Homeostatic Plasticity and Therapeutic Approaches in Neurodegeneration

The synapses transmit signals between neurons in an ever-changing fashion. Changes of synaptic transmission arise from numerous mechanisms known as synaptic plasticity. The importance and complexity of the synapse has fueled research into the molecular mechanisms underlying synaptogenesis, synaptic transmission, and plasticity. Particularly, homeostatic plasticity refers to the local changes in synaptic activation to generate local synaptic adaptations and network-wide changes in activity to generate adjustments between excitation and inhibition. This review chapter will focus on synaptic phenomena and mechanisms that are likely to contribute to network homeostasis. In addition, it will be discussed a putative modulation of the signaling mechanisms serving a homeostatic function as a viable therapeutic approach for disease modification in neurological and neurodegenerative disorders. To sum up, the main role of the following players in homeostatic plasticity will be analyzed, based on what a growing body of evidence has suggested recently: BDNF-mediated TrkB system activation; adenosine modulation system; nitric oxide/soluble GC/cGMP signaling; astrocyte involvement—astroglial CB1 receptors; the microtubule-associated neuronal protein Tau; the signaling pathway of the Wnt protein family; extracellular vesicles in the intercellular communication; and estrogen involvement in non-reproductive functions

Aspectos farmacológicos del citocromo P-450

Aspectos farmacológicos del citocromo P-450

Cineforum como recurso docente en el proceso de enseñanza-aprendizaje de la Farmacología

El cine ha demostrado ser una herramienta educativa muy útil cuando sus características lúdicas, versátiles y multi-sensoriales se utilizan adecuadamente y con unos objetivos claros de aprendizaje. Es necesario dirigir al alumno mediante la ilustración del tema, el planteamiento de preguntas, la invitación a la reflexión y a la crítica, fomentando el debate, la participación y la implicación de los alumnos en la asignatura. Es entonces cuando el cine se convierte en un instrumento de formación que permite la adquisición tanto de competencias específicas como transversales. Se utilizaron 2 películas comerciales (“Contagio” y “Despertares”) de temática centrada en el ámbito de las ciencias de la salud. Aunque las películas son de naturaleza y temática muy diferentes, los aspectos narrativos y los personajes en los que se sumergen los temas farmacológicos de interés formativo muestran que, tras cada enfermedad, tras cada tratamiento farmacológico, tras cada reacción adversa… hay muchas historias humanas. Los alumnos toman conciencia de que su actual formación educativa y profesional como farmacéuticos tendrá indefectiblemente un impacto en la vida de otras personas. Los alumnos valoraron diferentes aspectos de la incidencia formativa de la experiencia Cineforum. Los resultados de la valoración global del proyecto Cineforum por parte de los alumnos fue muy positiva, obteniéndose una calificación global de 8,3 sobre 10 es decir entre “Muy buena” y “Excelente”. Las calificaciones más bajas correspondieron a valores entre 7,4 y 7,9, entre “Buena y “Muy buena”. No obstante, la valoración global para cada película por separado fue también muy positiva indicando que, aunque con pequeñas diferencias, es la experiencia formativa del Cineforum en sí misma, y no la película en particular, la que ha sido valorada positivamente por los alumnos

A Diet Containing Rutin Ameliorates Brain Intracellular Redox Homeostasis in a Mouse Model of Alzheimer’s Disease

Quercetin has been studied extensively for its anti-Alzheimer’s disease (AD) and anti-aging effects. Our previous studies have found that quercetin and in its glycoside form, rutin, can modulate the proteasome function in neuroblastoma cells. We aimed to explore the effects of quercetin and rutin on intracellular redox homeostasis of the brain (reduced glutathione/oxidized glutathione, GSH/GSSG), its correlation with β-site APP cleaving enzyme 1 (BACE1) activity, and amyloid precursor protein (APP) expression in transgenic TgAPP mice (bearing human Swedish mutation APP transgene, APPswe). On the basis that BACE1 protein and APP processing are regulated by the ubiquitin–proteasome pathway and that supplementation with GSH protects neurons from proteasome inhibition, we investigated whether a diet containing quercetin or rutin (30 mg/kg/day, 4 weeks) diminishes several early signs of AD. Genotyping analyses of animals were carried out by PCR. In order to determine intracellular redox homeostasis, spectrofluorometric methods were adopted to quantify GSH and GSSG levels using o-phthalaldehyde and the GSH/GSSG ratio was ascertained. Levels of TBARS were determined as a marker of lipid peroxidation. Enzyme activities of SOD, CAT, GR, and GPx were determined in the cortex and hippocampus. ΒACE1 activity was measured by a secretase-specific substrate conjugated to two reporter molecules (EDANS and DABCYL). Gene expression of the main antioxidant enzymes: APP, BACE1, a Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), caspase-3, caspase-6, and inflammatory cytokines were determined by RT-PCR. First, overexpression of APPswe in TgAPP mice decreased GSH/GSSG ratio, increased malonaldehyde (MDA) levels, and, overall, decreased the main antioxidant enzyme activities in comparison to wild-type (WT) mice. Treatment of TgAPP mice with quercetin or rutin increased GSH/GSSG, diminished MDA levels, and favored the enzyme antioxidant capacity, particularly with rutin. Secondly, both APP expression and BACE1 activity were diminished with quercetin or rutin in TgAPP mice. Regarding ADAM10, it tended to increase in TgAPP mice with rutin treatment. As for caspase-3 expression, TgAPP displayed an increase which was the opposite with rutin. Finally, the increase in expression of the inflammatory markers IL-1β and IFN-γ in TgAPP mice was lowered by both quercetin and rutin. Collectively, these findings suggest that, of the two flavonoids, rutin may be included in a day-to-day diet as a form of adjuvant therapy in AD

Demethylcalabaxanthone from <i>Garcinia mangostana</i> Exerts Antioxidant Effects through the Activation of the Nrf2 Pathway as Assessed via Molecular Docking and Biological Evaluation

Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation promotes the expression of antioxidant enzymes in response to rising oxidative stress, resulting in reactive oxygen species (ROS) detoxification and playing a central role in the maintenance of intracellular redox homeostasis and regulation of inflammation. Moreover, the biological effects of Nrf2 pathway activation contribute to reducing apoptosis and enhancing cell survival. The activity of Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1). Prompted by the recent results reporting the impact of xanthone metabolites on oxidative stress, cancer, and inflammation, the antioxidant properties of xanthones isolated from Garcinia mangostana (γ-mangostin, α-mangostin, 8-deoxygartanin, demethylcalabaxanthone, garcinone D) were assessed. In particular, the capability of these natural products to disrupt the interaction between Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor erythroid 2-related factor 2 (Nrf2), triggering the activation of the Nrf2-mediated pathway, was evaluated using molecular docking experiments and in vitro tests. The modulation of some key Nrf2-related mediators like glutathione (GSH) and lactate dehydrogenase (LDH) to highlight a possible direct antioxidant effect was investigated. Among the tested compounds, demethylcalabaxanthone showed an indirect antioxidant effect, as corroborated by a Western blot assay, displaying a significant increase in the translocated protein upon its administration

Cineterapia: las enfermedades neurológicas a través del cine

La «Cineterapia» consiste en el uso del cine como recurso terapéutico, preventivo o de aprendizaje. Los expertos han recurrido a determinadas películas para que una persona en tratamiento psicológico y/o psiquiátrico consiga identificar su problema, se vea motivada a comunicar sus emociones y logre resolver dicho problema con recursos propios. El uso de esta metodología, por tanto, se ha centrado fundamentalmente en la terapia de los trastornos afectivos y comportamentales. Sin embargo, hasta la fecha no se ha descrito una aplicación real de la cineterapia en personas con patologías neurodegenerativas y neurológicas. Por ello, con la presente propuesta, pretendemos formar y capacitar a estudiantes de 4º curso de Grado en Farmacia para que, a través de la cineterapia, puedan dar una respuesta real a las necesidades terapéuticas (farmacológicas y no farmacológicas) y sociales de personas (pacientes) que sufren Parkinson, deterioro cognitivo leve, epilepsia o esclerosis múltiple. A través del visionado de determinadas películas y un debate posterior dirigido por los estudiantes, se abordarán aspectos como el uso de fármacos en el tratamiento de la enfermedad, la relación paciente-neurólogo y las causas de la estigmatización de la enfermedad (escasa información sobre la enfermedad o sobre el tratamiento). Se dará voz a los pacientes para obtener una visión integrada de su situación concreta debida a la sintomatología de la enfermedad, a efectos adversos de fármacos, a dificultades del cumplimiento terapéutico y a su percepción de la evolución de la enfermedad. Mediante la prestación de este servicio a una comunidad de pacientes, se pretende favorecer que el estudiante se enfrente a situaciones reales de una enfermedad determinada y a su tratamiento farmacológico, y a que influya positivamente en el proyecto de vida del paciente. Es así como el estudiante podrá reconocer que la práctica de la profesión sanitaria se centra en el paciente

Corylus avellana cultivar “Tonda di Giffoni”, source of antioxidant diarylheptanoids: Biological evaluation and molecular docking analysis

Hazelnut “Tonda di Giffoni” (Corylus avellana L.) is a PGI (Protected Geographical Indication) product of the Campania region, Southern Italy, marked for its processing quality which guarantees origin, typical features, high physicochemical quality, and organoleptic properties. Previous investigations on hazelnut and its byproducts revealed the presence of diarylheptanoid derivatives, natural compounds with antioxidant properties. With the aim of exploring the nutraceutical properties of hazelnut diarylheptanoids, the antioxidant properties of giffonins E (1), H (2), and J (3), three cyclic diaryletherheptanoids, and carpinontriol B (4), a cyclic diarylheptanoid, were investigated. Tested compounds showed significant protection against hydrogen peroxide (H2O2)-induced cytotoxic damage in human neuroblastoma and embryonic kidney cell lines. Compounds 1–4 were also able to prevent oxidative stress by decreasing reactive oxygen species (ROS) production and levels of lipid peroxidation, and attenuating cell apoptosis (caspase-3 activity).Moreover, considering that the nuclear factor erythroid 2-related factor 2 (Nrf2) is responsible for regulating an extensive panel of antioxidant enzymes, the capability of these natural products to disrupt the interaction between Kelch-like ECH-associated protein 1 (Keap1), thereby activating the Nrf2-mediated pathway, was evaluated by molecular docking experiments and in vitro tests.The Western blot analysis revealed that giffonin H and carpinontriol B had an indirect antioxidant action, as evidenced by a significant rise in the translocated protein following their administration

Synthesis and evaluation of arylquinones as BACE1 inhibitors, b-amyloid peptide aggregation inhibitors, and destabilizers of preformed b-amyloid fibrils

BACE1 activity, inhibition of Ab aggregation, and disaggregation of preformed Ab fibrils constitute the three major targets in the development of small-molecule lipophilic new drugs for the treatment of Alzheimer’s disease (AD). Quinones are widely distributed among natural products and possess relevant and varied biological activities including antitumor and antibiotic, inhibition of HIV-1 reverse transcriptase, antidiabetic, or COX-inhibition, among others. We report herein the interaction of several arylquinones and their derivatives with the amyloidogenic pathway of the amyloid precursor protein processing. Our studies put forward that these compounds are promising candidates in the development of new drugs which are effective simultaneously towards the three major targets of ADAndrea Ortega (PhD fellow) thanks the government of Chile and the ‘Universidad Católica del Norte’ (Antofagasta, Chile) for a grant (MECESUP program, UCN0604). Projects CTQ2009-14124-C02-01, CTQ2010-16170 and SAF2009-10399 from the Spanish government are gratefully acknowledged for financial supportPeer reviewe