Publication: Cambios inducidos por MDMA sobre la actividad de las metaloproteinasas e integridad de la barrera hematoencefálica
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2017-09-06
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Universidad Complutense de Madrid
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Abstract
La 3,4-metilendioximetanfetamina (MDMA), comúnmente denominada éxtasis, es una droga psicoactiva de diseño cuya administración periférica produce liberación masiva e inmediata de monoaminas [1] y neurotoxicidad serotoninérgica a largo plazo [2-6]. A corto plazo activa la respuesta neuroinflamatoria [7-10] e induce hipertermia [1, 11] en correlación a la magnitud del daño neurotóxico en ratas. Tanto el metabolismo de la MDMA como el de las monoaminas induce de forma inmediata la generación de especies reactivas de oxígeno que participan notablemente en la neurotoxicidad [1]. Algunos de estos efectos, concretamente el intenso estrés oxidativo, la activación de la respuesta inflamatoria y la hipertermia cerebral, son factores implicados en la alteración de la barrera hematoencefálica (BHE) en patologías como la isquemia, la esclerosis múltiple, la epilepsia o las enfermedades neurodegenerativas, [12-20]. Las citoquinas proinflamatorias (IL-1β, IL-6 y TNF-α) y las especies reactivas de oxígeno pueden modificar la permeabilidad o integridad de la BHE a través de la producción o activación de proteasas [15, 21]. La microglía y los astrocitos son capaces de producir estos mediadores durante la respuesta neuroinflamatoria. Uno de los principales receptores involucrados en la activación glial en condiciones de daño tisular es el receptor P2X7 [22-25]. Las enzimas proteolíticas metaloproteinasas (MMPs) y serín-proteasas como el activador tisular del plasminógeno (tPA) pueden modular la permeabilidad de la BHE al degradar proteínas de la lámina basal y de las uniones estrechas. El incremento en la actividad de estas proteasas es frecuente en patologías que cursan con alteración la de la barrera [14, 26-29]. Las principales MMPs involucradas en este contexto son las gelatinasas (MMP-2 y MMP-9) y la estromelisina-1 (MMP-3) [15, 30-32]. El tPA participa en la producción y activación de MMP-9 mediante su interacción con el receptor de lipoproteínas de baja densidad tipo 1 (LRP-1) y en la activación de MMP-3 por plasmina que se genera a partir del plasminógeno, su principal sustrato [31, 33, 34]. La alteración de la BHE puede facilitar la entrada de agua al tejido desde la sangre y producirse un desequilibrio electrolítico que desencadenaría la formación de edema vasogénico [35-37]. En conjunto, todas las consecuencias derivadas de la alteración de la BHE contribuirían, en última instancia a producir o agravar el daño tisular, la disfunción neuronal y la neurodegeneración [16]...
3,4-Methylenedioxymethamphetamine (MDMA), commonly named ecstasy, is a psychoactive designer drug. MDMA peripheral administration induces the immediate massive release of monoamines [1] and a long-term serotoninergic neurotoxicity [2-6]. In addition, MDMA activates a short-term neuroinflammatory response [7-10] and induces hyperthermia [1, 11] correlating with the long-term cerebral neurotoxicity in rats. Furthermore, both MDMA and monoamine metabolism produce oxygen and nitrogen reactive species which are strongly implicated in MDMA neurotoxicity [1]. Various of the consequences of MDMA, in particular the intense oxidative stress, the inflammatory response and the cerebral hyperthermia, are factors involved in blood-brain barrier (BBB) integrity and permeability disruption in ischemia, multiple sclerosis, epilepsy or neurodegenerative disorders [12-20]. There are evidences showing proinflammatory cytokines (IL-1β, IL-6 y TNF-α) and oxygen reactive species could modify BBB permeability or integrity through the production or activation of proteases [15, 21]. As a result of the activation of the neuroinflammatory response, microglia and astrocytes are capable of producing these mediators. One of the receptors involved in activating glial cells during tissue injury is the purinergic receptor, P2X7. High extracellular ATP levels released after cellular injury could activate P2X7 receptors, which subsequently increase glial reactivity through inflammasome activation [22-25]. Proteolytic enzymes metalloproteinases (MMPs) and serine proteases such as tissue plasminogen activator (tPA), could modulate BBB permeability by degrading tight junction and basal lamina proteins. The increase in proteolytic activity of these proteases is often detected in pathologies that are accompanied by BBB alterations [14, 26-29]. In this context, the most studied MMPs are gelatinases (MMP-2 and MMP-9) and stromelysin-1 (MMP-3) [15, 30-32]. The interaction between tPA and low density lipoprotein receptor-related protein 1 (LRP-1) induces MMP-9 production, whereas plasmin formed from tPA-induced plasminogen proteolysis stimulates MMP-3 activation [31, 33, 34]. BBB alteration could facilitate the access of water from blood vessels to tissue and disrupt the electrolytic balance leading to vasogenic edema [35-37] and seizures [16, 17, 38]. Overall, BBB disruption could contribute to damaging or enhancing tissue injury, to neuronal dysfunction and to neurodegeneration [16]...
3,4-Methylenedioxymethamphetamine (MDMA), commonly named ecstasy, is a psychoactive designer drug. MDMA peripheral administration induces the immediate massive release of monoamines [1] and a long-term serotoninergic neurotoxicity [2-6]. In addition, MDMA activates a short-term neuroinflammatory response [7-10] and induces hyperthermia [1, 11] correlating with the long-term cerebral neurotoxicity in rats. Furthermore, both MDMA and monoamine metabolism produce oxygen and nitrogen reactive species which are strongly implicated in MDMA neurotoxicity [1]. Various of the consequences of MDMA, in particular the intense oxidative stress, the inflammatory response and the cerebral hyperthermia, are factors involved in blood-brain barrier (BBB) integrity and permeability disruption in ischemia, multiple sclerosis, epilepsy or neurodegenerative disorders [12-20]. There are evidences showing proinflammatory cytokines (IL-1β, IL-6 y TNF-α) and oxygen reactive species could modify BBB permeability or integrity through the production or activation of proteases [15, 21]. As a result of the activation of the neuroinflammatory response, microglia and astrocytes are capable of producing these mediators. One of the receptors involved in activating glial cells during tissue injury is the purinergic receptor, P2X7. High extracellular ATP levels released after cellular injury could activate P2X7 receptors, which subsequently increase glial reactivity through inflammasome activation [22-25]. Proteolytic enzymes metalloproteinases (MMPs) and serine proteases such as tissue plasminogen activator (tPA), could modulate BBB permeability by degrading tight junction and basal lamina proteins. The increase in proteolytic activity of these proteases is often detected in pathologies that are accompanied by BBB alterations [14, 26-29]. In this context, the most studied MMPs are gelatinases (MMP-2 and MMP-9) and stromelysin-1 (MMP-3) [15, 30-32]. The interaction between tPA and low density lipoprotein receptor-related protein 1 (LRP-1) induces MMP-9 production, whereas plasmin formed from tPA-induced plasminogen proteolysis stimulates MMP-3 activation [31, 33, 34]. BBB alteration could facilitate the access of water from blood vessels to tissue and disrupt the electrolytic balance leading to vasogenic edema [35-37] and seizures [16, 17, 38]. Overall, BBB disruption could contribute to damaging or enhancing tissue injury, to neuronal dysfunction and to neurodegeneration [16]...