Examinando por Autor "Moya, Pablo"
Mostrando 1 - 3 de 3
Resultados por página
Opciones de ordenación
Ítem Efecto de la interacción de los receptores 5-HT₂𝑐 y TRPV1 sobre las conductas de tipo ansiosas(Universidad de Valparaíso, 2024-03) Haro Acuña, Valentina; Moya, Pablo; Profesor co-guía: Chávez, AndrésEl sistema serotoninérgico juega un papel clave en la patogénesis y tratamiento de los trastornos de ansiedad. Es sabido que la activación de los receptores de serotonina del subtipo 2C (5-HT2CR) genera conductas del tipo ansiosas en roedores. Por otra parte, existe evidencia que indica que la activación del receptor de potencial transitorio vaniloide 1 (TRPV1), un canal catiónico no selectivo activado por ligando podría estar regulando este tipo de conductas, ya que animales deficientes para este receptor muestran menores niveles de ansiedad. Los 5-HT2cR están acoplados a proteína Gq/11, cuya activación produce una amplia variedad de mediadores lipídicos como los endovanilloides/endocanabinoides, incluyendo a la anandamida que actúa como un agonista endógeno de TRPV1. Por lo tanto, sugerimos que la interacción de ambos receptores 5-HT2CR y TRPV1 podria regular los comportamientos ansiosos. Para comprobar esta hipótesis, primero evaluamos mediante una batería de paradigmas comportamentales como los ensayos de campo abierto, laberinto elevado en cruz y de luz/oscuridad, si la activación farmacológica in vivo de 5-HT2CR recapitula un efecto ansiogénico en ratones. Luego, evaluamos si el bloqueo selectivo de TRPV1 modifica los efectos ansiogenicos producidos por la activación de 5-HT2CR. Por último, evaluamos los efectos de la activación de los 5-HT2CR en ratones deficientes de TRPV1 (TRPV1 KO). Nuestros resultados indican que la administración sistémica de dos agonistas diferentes para 5-HT2CR, mCPP y MK212, producen un efecto ansiogénico que fue eliminado por el pretratamiento con el antagonista selectivo de 5-HT2CR SB242084. Mas importante aún, y en concordancia con nuestra hipótesis, estos efectos ansiogénicos son eliminados por la administración conjunta con el antagonista de los TRPV1 capzasepina (CPZ), y están ausentes en los ratones TRPV1 KO. Además, demostramos que el bloqueo de TRPV1 con CPZ rescató los comportamientos del tipo ansiosos, observados en ratones deficientes del transportador de serotonina (SERT KO), un modelo genético clásico de ansiedad. En conjunto, estos resultados sugieren fuertemente una interacción entre los 5-HT2cR y TRPV1 para regular los comportamientos angiogénicos en ratones, abriendo nuevas posibilidades para la generación de nuevas herramientas farmacológicas para tratar este tipo de patologías.Ítem Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders(Springer, 2021) Spaas, Jan; Van Veggel, Lieve; Schepers, Melissa; Tiane, Assia; Van Horssen, Jack; Wilson, David M.; Moya, Pablo; Piccart, Elisabeth; Hellings, Niels; Eijnde, Bert O.; Derave, Wim; Schreiber, Rudy; Vanmierlo, TimOligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or infammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC diferentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC diferentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily afect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type.The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC diferentiation remain enigmatic and a focus of current research eforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC diferentiation. In particular, oligodendrocyte (epi)geneticsÍtem Role of glutamate transporters and glutamatergic system in cortical and limbic brain areas in an animal model of depression(Universidad de Valparaíso, 2021-05) Ardiles Gálvez, Nicolás; Moya, PabloMajor depressive disorder affects around 5% of the world´s population. Most antidepressant drugs have focused mainly on monoamine neurotransmitters synaptic levels in the brain such as serotonin, noradrenaline and dopamine. However, the delayed latency of the therapeutic actions of antidepressants and the poor efficacy for some subpopulations of patients suggest that mechanisms beyond monoaminergic modulation at synapses may be involved in the antidepressant actions. Several lines of evidence indicate that the pathophysiology of depression is associated with dysregulation of glutamate system and clearance mechanisms in brain regions mediating cognitive-emotional behaviors. Chronic stress results in an increase in extracellular glutamate and dysregulation of the glutamatergic system in cortical and limbic brain areas in patients with MDD and animal models of depression. However, the mechanisms underlying the abnormal glutamatergic transmission in depression are incompletely understood. The excitatory amino acid transporter 3 (EAAT3) - a member of the high-affinity glutamate transporters - which plays an essential role in transporting glutamate across plasma membranes in neurons, and in maintaining extracellular glutamate concentrations below neurotoxic levels, may have a pivotal role in dysregulation of glutamatergic signaling associated to depression. This study aims to evaluate the consequences of unpredictable chronic mild stress (UCMS) on the expression of glutamate transporters and ionotropic receptors in the cortical-limbic brain areas in wild type (WT) mice; and to determine if increased EAAT3 expression in the forebrain in mice can reduce susceptibility to UCMS. On the other hand, we evaluated the consequences of psychosocial stress at the behavioral level in WT mice subjected to chronic social defeat stress (CSDS). WT mice subjected to UCMS and control group were tested to anxiety- and depressive- like behaviors. Moreover, we evaluated long-term memory using object location and recognition tasks. Protein levels of AMPA and NMDA receptors subunits and glutamate transporters were analyzed by western blot. Mice with EAAT3 overexpression driven by CaMKIIα-promoter (EAAT3glo/CMKII) and control (EAAT3glo) littermates were assessed to anxiety- and depressive- like behaviors, and memory tests in baseline and UCMS conditions. Longer immobility time was observed in the tail suspension test in WT mice susceptible to CSDS. However, no significant differences were found between resilient and susceptible individuals in anxiety-like behaviors and anhedonia. Apparently, social defeat in WT mice would only be concerning sociability to an unknown aggressive mouse and the despair behavior. In WT mice, we observed that chronic stress induced anxiety- and depressive-like behaviors and deficits in memory tests, in addition to increased EAAT1, NMDA receptors GluN2A and GluN2B subunits, and AMPA receptors GluA1 subunits protein levels in the hippocampus. Furthermore, in baseline conditions EAAT3glo/CMKII mice showed anxiety-like behavior in the open field test. Interestingly, mice with EAAT3 overexpression driven by CaMKIIα-promoter challenged to UCMS did neither show depressive-like behaviors nor impairment in sociability and memory. Hippocampal glutamatergic system alterations may underlie the depressive-like behaviors. Moreover, we suggest that EAAT3 overexpression in the forebrain in mice may be linked to a resilient phenotype to chronic stress.