Publication: Efectos neurotóxicos del cadmio sobre las neuronas colinérgicas del prosencéfalo basal y su implicación en la inducción de alteraciones cognitivas
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2018-11-27
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Universidad Complutense de Madrid
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Abstract
El cadmio (Cd) es un compuesto neurotóxico que produce disfunciones cognitivas, aunque los mecanismos implicados son desconocidos. Los procesos de aprendizaje y memoria son regulados por el sistema colinérgico del prosencéfalo basal, por lo tanto, el bloqueo de la transmisión colinérgica o la muerte de neuronas colinérgicas en esta región podrían estar relacionados con el deterioro de la memoria inducido por el cadmio. En este sentido, se ha descrito en otras regiones cerebrales que el cadmio bloquea la transmisión colinérgica a través de la reducción de la actividad de la acetilcolina transferasa (ChAT) y a su vez bloquea receptores muscarínicos, los cuales pueden además de participar en la transmisión colinérgica participar en el mantenimiento de la viabilidad neuronal, específicamente los receptores muscarínicos M1 (RM1). También se ha descrito que induce la muerte selectiva de neuronas colinérgicas a nivel periférico. Además, se ha descrito que el cadmio activa la enzima glucógeno sintetasa quinasa 3 (GSK-3β), induce la fosforilación de proteínas Tau y la formación de proteínas amiloideas beta (Aβ) en regiones cerebrales distintas al prosencéfalo basal, y dichos mecanismos se han relacionado con la inducción de muerte selectiva de neuronas colinérgicas del prosencéfalo basal en la enfermedad de Alzheimer. También, se ha descrito que el cadmio genera especies reactivas de oxigeno (ERO) las cuales pueden inducir los mecanismos descritos. Finalmente, se ha descrito en otras regiones cerebrales que todos estos efectos son regulados por el receptor M1. En consecuencia, nosotros hipotetizamos que el cadmio induce el bloqueo de la transmisión colinérgicas y una muerte selectiva de las neuronas colinérgicas del prosencéfalo basal mediada por la generación de ERO que media en parte el bloqueo de los receptores M1, los cuales desencadenan este efecto a través de la inducción de los mecanismos descritos en otras regiones cerebrales a través de la alteración de la expresión de las variantes de la AChE. Nuestros resultados podrían ayudar a explicar las disfunciones cognitivas observadas en la toxicidad de cadmio...
Cadmium (Cd) is a neurotoxic compound that produces cognitive dysfunctions, although the mechanisms involved are unknown. The learning and memory processes are regulated by the cholinergic system of the basal forebrain, therefore blockade of cholinergic transmission or death of cholinergic neurons in this region could be related to the deterioration of cadmiuminduced memory. In this sense, it has been described in other brain regions that cadmium blocks cholinergic transmission through the reduction of choline acetyltransferase (ChAT) activity and in turn blocks muscarinic receptors which may, in addition to participating in cholinergic transmission, participate in the maintenance of neuronal viability, specifically the muscarinic M1receptor (M1R). It has also been reported to induce selective killing of cholinergic neurons at the peripheral level. In addition, cadmium has been reported to activate the enzyme glycogen synthase kinase 3 (GSK-3β), induces phosphorylation of Tau proteins and formation of amyloid beta (Aβ) proteins in brain regions other than the basal forebrain, and these mechanisms have been linked to the induction of selective killing of cholinergic neurons Of the basal forebrain in Alzheimer's disease. Also, it has been pointed out that cadmium generates reactive oxygen species (ROS) which can induce the described mechanisms. Finally, it has been described in other brain regions that all these effects are regulated by the M1 receptor. Consequently, we hypothesized that cadmium induces blockade of cholinergic transmission and a selective death of cholinergic neurons of the basal forebrain mediated by the generation of ROS that partly mediate the blockade of M1 receptors, which trigger this effect through of the induction mechanisms described in other brain regions through altered expression of acethylcholinesterase (AChE) variants. Our results may help explain the cognitive dysfunctions observed in cadmium toxicity...
Cadmium (Cd) is a neurotoxic compound that produces cognitive dysfunctions, although the mechanisms involved are unknown. The learning and memory processes are regulated by the cholinergic system of the basal forebrain, therefore blockade of cholinergic transmission or death of cholinergic neurons in this region could be related to the deterioration of cadmiuminduced memory. In this sense, it has been described in other brain regions that cadmium blocks cholinergic transmission through the reduction of choline acetyltransferase (ChAT) activity and in turn blocks muscarinic receptors which may, in addition to participating in cholinergic transmission, participate in the maintenance of neuronal viability, specifically the muscarinic M1receptor (M1R). It has also been reported to induce selective killing of cholinergic neurons at the peripheral level. In addition, cadmium has been reported to activate the enzyme glycogen synthase kinase 3 (GSK-3β), induces phosphorylation of Tau proteins and formation of amyloid beta (Aβ) proteins in brain regions other than the basal forebrain, and these mechanisms have been linked to the induction of selective killing of cholinergic neurons Of the basal forebrain in Alzheimer's disease. Also, it has been pointed out that cadmium generates reactive oxygen species (ROS) which can induce the described mechanisms. Finally, it has been described in other brain regions that all these effects are regulated by the M1 receptor. Consequently, we hypothesized that cadmium induces blockade of cholinergic transmission and a selective death of cholinergic neurons of the basal forebrain mediated by the generation of ROS that partly mediate the blockade of M1 receptors, which trigger this effect through of the induction mechanisms described in other brain regions through altered expression of acethylcholinesterase (AChE) variants. Our results may help explain the cognitive dysfunctions observed in cadmium toxicity...
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Tesis de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Toxicología y Legislación Sanitaria, leída el 20/02/2018