Mecanismos biológicos involucrados en la propagación del daño en el traumatismo encéfalo craneano

doi:10.1016/j.medin.2011.06.008

Medicina Intensiva

Volume 36, Issue 1, January–February 2012, Pages 37-44

https://doi.org/10.1016/j.medin.2011.06.008 Get rights and content

Resumen

El traumatismo encéfalo craneano (TEC) es un problema de salud de distribución mundial, y es especialmente prevalente en la población adulta joven. Es característica la presencia de uno o más focos de daño, que luego progresan hacia áreas inicialmente no lesionadas, mediante cascadas de respuesta inflamatoria, excitotoxicidad, condiciones de falla energética, y la participación de la glía amplificando la respuesta tisular al daño inicial. Esta progresión es, en teoría, susceptible de una intervención terapéutica. Sin embargo, hasta ahora todos los estudios con fármacos neuroprotectores han fracasado, no existiendo un tratamiento específico efectivo. Los resultados negativos se explican en parte por el empleo de una estrategia centrada solo en las neuronas, sin considerar otras células participantes, u otros mecanismos patogénicos. Para cambiar este panorama, es necesario re-enfocar el problema a través de una mejor comprensión de los mecanismos que determinan la progresión del daño. En esta revisión discutiremos los principales mecanismos biológicos involucrados en la progresión del daño tisular post-trauma. Se aborda la fisiopatología general de los tipos de traumatismos, mecanismos celulares del daño secundario incluyendo inflamación, apoptosis, tumefacción celular, excitoxicidad, y participación de la glía en la propagación del daño. Se destaca el papel de la glía en cada uno de los mecanismos celulares mencionados. Se incluyen algunas aproximaciones terapéuticas relacionadas con los mecanismos descritos. Se finaliza con un diagrama general que resume los principales aspectos discutidos.

Abstract

Traumatic brain injury (TBI) is a worldwide health problem that is especially prevalent in young adults. It is characterized by one or more primary injury foci, with secondary spread to initially not compromised areas via cascades of inflammatory response, excitotoxicity, energy failure conditions, and amplification of the original tissue injury by glia. In theory, such progression of injury should be amenable to management. However, all neuroprotective drug trials have failed, and specific treatments remain lacking. These negative results can be explained by a neuron centered approach, excluding the participation of other cell types and pathogenic mechanisms. To change this situation, it is necessary to secure a better understanding of the biological mechanisms determining damage progression or spread. We discuss the biological mechanisms involved in the progression of post-trauma tissue damage, including the general physiopathology of TBI and cellular mechanisms of secondary damage such as inflammation, apoptosis, cell tumefaction, excitotoxicity, and the role of glia in damage propagation. We highlight the role of glia in each cellular mechanism discussed. Therapeutic approaches related to the described mechanisms have been included. The discussion is completed with a working model showing the convergence of the main topics.

Section snippets

Relevancia del problema

El traumatismo encéfalo craneano (TEC) es la principal causa de morbimortalidad en la población menor de 45 años. Cada año, 1,4 millones de personas sufren un TEC en los EE.UU.¹, la mitad de los cuales son severos (escala de Glasgow < 8), y tienen una mortalidad de ∼35% al año. En Europa el panorama no es diferente, la incidencia estimada es de 235 casos por 100.000 habitantes/año con una mortalidad de ∼11%². Además, el TEC es un factor de riesgo conocido para el desarrollo de enfermedades

Tipos de traumatismo encéfalo craneano según su mecanismo de daño directo

Dependiendo de la biomecánica del trauma, los TEC se clasifican en lesión 1) focal y 2) difusa. En la lesión focal por contacto directo, se encuentran los hematomas epi- y subdurales, contusiones y hematomas intraparenquimatosos⁴. En cambio, en la lesión difusa por aceleración/desaceleración, predominan los fenómenos de daño axonal difuso y edema cerebral⁴.

En las primeras horas post-TEC, en el cerebro se observan islotes de daño celular en la lesión focal versus un compromiso extenso en las

Propagación del daño

Una vez establecido el daño tisular directo, tanto en las lesiones focales como difusas, se desarrolla un fenómeno complejo de progresión del daño que involucra factores locales y sistémicos que en conjunto se conocen como mecanismos de daño secundario (fig. 1).

Entre los factores sistémicos que agravan el daño secundario destaca la presencia de hipotensión e hipoxia. El 90% de los pacientes que fallecen con un TEC grave presentan hallazgos compatibles con isquemia; hipotensión e hipoxia se

Inflamación

La respuesta inflamatoria post-TEC está mediada tanto por leucocitos circulantes, que son reclutados en la zona dañada, como por células residentes: microglías y astrocitos. Las microglías son macrófagos residentes del sistema nervioso central (SNC) y son responsables de la respuesta inmune innata del sistema nervioso¹¹. Aun en ausencia de daño o estimulación exógena, las microglías despliegan una constante actividad de vigilancia remodelando continuamente sus procesos, pudiendo inspeccionar

Apoptosis

Durante un TEC se observan grados variables de daño sobre las células del parénquima cerebral. Los TEC severos resultan en una necrosis rápida, estableciéndose los focos de daño celular directo ya mencionados. Sin embargo, condiciones de daño sub-letales, o la propagación de señales de daño hacia sitios alejados del lugar de daño directo, determinan la aparición de muerte celular por apoptosis en dichas regiones²³.

La existencia de apoptosis post-TEC ha sido observada en modelos animales y en

Tumefacción celular

El edema cerebral y las complicaciones asociadas dan cuenta de aproximadamente el 50% de las muertes por TEC³⁴. Klatzo en 1967, usando un modelo de trauma por frío, describió dos tipos de edema cerebral dependiendo de su origen: edema vasogénico (extracelular) y citotóxico, el que más correctamente corresponde a una tumefacción celular³⁵. Recientemente, mediante técnicas de neuroimagen, se determinó que el edema citotóxico es el componente mayoritario del edema cerebral post-TEC focal y difuso³⁶

Excitoxicidad

Tras un TEC, en un plazo de minutos, se observa una elevación aguda de los niveles extracelulares de glutamato, que ha sido documentada en trabajos experimentales y clínicos44, 45. La elevación del glutamato extracelular es principalmente consecuencia de la despolarización neuronal masiva por el traumatismo y la falla energética asociada ya mencionada en la sección previa. Este exceso de glutamato induce un incremento de la entrada de Na⁺ y Ca²⁺ a la célula, la sobrecarga de Ca²⁺ intracelular

Propagación del daño, papel de la glía

Las glías, y los astrocitos en particular, considerados originalmente solo como soporte de las neuronas, han recibido poca atención en el estudio del TEC. Sin embargo, en la última década su papel ha sido reinterpretado. Los astrocitos forman la microarquitectura del sistema nervioso, expresan receptores, canales y estructuralmente están organizados en redes que se comunican a través de CUH, estableciendo sincitios funcionales⁵⁵.

La progresión del daño celular podría estar facilitada por la

Daño axonal difuso

Una mención especial merece el daño axonal difuso, donde las lesiones comprometen fundamentalmente la sustancia blanca. La sustancia blanca está compuesta por haces axonales envainados con mielina, formada por los oligodendrocitos (OLG), encontrándose además astrocitos y células endoteliales. La interacción célula-célula entre los OLG y los axones neuronales es crítica en la formación de la mielina, el mantenimiento y la reparación de la sustancia blanca⁶⁹.

El daño axonal difuso se presenta

Recapitulación

Durante un TEC se establecen focos de daño celular directo. Sin embargo, diversos mecanismos de propagación de daño, tanto locales como sistémicos, independizan la progresión del daño de la noxa inicial. Entre los mecanismos locales destaca el papel de las glías, tanto de la microglía que participa como sensor del daño y coordinador de la respuesta inflamatoria, secretando numerosos mediadores de citotoxicidad, como de los astrocitos, los cuales, estando altamente interconectados, participan

Financiación

Proyecto PMD-10/09, Dirección de Investigación de la Facultad de Medicina-PUC (M.R.).

Beca de apoyo a la realización de tesis doctoral 2010, AT-24100202 CONICYT (M.R.).

Fondecyt 1070591 (J.C.S.); Fondecyt 1090353 (R.vB.).

Conflicto de interés

Los autores declaran no tener ningún conflicto de intereses.

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Cited by (39)

Traumatic Brain Injury–Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine
2024, Biological Psychiatry
Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization and the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI.
To identify the neural ensembles mediating fear generalization, we utilized ArcCreER^T2 × enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact model of TBI. Mice were then administered a contextual fear discrimination paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice.
TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the dentate gyrus, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination, and this behavioral improvement was reflected in dentate gyrus memory trace activity.
These data show that TBI induces fear generalization by altering fear memory traces and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.
Metabotropic glutamate receptor 5 upregulation of γ-aminobutyric acid transporter 3 expression ameliorates cognitive impairment after traumatic brain injury in mice
2022, Brain Research Bulletin
Traumatic brain injury (TBI) causes neurotransmitter disturbances contributing to neuronal cell death and neurological deficits. In humans, brain injuries impair γ-aminobutyric acid (GABA) uptake and ultimately result in cognitive impairment. GABA transporter 3 (GAT3) is a vital approach of GABA reuptake and catabolism. The contribution of GAT3 in TBI-induced cognitive impairment and its underlying mechanisms remain unknown, which were explored in the present study. Here, we found that expression of GAT3 was downregulated to increase GABA concentration in the mouse brain after TBI. And GAT3 was detected in neurons and astrocytes after TBI unexpectedly, instead of merely expressed on astrocytes in physiological states. Subsequently, activated metabotropic glutamate receptor 5 (mGluR5) reduced GABA content by elevating the expression levels of GAT3. Then, increased mGluR5 activity obviously improved cognitive impairment. Mechanistically, mGluR5 was activated to evidently induce the expression of p-ERK, CREB, and p-CREB after TBI. The inhibition of CREB decreased the expression of CREB, p-CREB, and GAT3 elevated by active mGluR5. However, the CREB inhibitor increased GABA content. Furthermore, Rab11a regulating GAT3 trafficking by endocytosis was elevated after TBI. And Rab11a downregulated by active mGluR5 was reversed by CREB inhibitor. In summary our findings elucidated that activated mGluR5 ameliorated cognitive function by upregulating GAT3 in TBI. And mGluR5 possibly regulated GAT3 by ERK/CREB/Rab11a pathway. GAT3 could serve as a potential target for TBI cognitive treatment.
Serum caspase-3 levels during the first week of traumatic brain injury
2021, Medicina Intensiva
Citation Excerpt :
In TBI appears a cerebral damage due to the primary brain injury produced by the physical forces in the moment of trauma, and also a cerebral damage due to the secondary brain injury produced by the activation in the following hours or days of different physiopathological ways such as apoptosis.4–7 The programed cell death by apoptosis occurs mainly through the activation of the extrinsic or death receptor pathway and the intrinsic or mitochondrial pathway, and both pathways (intrinsic and extrinsic) activate caspase-3 which motivate the cell changes that leads to death cell.4–7 There have been found increased caspase-3 in brain tissues of TBI animal models,8–20 in cerebrospinal fluid (CSF) of TBI patients,21–23 and in brain tissues of TBI patients.24,25
Confluence between the intrinsic and extrinsic apoptosis pathways is reached at the point of caspase-3 activation, which induces death cell. Higher serum caspase-3 levels have been recorded on day 1 of traumatic brain injury (TBI) in 30-day non-survivors compared to survivors. The objectives of this study therefore were to determine whether serum caspase-3 levels are persistently higher in non-survivors than in survivors, and whether these levels may be used to predict 30-day mortality.
A prospective observational study was carried out.
Six Spanish Intensive Care Units.
Patients with severe isolated TBI (defined as Glasgow Coma Scale <9 points and non-cranial Injury Severity Score <10 points).
Serum caspase-3 concentrations were measured on days 1, 4 and 8 of TBI.
Thirty-day mortality was considered as the study endpoint.
In comparison with non-survivors (n = 34), 30-day survivors (n = 90) showed lower serum caspase-3 levels on days 1 (p = 0.001), 4 (p < 0.001) and 8 (p < 0.001) of TBI. Analysis of the ROC curves showed serum caspase-3 concentrations on days 1, 4 and 8 of TBI to have an AUC (95% CI) in predicting 30-day mortality of 0.70 (0.61–0.78; p = 0.001), 0.83 (0.74–0.89; p < 0.001) and 0.87 (0.79–0.93; p < 0.001), respectively.
The novel findings of our study were that serum caspase-3 levels during the first week of TBI were lower in survivors and could predict 30-day mortality.
La vía intrínseca y extrínseca de la apoptosis confluyen en la activación de caspasa-3. Se han encontrado mayores niveles séricos de caspasa-3 en el día 1 del traumatismo craneoencefálico (TCE) en los pacientes que fallecen en los primeros 30 días que en supervivientes. Por tanto, los objetivos de este estudio es determinar si los niveles séricos de caspasa-3 se mantienen superiores en los pacientes fallecidos que en los supervivientes, y si podrían utilizarse para predecir la mortalidad a 30 días.
Estudio observacional y prospectivo.
Seis unidades de cuidados intensivos españolas.
Enfermos con un TCE grave y aislado (definido como escala de coma de Glasgow < 9 y puntuación de gravedad de la lesión Score en lesiones no craneales < 10).
Se midieron los niveles séricos de caspasa-3 en los días 1, 4 y 8 del TCE.
Mortalidad a los 30 días.
Los pacientes supervivientes a los 30 días (n = 90) presentan menores niveles séricos de caspasa-3 en los días 1 (p = 0,001), 4 (p < 0,001) y 8 (p < 0,001) del TCE que los fallecidos (n = 34). Los niveles séricos de caspasa-3 en los días 1, 4 y 8 del TCE tenían un área bajo la curva (intervalo de confianza del 95%) para predecir la mortalidad de 0,70 (0,61-0,78; p = 0,001), 0,83 (0,74-0,89; p < 0,001) y 0,87 (0,79-0,93; p < 0,001), respectivamente.
Los nuevos hallazgos de nuestro estudio fueron que los niveles séricos de caspasa-3 durante la primera semana del TCE fueron menores en los pacientes supervivientes, y que pueden predecir la mortalidad a los 30 días.
Role of astrocyte connexin hemichannels in cortical spreading depression
2018, Biochimica et Biophysica Acta - Biomembranes
Cortical spreading depression (CSD) is an intriguing phenomenon consisting of massive slow brain depolarizations that affects neurons and glial cells. It has been recognized since 1944, but its pathogenesis has only been uncovered during the last decade. Acute brain injuries can be further complicated by CSD in > 50% of severe cases. This phenomenon is repetitive and produces a metabolic overload that increments secondary damage. Propagation of CSD is known to be linked to excitotoxicity, but the mechanisms associated with its initiation remain less understood. It has been shown that CSD can be initiated by increases in extracellular [K⁺] ([K⁺]_e), and animal models use high [K⁺]_e to promote CSD. Connexin hemichannel activity increases due to high [K⁺]_e and low extracellular [Ca^2 +], conditions that occur after brain injury. Moreover, glial cell gap junction channels are fundamental in controlling extracellular medium composition, particularly in maintaining normal extracellular glutamate and K⁺ concentrations through “spatial buffering”. However, the role of astrocytic gap junctions under tissue stress can change to damage spread in the acute damage zone whereas the reduced communication in adjacent zone would reduce cell dead propagation. Here, we review the main findings associated with CSD, and discuss the possible involvement of astrocytic connexin-based channels in secondary damage propagation. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.
Initial evaluation of the intracranial pressure in cases of traumatic brain injury without hemorrhage
2016, Journal of the Neurological Sciences
Our objective was to apply the technique of measuring diameters of optic nerve sheath (ONSD) for the intracranial pressure assessment for the cases with traumatic head injury without hemorrhage. In a retrospective study, CT data of 720 adult patients were collected and analyzed. ONSDs were measured at the point where the ophthalmic artery crosses the optic nerve (anatomical landmark) together with the eyeball transverse diameter (ETD). The ONSD/ETD index was calculated. The correlation analysis was performed with gender, age, the Glasgow Coma Scale score, and the Glasgow Outcome Score. ONSD was enlarged in 82% cases (n = 591). Enlarged right/left ONSDs were 6.7 ± 1.0/6.7 ± 0.9 mm (cut-off value ˃ 5.5 mm). ONSD/ETD ratio was 0.28 ± 0.05 against 0.19 ± 0.02 in healthy adults (p = 0.02). We did not find correlation between ONSD/ETD ratio with initial Glasgow Coma Scale score but there was an inverse correlation between ONSD/ETD ratio and the Glasgow Outcome Score (r = − 0.64). We conclude that in majority of cases with traumatic head injury without hemorrhage the ONSD is significantly enlarged indicating elevated intracranial pressure even if CT scans are negative.
Improvement in the neural stem cell proliferation in rats treated with modified "shengyu" decoction may contribute to the neurorestoration
2015, Journal of Ethnopharmacology
Citation Excerpt :
TBI not only produces high mortality, but also significantly affect the socioeconomic lives of survivors, some of which even have long-term disabilities (Corrigan, et al., 2010; Feigin, et al., 2013; Gean and Fischbein, 2010; Hyder, et al., 2007). TBI includes the primary injury produced by transient mechanical damage and the secondary brain injury caused by a complex sequence of cascade responses triggered by the primary injury (Rovegno, et al., 2012). Due to the irreversibility of the primary injury, many treatment strategies for the TBI have been tried to inhibit the secondary injury, but the results of clinical trials on neuroprotective agents have been disappointing (Xiong, et al., 2010a).
"Shengyu" decoction, a traditional Chinese medicine, has been used to treat diseases with deficit in “qi” and “blood”. The modified "Shengyu" decoction (MSD) used in the present study was designed to treat traumatic brain injury (TBI) on the basis of the "Shengyu" decoction, in which additional four herbs were added. Many ingredients in these herbs have been demonstrated to be effective for the treatment of brain injury. The present study was performed to evaluate the neurorestorative effect and the underlying mechanisms of MSD on the rat brain after a TBI.
TBI was induced in the right cerebral cortex of adult rats using Feeney’s weight-drop method. Intragastrical administration of MSD (1.0 ml/200 g) was begun 6 h after TBI. The neurological functions and neuronal loss in the cortex and hippocampus were determined. The levels of nerve growth-related factors GDNF, NGF, NCAM, TN-C, and Nogo-A and the number of GFAP⁺/GDNF⁺, BrdU⁺/nestin⁺, BrdU⁺/NeuN⁺ immunoreactive cells in the brain ipsilateral to TBI were also measured. Moreover, the influences of MSD on these variables were observed at the same time.
We found that treatment with MSD in TBI rats ameliorated the neurological functions and alleviated neuronal loss. MSD treatment elevated the expression of GDNF, NGF, NCAM, and TN-C, and inhibited the expression of Nogo-A. Moreover, MSD treatment increased the number of GFAP⁺/GDNF⁺, BrdU⁺/nestin⁺, and BrdU⁺/NeuN⁺ immunoreactive cells in the cortex and hippocampus.
The present results suggest that MSD treatment in TBI rats could improve the proliferation of neural stem/progenitor cells and differentiation into neurons, which may facilitate neural regeneration and tissue repair and thus contribute to the recovery of neurological functions. These effects of modified “Shengyu” decoction may provide a foundation for the use of MSD as a prescription of medicinal herbs in the traditional medicine to treat brain injuries in order to improve the neurorestoration.

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RevisiónMecanismos biológicos involucrados en la propagación del daño en el traumatismo encéfalo craneanoBiological mechanisms involved in the spread of traumatic brain damage

Resumen

Abstract

Section snippets

Relevancia del problema

Tipos de traumatismo encéfalo craneano según su mecanismo de daño directo

Propagación del daño

Inflamación

Apoptosis

Tumefacción celular

Excitoxicidad

Propagación del daño, papel de la glía

Daño axonal difuso

Recapitulación

Financiación

Conflicto de interés

Br J Anaesth

Surg Clin North Am

J Neuroimmunol

Curr Opin Neurobiol

Injury

Brain ResV 713

Neuroscience

Neuroscience

Brain Res

Brain Res

Exp Neurol

Trends Neurosci

Biochem Biophys Res Commun

Life Sci

Drug Discov Today

Lancet Neurol

Curr Opin Neurobiol

Prog Brain Res

Neuroscience

Prog Brain Res

The epidemiology and impact of traumatic brain injury: a brief overview

J Head Trauma Rehabil

A systematic review of brain injury epidemiology in Europe

Acta Neurochir (Wien)

Clinical trials in head injury

J Neurotrauma

Brain damage in fatal non-missile head injury

J Clin Pathol

Genetic association studies in patients with traumatic brain injury

Neurosurg Focus

Meta-analysis of APOE4 allele and outcome after traumatic brain injury

J Neurotrauma

Relationship between the Arg72Pro polymorphism of p53 and outcome for patients with traumatic brain injury

Intensive Care Med

IL-1RN and IL-1B gene polymorphisms and cerebral hemorrhagic events after traumatic brain injury

Neurology

Microglial physiology: unique stimuli, specialized responses

Annu Rev Immunol

Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo

Science

ATP mediates rapid microglial response to local brain injury in vivo

Nat Neurosci

Monocyte chemoattractant protein-1 increases microglial infiltration and aggressiveness of gliomas

Ann Neurol

Opposing roles for reactive astrocytes following traumatic brain injury

Neurosignals

Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury

Shock

Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months

Lancet

Neutralization of interleukin-1beta modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice

Eur J Neurosci

Revisión
Mecanismos biológicos involucrados en la propagación del daño en el traumatismo encéfalo craneanoBiological mechanisms involved in the spread of traumatic brain damage