Una reciente investigación ha descubierto en animales de experimentación un nuevo mecanismo que contribuye al mejor conocimiento del daño neuronal ocurrido tras un ictus. El trabajo abre la puerta al desarrollo de nuevos tratamientos neuroprotectores que palien los trastornos neurológicos provocados por la isquemia cerebral. Una parte importante del deterioro neuronal causado por una isquemia cerebral se debe a la alteración en los niveles de glutamato, el neurotransmisor excitador más abundante del cerebro, que actúa a su vez como una potente neurotoxina cuando su concentración se eleva, como ocurre durante la isquemia. El nuevo hallazgo pone de manifiesto la importancia de una molécula, el intercambiador cistina-glutámico (xCT), en el aumento de la concentración de glutamato hasta niveles tóxicos en modelos experimentales que reproducen las principales características del ictus en pacientes. Los resultados evidencian que, durante la isquemia, el glutamato se transporta fuera de la célula a través del intercambiador xCT, acumulándose hasta niveles letales para las neuronas. A su vez, mediante tomografía por emisión de positrones se ha observado que los niveles de xCT están elevados en ratas sometidas a isquemia, lo cual subraya su importancia en el proceso de ictus.
La liberación de glutamato contribuye al daño isquémico
Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage.
Soria FN, Pérez-Samartín A, Martin A, Gona KB, Llop J, Szczupak B, Chara JC, Matute C, Domercq M.
J Clin Invest. 2014 Aug 1;124(8):3645-55. doi: 10.1172/JCI71886. Epub 2014 Jul 18.
Abstract
During brain ischemia, an excessive release of glutamate triggers neuronal death through the overactivation of NMDA receptors (NMDARs); however, the underlying pathways that alter glutamate homeostasis and whether synaptic or extrasynaptic sites are responsible for excess glutamate remain controversial. Here, we monitored ischemia-gated currents in pyramidal cortical neurons in brain slices from rodents in response to oxygen and glucose deprivation (OGD) as a real-time glutamate sensor to identify the source of glutamate release and determined the extent of neuronal damage. Blockade of excitatory amino acid transporters or vesicular glutamate release did not inhibit ischemia-gated currents or neuronal damage after OGD. In contrast, pharmacological inhibition of the cystine/glutamate antiporter dramatically attenuated ischemia-gated currents and cell death after OGD. Compared with control animals, mice lacking a functional cystine/glutamate antiporter exhibited reduced anoxic depolarization and neuronal death in response to OGD. Furthermore, glutamate released by the cystine/glutamate antiporter activated extrasynaptic, but not synaptic, NMDARs, and blockade of extrasynaptic NMDARs reduced ischemia-gated currents and cell damage after OGD. Finally, PET imaging showed increased cystine/glutamate antiporter function in ischemic rats. Altogether, these data suggest that cystine/glutamate antiporter function is increased in ischemia, contributing to elevated extracellular glutamate concentration, overactivation of extrasynaptic NMDARs, and ischemic neuronal death.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109556/pdf/JCI71886.pdf
http://www.jci.org/articles/view/71886/pdf
Atentamente
Anestesiología y Medicina del Dolor
www.anestesia-dolor.org
La liberación de glutamato contribuye al daño isquémico
Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage.
Soria FN, Pérez-Samartín A, Martin A, Gona KB, Llop J, Szczupak B, Chara JC, Matute C, Domercq M.
J Clin Invest. 2014 Aug 1;124(8):3645-55. doi: 10.1172/JCI71886. Epub 2014 Jul 18.
Abstract
During brain ischemia, an excessive release of glutamate triggers neuronal death through the overactivation of NMDA receptors (NMDARs); however, the underlying pathways that alter glutamate homeostasis and whether synaptic or extrasynaptic sites are responsible for excess glutamate remain controversial. Here, we monitored ischemia-gated currents in pyramidal cortical neurons in brain slices from rodents in response to oxygen and glucose deprivation (OGD) as a real-time glutamate sensor to identify the source of glutamate release and determined the extent of neuronal damage. Blockade of excitatory amino acid transporters or vesicular glutamate release did not inhibit ischemia-gated currents or neuronal damage after OGD. In contrast, pharmacological inhibition of the cystine/glutamate antiporter dramatically attenuated ischemia-gated currents and cell death after OGD. Compared with control animals, mice lacking a functional cystine/glutamate antiporter exhibited reduced anoxic depolarization and neuronal death in response to OGD. Furthermore, glutamate released by the cystine/glutamate antiporter activated extrasynaptic, but not synaptic, NMDARs, and blockade of extrasynaptic NMDARs reduced ischemia-gated currents and cell damage after OGD. Finally, PET imaging showed increased cystine/glutamate antiporter function in ischemic rats. Altogether, these data suggest that cystine/glutamate antiporter function is increased in ischemia, contributing to elevated extracellular glutamate concentration, overactivation of extrasynaptic NMDARs, and ischemic neuronal death.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4109556/pdf/JCI71886.pdf
http://www.jci.org/articles/view/71886/pdf
Atentamente
Anestesiología y Medicina del Dolor
www.anestesia-dolor.org
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