¿Cómo reparar el daño cerebral isquémico? Utilidad de los modelos experimentales en la búsqueda de respuestas / How to repair an ischemic brain injury? Value of experimental models in search of answers

El objetivo principal de los modelos experimentales de isquemia cerebral es el estudio del daño isquémico cerebral en condiciones fisiológicamente controladas y reproducibles. Los estudios realizados han sido esenciales para establecer nuevos conceptos sobre los mecanismos subyacentes al daño cerebral isquémico tales como la penumbra isquémica, el daño por reperfusión, los mecanismos de muerte celular o la importancia del daño sufrido por las mitocondrias, las células gliales y la sustancia blanca. Sin embargo, debido a la discrepancia entre los estudios experimentales y clínicos respecto a la eficacia de las terapias que tratan de aminorar o revertir el daño isquémico cerebral, existe una polémica creciente en torno a la utilidad clínica de los modelos experimentales de isquemia cerebral. Uno de los principales motivos del fracaso de las diversas estrategias terapéuticas ensayadas en el ámbito clínico es el enfoque teórico reduccionista de la mayoría de los ensayos farmacológicos, que analizan el efecto de una molécula con un mecanismo de acción conocido dentro de una ruta concreta de progresión del daño isquémico. Este abordaje contrasta con la complejidad estructural y funcional del tejido cerebral y la intricada fisiopatología de las alteraciones celulares y moleculares inducidas por la isquemia. Creemos que el objetivo fundamental de los estudios realizados en modelos experimentales de isquemia cerebral debe ser la obtención de conocimientos básicos acerca de los procesos patobiológicos subyacentes al daño isquémico y que los ensayos clínicos no deberían iniciarse con agentes terapéuticos cuyos beneficios hayan sido escasos o inconsistentes en los estudios experimentales (AU)

The major aim of experimental models of cerebral ischemia is to study the cerebral ischemic damage under controlled and reproducible conditions. Experimental studies have been fundamental in the establishment of new concepts regarding the mechanisms underlying the ischemic brain injury, such as the ischemic penumbra, the reperfusion injury, the cell death or the importance of the damage induced on mitochondria, glial cells and white matter. Disagreement between experimental and clinical studies regarding the benefit of drugs to reduce or restore the cerebral ischemic damage has created a growing controversy about the clinical value of the experimental models of cerebral ischemia. One of the major explanations for the failure of the clinical trials is the reductionist approach of most therapies, which are focused on the known effect of a single molecule within a specific pathway of ischemic damage. This philosophy contrasts to the complex morphological design of the cerebral tissue and the complex cellular and molecular physiopathology underlying the ischemic brain injury. We believe that the main objective of studies carried out in experimental models of cerebral ischemic injury must be a better understanding of the fundamental mechanisms underlying progression of the ischemic injury. Clinical trials should not be considered if the benefit obtained in experimental studies is limited or weak (AU)

How to repair an ischemic brain injury? Value of experimental models in search of answers.

The major aim of experimental models of cerebral ischemia is to study the cerebral ischemic damage under controlled and reproducible conditions. Experimental studies have been fundamental in the establishment of new concepts regarding the mechanisms underlying the ischemic brain injury, such as the ischemic penumbra, the reperfusion injury, the cell death or the importance of the damage induced on mitochondria, glial cells and white matter. Disagreement between experimental and clinical studies regarding the benefit of drugs to reduce or restore the cerebral ischemic damage has created a growing controversy about the clinical value of the experimental models of cerebral ischemia. One of the major explanations for the failure of the clinical trials is the reductionist approach of most therapies, which are focused on the known effect of a single molecule within a specific pathway of ischemic damage. This philosophy contrasts to the complex morphological design of the cerebral tissue and the complex cellular and molecular physiopathology underlying the ischemic brain injury. We believe that the main objective of studies carried out in experimental models of cerebral ischemic injury must be a better understanding of the fundamental mechanisms underlying progression of the ischemic injury. Clinical trials should not be considered if the benefit obtained in experimental studies is limited or weak.

[Experimental models of cerebral ischemia]. / Modelos experimentales de isquemia cerebral.

AIM: To provide a summary of the different experimental models of cerebral ischemia designed both under in vivo and in vitro conditions. A clear and concise description of the specific types of brain lesion reproduced by each model is given together with the most frequent technical troubles associated. DEVELOPMENT: Experimental models of cerebral ischemia have contributed substantially to the understanding of the physiopathology of the ischemic brain injury and to test the beneficial effects of new therapies. Outcome of patients suffering from an ischemic stroke has improved considerably with the use of these models, particularly after the introduction of thrombolytic and neuroprotective drugs. Experimental models allow the study of the evolving ischemic brain injury under strict and controlled conditions. Usefulness of experimental models is limited by their reliability, simplicity and reproducibility among different researchers. Small rodents, especially rats, have been the preferred animals used to develop models of cerebral ischemic injury, due to their cerebral physiology and vascularisation which is closer to the human. CONCLUSION: The use of experimental models of cerebral ischemia constitutes the most suitable tool to investigate the physiopathology of this type of injury. However their simplicity prevents an exact reproduction of the cerebral damage observed in clinical settings. This could be the main reason for the discrepancies observed between the therapeutic effect in the experimental and clinical studies.

Modelos experimentales de isquemia cerebral / Experimental models of cerebral ischemia

Objetivo. Revisar los modelos experimentales de isquemia cerebral utilizados en la investigación de la fisiopatología y la terapéutica de esta afección. Se expone de forma clara y sencilla tanto el tipo de lesión cerebral isquémica que cada modelo trata de reproducir como los detalles técnicos específicos para su realización práctica. Desarrollo. Los modelos experimentalesde isquemia cerebral han permitido estudiar la fisiopatología de esta enfermedad bajo condiciones controladas por el investigador y analizar los efectos de nuevas estrategias terapéuticas. El conocimiento adquirido con estos modelos ha mejorado el pronóstico de los pacientes que han sufrido un infarto cerebral isquémico tras la introducción de agentes trombolíticosy neuroprotectores. Para que un modelo sea valioso debe ser fiable y fácil de realizar y debe reflejar lo más fielmente posible las condiciones clínicas que trata de imitar. Debe ser reproducible y tener una baja variabilidad entre individuos (animales) y entre investigadores. Los roedores pequeños, particularmente las ratas, son los animales con los que se han desarrollado la mayoría de estos modelos por tener una fisiología y vascularización cerebral similares a la humana. Conclusión. Los modelos experimentales suponen actualmente la mejor herramienta para el estudio de los mecanismos subyacentes al daño cerebral isquémico, aunque su simplicidad impide reproducir de forma exacta la lesión cerebral observada en la práctica clínica. Ésta puede ser la causa de la discrepancia en la respuesta terapéutica observada entre los estudios experimentalesy los clínicosPST

Aim. To provide a summary of the different experimental models of cerebral ischemia designed both under in vivoand in vitro conditions. A clear and concise description of the specific types of brain lesion reproduced by each model is given together with the most frequent technical troubles associated. Development. Experimental models of cerebral ischemia have contributed substantially to the understanding of the physiopathology of the ischemic brain injury and to test the beneficial effects of new therapies. Outcome of patients suffering from an ischemic stroke has improved considerably with the use of these models, particularly after the introduction of thrombolytic and neuroprotective drugs. Experimental models allow thestudy of the evolving ischemic brain injury under strict and controlled conditions. Usefulness of experimental models is limited by their reliability, simplicity and reproducibility among different researchers. Small rodents, especially rats, have been the preferred animals used to develop models of cerebral ischemic injury, due to their cerebral physiology and vascularisation which is closer to the human. Conclusion. The use of experimental models of cerebral ischemia constitutes the most suitable tool to investigate the physiopathology of this type of injury. However their simplicity prevents an exact reproduction of the cerebral damage observed in clinical settings. This could be the main reason for the discrepancies observed between the therapeutic effect in the experimental and clinical studies

Réplica. Impulso bioeléctrico, cuantificaciones sinápticas y de circuitos cerebrales, origen de la vida y composición principal de las neuronas / Reply. Bioelectrical impulse, synaptic and brain circuit quantifications, the origins of life and the main composition of neurons

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[Blood brain barrier: development of a structure which supports the functional heterogeneity of the central nervous system]. / La barrera hematoencefalica: desarrollo de una estructura que permite la heterogeneidad funcional del sistema nervioso central.

AIMS: To analyze the functional reasons justifying the existence of the blood brain barrier with an emphasis on its fundamental role supporting neuroglial coupling. DEVELOPMENT: We review in an integrated manner the contributions of different research areas in physiology and metabolism of the central nervous system which allow to understand the functional need for the existence of the blood brain barrier. In particular, we describe the physiological basis of the metabolic functional coupling and the metabolic interactions between neurons and glial cells, two properties directly derived from the presence of the blood brain barrier. Likewise the blood brain barrier is presented as an important determinant of the heterogeneous activation of cerebral tissue as detected by neuroimaging technologies as positron emission tomography and functional magnetic resonance imaging. CONCLUSIONS: The main function of the blood brain barrier is to maintain a stable composition of the extracellular milieu in nervous tissue. This allows the changes in ionic composition and neurotransmitter concentration in the extracellular milieu, to reflect indirectly the generation of action potentials and the state of neurotransmission of neuronal circuits. Glial cells induce the development of the blood brain barrier and are the main sensors of neuronal function, due to their important take up capacity for extracellular potassium and neurotransmitters. Glial homeostasis of the extracellular milieu is circuit specific, limiting the functional metabolic coupling to discrete regions of the brain and generating the classical pattern of heterogeneous activity in the different modules of the nervous tissue.

La barrera hematoencefálica: desarrollo de una estructura que permite la heterogeneidad funcional del sistema nervioso central / Blood-brain barrier: development of a structure which supports the functional heterogeneity of the central nervous system

Objetivo. Analizar las razones funcionales que justifican la existencia de la barrera hematoencefálica (BHE), con énfasis en su papel crucial como soporte de la unidad funcional neurona-glía.Desarrollo. Se revisan en detalle y de manera integrada las aportaciones de diversas áreas de investigación en fisiología y metabolismo del sistema nervioso central que permiten comprender la necesidad funcional de la existencia de la BHE. En especial, se describen las bases fisiológicas del acoplamiento metabólico-funcional en el tejido nervioso y las interacciones metabólicas entre las neuronas y las células gliales, dos propiedades derivadas directamente de la presencia de la BHE. Se presenta la barrera como un importante determinante de la activación heterogénea del tejido cerebral, detectable mediante tecnologías de neuroimagen funcional, como la tomografía de emisión de positrones y la imagen de resonancia magnética funcional. Conclusiones. La función principal de la BHE es mantener una composición estable del medio extracelular en el tejido nervioso. Esto permite que los cambios de composición iónica y de concentración de neurotransmisores del medio extracelular sean el reflejo indirecto de la generación de potenciales de acción y del estado de neurotransmisión de los circuitos neuronales. Las células gliales inducen el desarrollo de la barrera y son los principales sensores de la función neuronal, debido a su capacidad de recaptación del exceso extracelular de potasio y de neurotransmisores. La homeostasis glial del medio extracelular es específica de circuito, limita el acoplamiento metabólico-funcional a regiones discretas del cerebro y genera el patrón de actividad heterogénea en los diversos módulos del tejido nervioso (AU)

Aims. To analyze the functional reasons justifying the existence of the blood-brain barrier with an emphasis on its fundamental role supporting neuroglial coupling. Development. We review in an integrated manner the contributions of different research areas in physiology and metabolism of the central nervous system which allow to understand the functional need for the existence of the blood-brain barrier. In particular, we describe the physiological basis of the metabolic-functional coupling and the metabolic interactions between neurons and glial cells, two properties directly derived from the presence of the blood-brain barrier. Likewise the blood-brain barrier is presented as an important determinant of the heterogeneous activation of cerebral tissue as detected by neuroimaging technologies as positron emission tomography and functional magnetic resonance imaging. Conclusions. The main function of the blood-brain barrier is to maintain a stable composition of the extracellular milieu in nervous tissue. This allows the changes in ionic composition and neurotransmitter concentration in the extracellular milieu, to reflect indirectly the generation of action potentials and the state of neurotransmission of neuronal circuits. Glial cells induce the development of the blood-brain barrier and are the main sensors of neuronal function, due to their important take up capacity for extracellular potassium and neurotransmitters. Glial homeostasis of the extracellular milieu is circuit-specific, limiting the functional-metabolic coupling to discrete regions of the brain and generating the classical pattern of heterogeneous activity in the different modules of the nervous tissue (AU)