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Depto. de Química en Ciencias Farmacéuticas, Fac. de Farmacia, pub

Agmatine, an endogenous neuromodulator, is a potential candidate to constitute an adjuvant/monotherapy for the management of depression. A recent study by our group demonstrated that agmatine induces Nrf2 and protects against corticosterone effects in a hippocampal neuronal cell line. The present study is an extension of this previous study by assessing the antidepressant-like effect of agmatine in an animal model of depression induced by corticosterone in mice. Swiss mice were treated simultaneously with agmatine or imipramine at a dose of 0.1 mg/kg/day (p.o.) and corticosterone for 21 days and the daily administrations of experimental drugs were given immediately prior to corticosterone (20 mg/kg/day, p.o.) administrations. Wild-type C57BL/6 mice (Nrf2 (+/+)) and Nrf2 KO (Nrf2 (-/-)) were treated during 21 days with agmatine (0.1 mg/kg/day, p.o.) or vehicle. Twenty-four hours after the last treatments, the behavioral tests and biochemical assays were performed. Agmatine treatment for 21 days was able to abolish the corticosterone-induced depressive-like behavior and the alterations in the immunocontent of mature BDNF and synaptotagmin I, and in the serotonin and glutamate levels. Agmatine also abolished the corticosterone-induced changes in the morphology of astrocytes and microglia in CA1 region of hippocampus. In addition, agmatine treatment in control mice increased noradrenaline, serotonin, and dopamine levels, CREB phosphorylation, mature BDNF and synaptotagmin I immunocontents, and reduced pro-BDNF immunocontent in the hippocampus. Agmatine's ability to produce an antidepressant-like effect was abolished in Nrf2 (-/-) mice. The present results reinforce the participation of Nrf2 in the antidepressant-like effect produced by agmatine and expand literature data concerning its mechanisms of action., Depto. de Bioquímica y Biología Molecular, Fac. de Medicina, TRUE, pub

Scope: We have studied if curcumin can protect glial cells under an oxidative stress and inflammatory environment, which is known to be deleterious in neurodegeneration. Methods and results: Primary rat glial cultures exposed to the combination of an oxidative (rotenone/oligomycin A) and a proinflammatory LPS stimuli reduced by 50% glial viability. Under these experimental conditions, curcumin afforded significant glial protection and reduction of reactive oxygen species; these effects were blocked by the HO-1 inhibitor tin protoporphyrin-IX (SnPP). These findings correlate with the observation that curcumin induced the antioxidative protein HO-1. Most interesting was the observation that the glial protective effects related to HO-1 induction were microglial specific as shown in glial cultures from LysM(Cre) Hmox(∆/∆) mice where curcumin lost its protective effect. Under LPS conditions, curcumin reduced the microglial proinflammatory markers iNOS and tumor necrosis factor, but increased the anti-inflammatory cytokine IL4. Analysis of the microglial phenotype showed that curcumin favored a ramified morphology toward a microglial alternative activated state against LPS insult also by a HO-1-dependent mechanism. Conclusion: The curry constituent curcumin protects glial cells and promotes a microglial anti-inflammatory phenotype by a mechanism that implicates HO-1 induction; these effects may have impact on brain protection under oxidative and inflammatory conditions., Depto. de Bioquímica y Biología Molecular, Fac. de Medicina, TRUE, pub

Activation of the peripheral immune system elicits a coordinated response from the central nervous system. Key to this immune to brain communication is that glia, microglia, and astrocytes, interpret and propagate inflammatory signals in the brain that influence physiological and behavioral responses. One issue in glial biology is that morphological analysis alone is used to report on glial activation state. Therefore, our objective was to compare behavioral responses after in vivo immune (lipopolysaccharide, LPS) challenge to glial specific mRNA and morphological profiles. Here, LPS challenge induced an immediate but transient sickness response with decreased locomotion and social interaction. Corresponding with active sickness behavior (2-12 h), inflammatory cytokine mRNA expression was elevated in enriched microglia and astrocytes. Although proinflammatory cytokine expression in microglia peaked 2-4 h after LPS, astrocyte cytokine, and chemokine induction was delayed and peaked at 12 h. Morphological alterations in microglia (Iba-1(+)) and astrocytes (GFAP(+)), however, were undetected during this 2-12 h timeframe. Increased Iba-1 immunoreactivity and de-ramified microglia were evident 24 and 48 h after LPS but corresponded to the resolution phase of activation. Morphological alterations in astrocytes were undetected after LPS. Additionally, glial cytokine expression did not correlate with morphology after four repeated LPS injections. In fact, repeated LPS challenge was associated with immune and behavioral tolerance and a less inflammatory microglial profile compared with acute LPS challenge. Overall, induction of glial cytokine expression was sequential, aligned with active sickness behavior, and preceded increased Iba-1 or GFAP immunoreactivity after LPS challenge, Depto. de Bioquímica y Biología Molecular, Fac. de Medicina, TRUE, pub

Background and purpose: Neurodegenerative diseases are a major problem afflicting ageing populations; however, there are no effective treatments to stop their progression. Oxidative stress and neuroinflammation are common factors in their pathogenesis. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of oxidative stress, and melatonin is an endogenous hormone with antioxidative properties that reduces its levels with ageing. We have designed a new compound that combines the effects of melatonin with Nrf2 induction properties, with the idea of achieving improved neuroprotective properties. Experimental approach: Compound ITH12674 is a hybrid of melatonin and sulforaphane designed to exert a dual drug-prodrug mechanism of action. We obtained the proposed hybrid in a single step. To test its neuroprotective properties, we used different in vitro models of oxidative stress related to neurodegenerative diseases and brain ischaemia. Key results: ITH12674 showed an improved neuroprotective profile compared to that of melatonin and sulforaphane. ITH12674 (i) mediated a concentration-dependent protective effect in cortical neurons subjected to oxidative stress; (ii) decreased reactive oxygen species production; (iii) augmented GSH concentrations in cortical neurons; (iv) enhanced the Nrf2-antioxidant response element transcriptional response in transfected HEK293T cells; and (v) protected organotypic cultures of hippocampal slices subjected to oxygen and glucose deprivation and re-oxygenation from stress by increasing the expression of haem oxygenase-1 and reducing free radical production. Conclusion and implications: ITH12674 combines the signalling pathways of the parent compounds to improve its neuroprotective properties. This opens a new line of research for such hybrid compounds to treat neurodegenerative diseases., Unión Europea, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Depto. de Bioquímica y Biología Molecular, Depto. de Bioquímica y Biología Molecular, Fac. de Medicina, Fac. de Medicina, TRUE, TRUE, pub, pub

Los últimos tres cursos académicos han quedado marcados, indudablemente, por la pandemia mundial que ha alterado el orden conocido a todos los niveles de nuestra vida, pero también ha cambiado la metodología docente, lo que ha supuesto un reto tanto para los docentes como para los alumnos se han enfrentado a ella. De esta forma, se han establecido puntos de partida para una nueva metodología de trabajo en la que los docentes nos enfrentamos a un alumnado cada vez más virtualizado. Nuestros alumnos han asumido las nuevas tecnologías y las redes sociales como parte de su rutina. De igual modo, su forma de aprender también ha cambiado. Esta virtualización del alumnado se ha producido en un momento que coexiste con un progresivo envejecimiento de la plantilla del profesorado. La plantilla PDI de la UCM, en el año 2021, tenía una edad media de 55,67 años, de los cuales, solo el 46% era personal permanente (según datos del Consejo de Gobierno de marzo de 2021). Esto significa que es una plantilla que irremediablemente tendrá que ser reemplazada, a corto plazo, por un gran número de nuevos docentes, sin el bagaje docente que dan los años de experiencia, pero con ideas frescas y nuevas que poner en marcha. Cómo se afronte esta nueva labor, será determinante para el futuro de nuestra Universidad. Nosotros nos proponemos realizar una reflexión y aprender de nuestra propia experiencia. A través del desarrollo de este proyecto queremos analizar cómo han afectado a los resultados académicos, los dos años de docencia virtual o semipresencial que hemos vivido. Pretendemos identificar las fortalezas de las medidas implementadas, pero también las carencias de un sistema que llegó de manera improvisada y, muchas veces, sin medios suficientes. Tanto el curso 2020-2021, como el curso 2021-2022 pusieron a prueba nuestra institución ya que nos enfrentamos al reto de asumir una docencia absoluta o parcialmente virtualizada. Proponemos un proyecto de innovación docente interfacultativo en