal injury (DAI), but the underlying mechanisms are not fully understood. Inactivation or deletion of erythropoietin-producing hepatoma (EPH) receptor A2 (EphA2) attenuated BBB damage and promoted tight junction formation. In this study, we aimed to investigate the role of EphA2 in the protection of BBB integrity and the relevant mechanisms involved in a rat model of DAI. Blocking activation of the EphA receptor by EphA2-Fc ameliorated axonal injury, cell apoptosis, and glial activation, protected BBB integrity and increased expression of the tight junction-associated proteins ZO-1, claudin-5 and occludin-1. In vitro BBB models established by human brain microvascular endothelial cells (HBMECs) were subjected to oxygen deprivation (OGD). Treatment with EphrinA1, which activates EphA2, exacerbated the OGD-induced destruction of permeability and integrity of the BBB models by reducing the expression of tight junction-associated proteins. However, inhibition of Rho-associated coiled coil-containing protein kinases 1 and 2 (ROCK1 and 2) abrogated all of the effects of EphrinA1 on the BBB models in vitro. In conclusion, we provide evidence that EphA2 plays an important role in the destruction of BBB integrity by decreasing the expression of tight junction proteins through the ROCK pathway.
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Barrera Hematoencefálica/patología , Lesión Axonal Difusa/patología , Receptor EphA2/metabolismo , Quinasas Asociadas a rho/metabolismo , Animales , Barrera Hematoencefálica/metabolismo , Lesión Axonal Difusa/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Nuclear factor erythroid 2-related factor 2 (Nrf2) can alleviate diffuse axonal injury (DAI)-induced apoptosis by regulating expression of heme oxygenase-1 (HO-1), while sulforaphane (SFN) was shown to reduce oxidative stress by increasing the expression of Nrf2. Therefore, we aimed to investigate therapeutic effect of SFN in the treatment of DAI and the ability of SFN to reduce oxidative stress. METHODS: The 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to observe the effects of H2 O 2 and SFN on cell viability. Fluorometric assay, Western blot analysis, and flow cytometry were conducted to validate the protective role of SFN in an animal model of DAI. In addition, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were measured in DAI rats treated by SFN, while Western blot, immunohistochemistry assay, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were carried out to verify the effect of SFN in different animal groups. RESULTS: Cell viability was reduced by H2 O 2 in a dose-dependent manner, while the treatment by SFN significantly promoted cell growth. Meanwhile the administration of SFN effectively reduced the levels of caspase-3/poly(ADP-ribose) polymerase (PARP) activity increased by the H 2 O 2 treatment, indicating that the protective effect of SFN could be mediated by its ability to suppress caspase-3 activation and PARP cleavage. In addition, the SFN treatment reduced the intracellular reactive oxygen species (ROS) generation induced by H 2 O 2 . Moreover, the MDA levels of SOD/GPx activity in various rat groups showed the protective effects of SFN in DAI rats. It is suspected that the protective effect of SFN was exerted via the activation of the Nrf2/HO-1 signaling pathway. In this study, DAI and DAI + phosphate-buffered saline (PBS) groups also showed the presence of more TUNEL-positive cells compared with the sham-operated group, while the SFN treatment reduced the extent of neuronal apoptosis. CONCLUSIONS: By activating the Nrf2/HO-1 signaling pathway and reducing the activity of caspase-3, SFN reduces the apoptosis of neurons in brain trauma-induced DAI.
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Axones/metabolismo , Axones/patología , Lesión Axonal Difusa/tratamiento farmacológico , Hemo Oxigenasa (Desciclizante)/metabolismo , Isotiocianatos/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Apoptosis , Supervivencia Celular , Lesión Axonal Difusa/metabolismo , Regulación de la Expresión Génica , Glutatión Peroxidasa/metabolismo , Peróxido de Hidrógeno/química , Masculino , Malondialdehído/metabolismo , Neuronas/metabolismo , Estrés Oxidativo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Sulfóxidos , Superóxido Dismutasa/metabolismo , Resultado del TratamientoRESUMEN
Diffuse axonal injury (DAI) is one of the most common and severe pathological consequences of traumatic brain injury (TBI). The molecular mechanism of DAI is highly complicated and still elusive, yet a clear understanding is crucial for the diagnosis, treatment, and prognosis of DAI. In our study, we used rats to establish a DAI model and applied isobaric tags for relative and absolute quantitation (iTRAQ) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to identify differentially expressed proteins (DEPs) in the corpus callosum. As a result, a total of 514 proteins showed differential expression between the injury groups and the control. Among these DEPs, 14 common DEPs were present at all seven time points postinjury (1, 3, 6, 12, 24, 48, and 72 h). Next, bioinformatic analysis was performed to elucidate the pathogenesis of DAI, which was found to possibly involve calcium ion-regulatory proteins (e.g., calsenilin and ryanodine receptor 2), cytoskeleton organization (e.g., peripherin, NFL, NFM, and NFH), apoptotic processes (e.g., calsenilin and protein kinase C delta type), and inflammatory response proteins (e.g., complement C3 and C-reactive protein). Moreover, peripherin and calsenilin were successfully confirmed by western blotting to be significantly upregulated during DAI, and immunohistochemical (IHC) analysis revealed that their expression increased and could be observed in axons after injury, thus indicating their potential as DAI biomarkers. Our experiments not only provide insight into the molecular mechanisms of axonal injury in rats during DAI but also give clinicians and pathologists important reference data for the diagnosis of DAI. Our findings may expand the list of DAI biomarkers and improve the postmortem diagnostic rate of DAI.
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Lesión Axonal Difusa/diagnóstico , Lesión Axonal Difusa/metabolismo , Lesión Axonal Difusa/patología , Animales , Axones/metabolismo , Biomarcadores/metabolismo , Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Cromatografía Liquida/métodos , Biología Computacional/métodos , Cuerpo Calloso/metabolismo , Femenino , Pronóstico , Proteómica/métodos , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem/métodosRESUMEN
The diagnosis of diffuse axonal injury (DAI) is an important task in forensic pathology and clinical medicine. This study aimed to explore the use of Fourier transform infrared spectroscopy (FTIR) to detect DAI. The DAI area of the rat model was detected point by point by the FTIR-mapping system. Infrared spectral data of DAI were obtained by selecting the amide A band, CH3 symmetric stretching, collagen triple-helix structure and asymmetric stretching vibrational frequency of nucleic acid and phospholipid PO2 as the target peak positions. The system can automatically draw infrared spectral color pathological images. In the DAI group, the amide A protein secondary amine N-H stretching vibration and the collagen triple-helix structure of the high-absorption area were consistent with the DAI area confirmed by the silver and ß-APP staining. The CH3 symmetric stretching, nucleic acid and phospholipid PO2 symmetric stretching vibration absorption spectra showed no significant differences between the experimental and verification groups. The FTIR-mapping technique can visually express the molecular characteristics of DAI, which is expected to be applied to the pathological diagnosis of DAI.
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Lesión Axonal Difusa/diagnóstico , Lesión Axonal Difusa/metabolismo , Patologia Forense/métodos , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Amidas/metabolismo , Animales , Colágeno/metabolismo , Lesión Axonal Difusa/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ácidos Nucleicos/metabolismo , Fosfolípidos/metabolismo , Ratas Sprague-Dawley , Coloración y EtiquetadoRESUMEN
Diffuse axonal injury (DAI) is an important consequence of traumatic brain injury (TBI). At the moment of trauma, axons rarely disconnect, but undergo cytoskeletal disruption and transport interruption leading to protein accumulation within swellings. The amyloid precursor protein (APP) accumulates rapidly and the standard histological evaluation of axonal pathology relies upon its detection. APP+ swellings first appear as varicosities along intact axons, which can ultimately undergo secondary disconnection to leave a terminal "axon bulb" at the disconnected, proximal end. However, sites of disconnection are difficult to determine with certainty using standard, thin tissue sections, thus limiting the comprehensive evaluation of axon degeneration. The tissue-clearing technique, CLARITY, permits three-dimensional visualization of axons that would otherwise be out of plane in standard tissue sections. Here, we examined the morphology and connection status of APP+ swellings using CLARITY at 6 h, 24 h, 1 week and 1 month following the controlled cortical impact (CCI) model of TBI in mice. Remarkably, many APP+ swellings that appeared as terminal bulbs when viewed in standard 8-µm-thick regions of tissue were instead revealed to be varicose swellings along intact axons when three dimensions were fully visible. Moreover, the percentage of these potentially viable axon swellings differed with survival from injury and may represent the delayed onset of distinct mechanisms of degeneration. Even at 1-month post-CCI, ~10% of apparently terminal bulbs were revealed as connected by CLARITY and are thus potentially salvageable. Intriguingly, the diameter of swellings decreased with survival, including varicosities along intact axons, and may reflect reversal of, or reduced, axonal transport interruption in the chronic setting. These data indicate that APP immunohistochemistry on standard thickness tissue sections overestimates axon disconnection, particularly acutely post-injury. Evaluating cleared tissue demonstrates a surprisingly delayed process of axon disconnection and thus longer window of therapeutic opportunity than previously appreciated. Intriguingly, a subset of axon swellings may also be capable of recovery.
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Lesión Axonal Difusa/patología , Técnicas Histológicas/métodos , Inmunohistoquímica/métodos , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Transporte Axonal , Axones/patología , Encéfalo/patología , Lesiones Encefálicas/patología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/fisiopatología , Lesión Axonal Difusa/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones EndogámicosRESUMEN
Diffuse axonal injury contributes to the long-term functional morbidity observed after pediatric moderate/severe traumatic brain injury (msTBI). Whole-brain proton magnetic resonance echo-planar spectroscopic imaging was used to measure the neurometabolite levels in the brain to delineate the course of disruption/repair during the first year post-msTBI. The association between metabolite biomarkers and functional measures (cognitive functioning and corpus callosum [CC] function assessed by interhemispheric transfer time [IHTT] using an event related potential paradigm) was also explored. Pediatric patients with msTBI underwent assessments at two times (post-acutely at a mean of three months post-injury, n = 31, and chronically at a mean of 16 months post-injury, n = 24). Healthy controls also underwent two evaluations, approximately 12 months apart. Post-acutely, in patients with msTBI, there were elevations in choline (Cho; marker for inflammation and/or altered membrane metabolism) in all four brain lobes and the CC and decreases in N-acetylaspartate (NAA; marker for neuronal and axonal integrity) in the CC compared with controls, all of which normalized by the chronic time point. Subgroups of TBI showed variable patterns chronically. Patients with slow IHTT had lower lobar Cho chronically than those with normal IHTT; they also did not show normalization in CC NAA whereas those with normal IHTT showed significantly higher levels of CC NAA relative to controls. In the normal IHTT group only, chronic CC Cho and NAA together explained 70% of the variance in long-term cognitive functioning. MR based whole brain metabolic evaluations show different patterns of neurochemistry after msTBI in two subgroups with different outcomes. There is a dynamic relationship between prolonged inflammatory responses to brain damage, reparative processes/remyelination, and subsequent neurobehavioral outcomes. Multimodal studies allow us to test hypotheses about degenerative and reparative processes in patient groups that have divergent functional outcome, with the ultimate goal of developing targeted therapeutic agents.
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Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/metabolismo , Lesión Axonal Difusa/diagnóstico por imagen , Lesión Axonal Difusa/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Adolescente , Lesiones Traumáticas del Encéfalo/complicaciones , Niño , Lesión Axonal Difusa/etiología , Femenino , Humanos , Masculino , Recuperación de la FunciónRESUMEN
Diffuse axonal injury (DAI) accounts for more than 50% of all traumatic brain injury. In response to the mechanical damage associated with DAI, the abnormal proteins produced in the neurons and axons, namely, ß-APP and p-tau, induce endoplasmic reticulum (ER) stress. Curcumin, a major component extracted from the rhizome of Curcuma longa, has shown potent anti-inflammatory, antioxidant, anti-infection, and antitumor activity in previous studies. Moreover, curcumin is an activator of nuclear factor-erythroid 2-related factor 2 (Nrf2) and promotes its nuclear translocation. In this study, we evaluated the therapeutic potential of curcumin for the treatment of DAI and investigated the mechanisms underlying the protective effects of curcumin against neural cell death and axonal injury after DAI. Rats subjected to a model of DAI by head rotational acceleration were treated with vehicle or curcumin to evaluate the effect of curcumin on neuronal and axonal injury. We observed that curcumin (20 mg/kg intraperitoneal) administered 1 h after DAI induction alleviated the aggregation of p-tau and ß-APP in neurons, reduced ER-stress-related cell apoptosis, and ameliorated neurological deficits. Further investigation showed that the protective effect of curcumin in DAI was mediated by the PERK/Nrf2 pathway. Curcumin promoted PERK phosphorylation, and then Nrf2 dissociated from Keap1 and was translocated to the nucleus, which activated ATF4, an important bZIP transcription factor that maintains intracellular homeostasis, but inhibited the CHOP, a hallmark of ER stress and ER-associated programmed cell death. In summary, we demonstrate for the first time that curcumin confers protection against abnormal proteins and neuronal apoptosis after DAI, that the process is mediated by strengthening of the unfolded protein response to overcome ER stress, and that the protective effect of curcumin against DAI is dependent on the activation of Nrf2.
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Apoptosis/efectos de los fármacos , Axones/efectos de los fármacos , Curcumina/farmacología , Lesión Axonal Difusa/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Animales , Apoptosis/fisiología , Axones/metabolismo , Axones/patología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Lesión Axonal Difusa/metabolismo , Lesión Axonal Difusa/patología , Modelos Animales de Enfermedad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/fisiología , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/etiología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Fosforilación/efectos de los fármacos , Distribución Aleatoria , Ratas Sprague-Dawley , eIF-2 Quinasa/metabolismoRESUMEN
The positron emission tomography (PET) radioligand for adenosine A1 receptor (A1R) [1-methyl-11C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX) has recently been developed for human brain imaging. In the present study, we evaluated the alteration of the A1R in patients with diffuse axonal injury (DAI) in chronic stage in vivo. Ten patients with DAI (7 men and 3 women) were included in this study. Three PET examinations were sequentially performed to measure A1R binding with 11C-MPDX, glucose metabolism with 18F-fluorodeoxyglucose (FDG), and central benzodiazepine receptor binding with 11C-flumazenil (FMZ), and decreases of 11C-FMZ uptake indicate neuronal loss. 11C- MPDX did not depict any lesion with significantly decreased nondisplaceable binding potential (BPND) in comparison to healthy controls (14 men) in region of interest (ROI) analysis. Instead, it showed a significant increase of BPND in the lower frontal and posterior cingulate cortexes and rolandic area (p < 0.05) in ROI analysis. In 18F-FDG PET, the standardized uptake values (SUVs) ratio to the whole brain were decreased in anterior and posterior cingulate gyrus compared to controls (14 men and 9 women; p < 0.01). In 11C-FMZ PET, the SUV ratio to the cerebellum was decreased in anterior cingulate gyrus in ROI analysis (controls, 9 men and 6 women; p < 0.01). The area with significantly increased 11C-MPDX binding, lower frontal cortex, rolandic area, and posterior cingulate gyrus, did not overlap with the areas of neuronal loss detected by decreased 11C-FMZ binding and did not completely overlap with area of reduced18F-FDG uptake. We obtained the first 11C-MPDX PET images reflecting the A1R BPND in human DAI brain in vivo. 11C-MPDX depicted increased A1R BPND in the areas surrounding the injured brain, whereas 18F-FDG demonstrated reduction throughout the brain. The results suggested that A1R might continuously confer neuroprotective or neuromodulatory effects in DAI even in the chronic stage.
Asunto(s)
Lesión Axonal Difusa/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Receptor de Adenosina A1/análisis , Adulto , Radioisótopos de Carbono , Enfermedad Crónica , Lesión Axonal Difusa/metabolismo , Femenino , Flumazenil , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Radiofármacos , XantinasRESUMEN
Traumatic brain injury (TBI) is one of the world's leading causes of morbidity and mortality among young individuals. TBI applies powerful rotational and translational forces to the brain parenchyma, which results in a traumatic diffuse axonal injury (DAI) responsible for brain swelling and neuronal death. Following TBI, axonal degeneration has been identified as a progressive process that starts with disrupted axonal transport causing axonal swelling, followed by secondary axonal disconnection and Wallerian degeneration. These modifications in the axonal cytoskeleton interrupt the axoplasmic transport mechanisms, causing the gradual gathering of transport products so as to generate axonal swellings and modifications in neuronal homeostasis. Oxidative stress with consequent impairment of endogenous antioxidant defense mechanisms plays a significant role in the secondary events leading to neuronal death. Studies support the role of an altered axonal calcium homeostasis as a mechanism in the secondary damage of axon, and suggest that calcium channel blocker can alleviate the secondary damage, as well as other mechanisms implied in the secondary injury, and could be targeted as a candidate for therapeutic approaches. Reactive oxygen species (ROS)-mediated axonal degeneration is mainly caused by extracellular Ca2+. Increases in the defense mechanisms through the use of exogenous antioxidants may be neuroprotective, particularly if they are given within the neuroprotective time window. A promising potential therapeutic target for DAI is to directly address mitochondria-related injury or to modulate energetic axonal energy failure.
Asunto(s)
Calcio/metabolismo , Lesión Axonal Difusa/patología , Estrés Oxidativo , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Lesión Axonal Difusa/tratamiento farmacológico , Lesión Axonal Difusa/metabolismo , Humanos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
OBJECTIVES: To screen for the differential expression proteins in brain tissues of SD rat after diffuse axonal injury ï¼DAIï¼ by isobaric tag for relative and absolute quantification-liquid chromatograph-mass spectrometer/mass spectrometer ï¼iTRAQ-LC-MS/MSï¼, and to explore potential biomarkers available for the diagnosis of DAI. METHODS: Animal models of DAI were established with the Marmarou method as reference, and the subjects were divided into blank control group ï¼n=4ï¼, sham strike group ï¼n=4ï¼ and fatal strike group ï¼n=4ï¼, respectively. The proteins in rat brain tissues were detected by iTRAQ-LC-MS/MS, and bioinformatics analysis and verification were performed on the results and screened for the differential expression proteins. RESULTS: A total of 2 016 proteins were identified and quantified. The bioinformatics analysis revealed that the proteins had wide distribution and function, and participated in different biological processes. There were 16 proteins showed differential expression in fatal strike group, including one up-regulated expression protein and 15 down-regulated expression proteins. The results of iTRAQ-LC-MS/MS were confirmed by Western blotting method. CONCLUSIONS: Multiple differential expression proteins in rat brain tissues after DAI can be screened by iTRAQ-LC-MS/MS. This not only indicates a research direction for exploring the pathogenesis of DAI, but also provides potential biomarkers available for the diagnosis of DAI.
Asunto(s)
Lesión Axonal Difusa/metabolismo , Proteómica/métodos , Animales , Biomarcadores/metabolismo , Encéfalo , Cromatografía Liquida/métodos , Lesión Axonal Difusa/fisiopatología , Regulación hacia Abajo , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Regulación hacia ArribaRESUMEN
Although millions of individuals suffer a traumatic brain injury (TBI) worldwide each year, it is only recently that TBI has been recognized as a major public health problem. Beyond the acute clinical manifestations, there is growing recognition that a single severe TBI (sTBI) or repeated mild TBIs (rTBI) can also induce insidious neurodegenerative processes, which may be associated with early dementia, in particular chronic traumatic encephalopathy (CTE). Identified at autopsy examination in individuals with histories of exposure to sTBI or rTBI, CTE is recognized as a complex pathology featuring both macroscopic and microscopic abnormalities. These include cavum septum pellucidum, brain atrophy and ventricular dilation, together with pathologies in tau, TDP-43, and amyloid-ß. However, the establishment and characterization of CTE as a distinct disease entity is in its infancy. Moreover, the relative "dose" of TBI, such as the frequency and severity of injury, associated with risk of CTE remains unknown. As such, there is a clear and pressing need to improve the recognition and diagnosis of CTE and to identify mechanistic links between TBI and chronic neurodegeneration.
Asunto(s)
Encéfalo/fisiopatología , Encefalopatía Traumática Crónica/fisiopatología , Lesión Axonal Difusa/fisiopatología , Péptidos beta-Amiloides/metabolismo , Atrofia , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Lesiones Traumáticas del Encéfalo/fisiopatología , Ventrículos Cerebrales/diagnóstico por imagen , Ventrículos Cerebrales/patología , Enfermedad Crónica , Encefalopatía Traumática Crónica/diagnóstico por imagen , Encefalopatía Traumática Crónica/metabolismo , Encefalopatía Traumática Crónica/patología , Proteínas de Unión al ADN/metabolismo , Lesión Axonal Difusa/diagnóstico por imagen , Lesión Axonal Difusa/metabolismo , Lesión Axonal Difusa/patología , Dilatación Patológica , Humanos , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/fisiopatología , Ovillos Neurofibrilares/patología , Tabique Pelúcido/diagnóstico por imagen , Tabique Pelúcido/metabolismo , Tabique Pelúcido/patología , Tabique Pelúcido/fisiopatología , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Therapeutics specific to neural injury have long been anticipated but remain unavailable. Axons in the central nervous system do not readily regenerate after injury, leading to dysfunction of the nervous system. This failure of regeneration is due to both the low intrinsic capacity of axons for regeneration and the various inhibitors emerging upon injury. After many years of concerted efforts, however, these hurdles to axon regeneration have been partially overcome. SCOPE OF REVIEW: This review summarizes the mechanisms regulating axon regeneration. We highlight proteoglycans, particularly because it has become increasingly clear that these proteins serve as critical regulators for axon regeneration. MAJOR CONCLUSIONS: Studies on proteoglycans have revealed that glycans not only assist in the modulation of protein functions but also act as main players-e.g., as functional ligands mediating intracellular signaling through specific receptors on the cell surface. By regulating clustering of the receptors, glycans in the proteoglycan moiety, i.e., glycosaminoglycans, promote or inhibit axon regeneration. In addition, proteoglycans are involved in various types of neural plasticity, ranging from synaptic plasticity to experience-dependent plasticity. GENERAL SIGNIFICANCE: Although studies on proteins have progressively facilitated our understanding of the nervous system, glycans constitute a new frontier for further research and development in this field. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.