Publication: La redacción de la concentración plasmática de glutamato mediante diálisis peritoneal como estrategia para disminuir el daño isquémico cerebral
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2017-08-21
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Universidad Complutense de Madrid
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Abstract
La isquemia cerebral o ictus es una enfermedad de una gran prevalencia, en especial en los países desarrollados, ya que, además de ser una de las principales causas de muerte en las poblaciones de estos países, es también una de las primeras causas de discapacidad y demencia, con el consecuente impacto socio-económico. Cuando se interrumpe o reduce el flujo sanguíneo al cerebro existe un área delimitada llamada core que corresponde a la zona más afectada y en la que se producirá el daño más grave. Alrededor de esta zona existe otra región, la penumbra, donde el flujo sanguíneo se ve reducido, aunque se puede mantener funcional durante un periodo de tiempo mayor, de forma que si se actúa de manera temprana, el tejido se considera potencialmente salvable (Astrup et al., 1977). El déficit energético producido como consecuencia de la reducción de oxígeno y glucosa al cerebro ocasiona la despolarización de la membrana plasmática (para revisión, ver Pulsinelli, 1992) con la consiguiente apertura de canales de Ca2+ voltaje-dependientes, lo que deriva en la liberación de glutamato al medio extracelular. La elevación de glutamato en el espacio extracelular produce a su vez la estimulación continuada de los receptores de glutamato AMPA y NMDA, lo que lleva a la entrada de Na+ y Ca2+ en la célula produciendo mayor despolarización de la membrana, la producción de edema y la expresión y/o activación de enzimas que finalmente conducen a la muerte celular (Choi, 1988; Kristian y Siesjo, 1998)...
Cerebral ischemia or stroke is a disease very present in today's world, especially in developed countries, as well as being one of the main causes of death in the populations of these countries. It is also one of the leading causes of disability and dementia, with consequent socio-economic impact. When the blood flow in the brain is interrupted or reduced there is an area called core which is a quite defined zone which will be the most affected area and in which the most severe damage will occur. Around this area there is another region, the penumbra, where blood flow is reduced, but it can be kept functional for a longer period of time, so if we act on this area, the tissue is considered potentially salvageable (Astrup et al., 1977). The energy deficit occurred as a result of reduced oxygen and glucose in the brain causes depolarization of the plasma membrane (for review, see Pulsinelli, 1992) with the subsequent opening of Ca2+ voltage-dependent, resulting in the release of glutamate into the extracellular medium. The increase of glutamate into the extracellular space in turn produces continued stimulation of glutamate receptors AMPA and NMDA, leading to the entrance of Na+ and Ca2+ in the cell causing increased membrane depolarization, the production of edema and expression and/or activation of enzymes that ultimately lead to cell death (Choi, 1988; Kristian y Siesjo, 1998). Glutamate is the major excitatory neurotransmissor in the central nervous system (for review, see Nicholls, 1993). Its concentration in CNS is not homogeneous: whereas in the extracellular space it remains about 1 μM at baseline, its intracellular concentration ranges from 5 to 10 mM, and reach concentrations between 50 and 100 mM in synaptic vesicles(Nicholls, 1993; Teichberg et al., 2009). Glutamate release is a process controlled by Ca2+ entry through the voltage-dependents channels and when it is released, glutamate is reuptaken by specific transporters localized in membranes of astrocytes and neurons for reuse, which can control its concentration in synaptic cleft (Nicholls y Attwell, 1990)...
Cerebral ischemia or stroke is a disease very present in today's world, especially in developed countries, as well as being one of the main causes of death in the populations of these countries. It is also one of the leading causes of disability and dementia, with consequent socio-economic impact. When the blood flow in the brain is interrupted or reduced there is an area called core which is a quite defined zone which will be the most affected area and in which the most severe damage will occur. Around this area there is another region, the penumbra, where blood flow is reduced, but it can be kept functional for a longer period of time, so if we act on this area, the tissue is considered potentially salvageable (Astrup et al., 1977). The energy deficit occurred as a result of reduced oxygen and glucose in the brain causes depolarization of the plasma membrane (for review, see Pulsinelli, 1992) with the subsequent opening of Ca2+ voltage-dependent, resulting in the release of glutamate into the extracellular medium. The increase of glutamate into the extracellular space in turn produces continued stimulation of glutamate receptors AMPA and NMDA, leading to the entrance of Na+ and Ca2+ in the cell causing increased membrane depolarization, the production of edema and expression and/or activation of enzymes that ultimately lead to cell death (Choi, 1988; Kristian y Siesjo, 1998). Glutamate is the major excitatory neurotransmissor in the central nervous system (for review, see Nicholls, 1993). Its concentration in CNS is not homogeneous: whereas in the extracellular space it remains about 1 μM at baseline, its intracellular concentration ranges from 5 to 10 mM, and reach concentrations between 50 and 100 mM in synaptic vesicles(Nicholls, 1993; Teichberg et al., 2009). Glutamate release is a process controlled by Ca2+ entry through the voltage-dependents channels and when it is released, glutamate is reuptaken by specific transporters localized in membranes of astrocytes and neurons for reuse, which can control its concentration in synaptic cleft (Nicholls y Attwell, 1990)...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Farmacología, leída el 14-01-2016