Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease

The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.This study was supported by the grants IT747-13, PI12/00613, UPV/EHU UFI11/32

Ketamina eta esketaminaren erabilera depresioerresistentea tratatzeko: etorkizunerako erronkak

Depressive disorders have become one of the major public health problems in recent years, not only because of their impact on quality of life, but also because of the partial response or lack of response to antidepressant treatment. Therefore, the rapid and potent antidepressant effect of (R,S)-ketamine (ketamine) is considered one of the most important psychiatric discoveries of the last decades. Although, intravenous administration of ketamine has prevailed in most clinical trials conducted so far, the intranasal route has been considered a useful and safe alternative. Thus, the FDA (Food and Drug Administration) and the EMA (European Medicines Agency) approved a esketamine nasal spray named Spravato for the use in treatment resistant depression, although clinical trials supporting its marketing are not long-term. In line with this, major long-term safety concerns, such as dependence and cognitive impairment, has not been assessed so far. Therefore, there is an urgent need to investigate the relevance ofrepeated administration protocols on the long-term antidepressant response and safety. In this regard, potential pharmacological interactions between ketamine and some antidepressant drugs and benzodiazepines may impact the antidepressant response. In fact, while in some clinical trials adjunctive antidepressant medication is allowed, in others it is specifically removed, and this pharmacological variability may alter the efficacy of the treatment. Consequently, it is undeniable that in addition to massive long-term clinical trials, post-marketing studies are necessary to ensure the safety and efficacy of long-term ketamine and esketamine use.; Nahasmendu depresiboak osasun publikoko arazo handienetako bat bilakatu dira azken urteotan, ez bakarrik bizi-kalitatean duten eraginagatik, baita tratamendu antidepresiboaren erantzun partzial edo erantzun ezagatik ere. Hori dela eta, (R,S)-ketaminaren (ketamina) efektu antidepresibo azkarra eta eraginkorra azken hamarkadetako aurkikuntza garrantzitsuenen artean dago psikiatria arloan. Orain arteko entseguetan ketaminaren zain barneko bidea gailendu den arren sudur bideko administrazioa aukera erabilgarri eta segurutzat jo da. Hori dela eta, FDAk (Food and Drug Administration) eta EMAk (European Medicines Agency) S-ketamina (esketamina) baimendu dute Spravato izen komertzialarekin merkaturatutako sudur-lainoztagailurako soluzio bezala, depresio erresistentea tratatzeko, farmako horren merkaturatze-baimena sostengatzen duten entsegu klinikoak epe luzekoak ez diren arren. Horregatik, epe luzeko segurtasun-profila ikertzea premiazkoa da, eta, testuinguru berean, baita administrazio-protokolo errepikatuen egokitasuna ere. Izan ere, ketaminak farmako antidepresibo batzuekin eta bentzodiazepinekin izan ditzakeen elkarrekintzak ebaluatzea gomendatzen da, tratamenduaren eragin antidepresiboa baldintza dezaketelako. Ildo horretan, orain arte egindako entseguen diseinuaren aldakortasuna kontuan hartzeko ezaugarria litzatekeela proposatu da. Izan ere, entsegu batzuetan, tratamendu antidepresibo gehigarria baztertzen da, eta beste batzuetan, berriz, mantendu egiten da; aldakortasun metodologiko horrek tratamendu antidepresiboaren eraginkortasuna alda dezake. Ondorioz, uka ezina da epe luzerako entsegu klinikoak egiteaz gain merkaturatze ondorengo farmakozaintza-azterlanak ere nahitaezkoak direla ketaminaren eta esketaminaren segurtasuna eta eraginkortasuna epe luzera bermatzeko

Analysis of Acetylcholinesterase Activity in Cell Membrane Microarrays of Brain Areas as a Screening Tool to Identify Tissue Specific Inhibitors

Acetylcholinesterase (AChE) is responsible for hydrolyzing the acetylcholine neurotransmitter, bringing an end point to cholinergic neurotransmission. Thus, AChE is the primary target of a wide spectrum of compounds used as pesticides, nerve agents or therapeutic drugs for neurodegenerative diseases such as Alzheimer’s disease (AD). This enzyme is heterogeneously distributed in the brain showing different activity depending on the nervous region. Therefore, the aim of this work is to report a novel technology that enables the simultaneous determination of tissue specific AChE activity, as well as the analysis and screening of specific inhibitors, by using cell membrane microarrays. These microarrays were composed of cell membranes, isolated from 41 tissues, organs and brain areas, that were immobilized over a slide, maintaining the functionality of membrane proteins. To validate this platform, demonstrating its usefulness in drug discovery as a high throughput screening tool, a colorimetric protocol to detect the membrane-bound AChE activity was optimized. Thus, rat cortical and striatal AChE activities were estimated in presence of increased concentrations of AChE inhibitors, and the donepezil effect was assessed simultaneously in 41 tissues and organs, demonstrating the major potential of this microarray’s technology.The Spanish Ministry of Economy and Competitiveness (Innpacto program: IPT-2011-1205-010000), and the Basque Government Department of Economic Development, sustainability and environment (Etorgai program: ER-2011/00015, Bikaintek program: 48-AF-W2-2019-7)

Study of Tissue-Specific Reactive Oxygen Species Formation by Cell Membrane Microarrays for the Characterization of Bioactive Compounds

The production of reactive oxygen species (ROS) increases considerably in situations of cellular stress, inducing lipid peroxidation and multiple alterations in proteins and nucleic acids. However, sensitivity to oxidative damage varies between organs and tissues depending on the triggering process. Certain drugs used in the treatment of diverse diseases such as malaria have side effects similar to those produced by oxidative damage, although no specific study has been conducted. For this purpose, cell membrane microarrays were developed and the superoxide production evoked by the mitochondrial activity was assayed in the presence of specific inhibitors: rotenone, antimycin A and azide. Once the protocol was set up on cell membrane isolated from rat brain areas, the effect of six antimalarial drugs (atovaquone, quinidine, doxycycline, mefloquine, artemisinin, and tafenoquine) and two essential oils (Rosmarinus officinalis and Origanum majoricum) were evaluated in multiple human samples. The basal activity was different depending on the type of tissue, the liver, jejunum and adrenal gland being the ones with the highest amount of superoxide. The antimalarial drugs studied showed specific behavior according to the type of human tissue analyzed, with atovaquone and quinidine producing the highest percentage of superoxide formation, and doxycycline the lowest. In conclusion, the analysis of superoxide production evaluated in cell membranes of a collection of human tissues allowed for the characterization of the safety profile of these antimalarial drugs against toxicity mediated by oxidative stressThis work has been partially supported by grant Ministry of Economy and Competitiveness PID2019-106222RB-C31/SRA (State Research Agency, 10.13039/501100011033), the Basque Government Department of Economic Development, Sustainability and Environment (PUE21-03 and Bikaintek program: 48-AF-W2-2019-7 and 007-B2/2020) and University of the Basque Country (price to the best Master Thesis in collaboration with Institutions and Business)

Origin and trajectory of the teaching team forMultidisciplinary Biosanitary Education (IKAsasun)

El objetivo de este trabajo es dar a conocer el origen y la trayectoria del equipo docente estructurado IKAsasun (edIKDit-18-2, equipo docente para la Enseñanza Multidisciplinar Biosanitaria). El equipo está compuesto por personal docente investigador adscrito a los Campus de Leioa (Facultad de Medicina y Enfermería) y de Vitoria-Gasteiz (Facultad de Farmacia) de la Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU). La docencia que se imparte comprende a distintas disciplinas de Grados mayoritariamente relacionados con las Ciencias de la Salud (Enfermería, Farmacia, Fisioterapia, Medicina, Nutrición Humana y Dietética, Odontología, Ciencia y Tecnología de los Alimentos y Ciencias Ambientales). Desde el inicio de la andadura como equipo docente en el año 2015, el grupo ha participado en dos Proyectos de Innovación Educativa(PIE) subvencionados por la UPV/EHU (PIE nº 40 y nº 96). Estos proyectos están dirigidos a ayudar al alumnado a desarrollar, de una manera eficaz, las competencias específicas y transversales propias de cada Grado y a conseguir que se involucren en su propio aprendizaje. En ambos proyectos se ha incidido en la importancia de trabajar en equipos multidisciplinares, apostando por la utilización de metodologías de aprendizaje activo. En el primero de ellos (PIE nº 40; 2015-2017), se planteó la participación activa del alumnado en la resolución de casos clínicos complejos que requieren una bordaje multidisciplinar para garantizar la asistencia integral al paciente. En el segundo proyecto(PIE nº 96; 2018-2020), se llevó a cabo un abordaje multidisciplinar de temas relacionados con la salud biomédica y científica desde distintos Grados, y posterior divulgación enfocada a diferentes sectores de la sociedad. Los resultados obtenidos tras el desarrollo de ambos proyectos han sido muy alentadores, y alumnado, profesorado y personas externas colaboradoras han valorado muy positivamente la experiencia, que ha quedado reflejada en varias publicaciones y comunicaciones a congresos.The aim of this work is to provide an insight into the origin and background of theIKAsasun structured teaching team (edIKDit-18-2, teaching team for Multidisciplinary BiosanitaryEducation). Team is formed by an interdisciplinary group of teachers and researchers that belongsto the Campuses of Leioa (Faculty of Medicine and Nursing) and Vitoria-Gasteiz (Faculty ofPharmacy) of the University of the Basque Country (UPV/EHU). The teaching activity of thegroup covers different disciplines of the Degrees mostly related to Health Sciences (Nursing,Pharmacy, Physiotherapy, Medicine, Human Nutrition and Dietetics, Dentistry, EnvironmentalSciences and Food Sciences and Technology). Since the beginning of the journey as a teachingteam in 2015, the group has participated in two educational innovation projects (PIE) funded bythe UPV/EHU (PIE no. 40 and 96) aimed at helping students to effectively develop the specificand transversal competences of each degree, and to get them involved in their own learning.These projects have emphasized the importance of working in multidisciplinary teams, promotingthe implementation of active learning methodologies. In the first project (2015-2017), we proposedthe resolution of complex clinical cases that require a multidisciplinary approach to ensureintegral patient care. In the second one (2018-2020), we proposed a multidisciplinary approach toissues related to biomedical and scientific health from different Degrees, and their subsequentdissemination focusing on different sectors of society. The results obtained after the developmentof both projects have been very encouraging and both students, teaching staff and externalcollaborators have valued the experience very positively, which has been reflected in severalpublications and communications to conferences

Origen y trayectoria del equipo docente para la Enseñanza Multidisciplinar Biosanitaria (IKAsasun)

The aim of this work is to provide an insight into the origin and background of the IKAsasun structured teaching team (edIKDit-18-2, teaching team for  Multidisciplinary Biosanitary Education). Team is formed by an interdisciplinary group of teachers and researchers that belongs to the Campuses of Leioa (Faculty of Medicine and Nursing) and Vitoria-Gasteiz (Faculty of Pharmacy) of the University of the Basque Country (UPV/EHU). The teaching activity of the group covers different disciplines of the Degrees mostly  related to Health Sciences (Nursing, Pharmacy, Physiotherapy, Medicine, Human Nutrition and Dietetics, Dentistry, Environmental Sciences and Food Sciences and Technology). Since the beginning of the journey as a teaching team in 2015, the group has participated in two educational innovation projects (PIE) funded by the UPV/EHU (PIE no. 40 and 96) aimed at helping students to effectively develop the specific and transversal competences of each degree, and to get them involved in their own learning. Theseprojects have emphasized the importance of working in multidisciplinary teams, promoting the implementation of active learning methodologies. In the first project (2015-2017), we proposed the resolution of complex clinical cases that require a multidisciplinary approach to ensure integral patient care. In the second one (2018-2020), we proposed a multidisciplinary approach to issues related to biomedical and scientific health from different Degrees, and their subsequent dissemination focusing on different sectors of society. The results obtained after the development of both projects have been very encouraging and both students, teaching staff and external collaborators have valued the experience very positively, which has been reflected in several publications and communications to conferences.El objetivo de este trabajo es dar a conocer el origen y la trayectoria del equipo docente estructurado IKAsasun (edIKDit-18-2, equipo docente para la Enseñanza Multidisciplinar Biosanitaria). El equipo está compuesto por personal docente investigador adscrito a los Campus de Leioa (Facultad de Medicina y Enfermería) y de Vitoria-Gasteiz (Facultad de Farmacia) de la Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU). La docencia que se imparte comprende a distintas disciplinas de Grados mayoritariamente relacionados con las Ciencias de la Salud (Enfermería, Farmacia, Fisioterapia, Medicina, Nutrición Humana y Dietética, Odontología, Ciencia y Tecnología de los Alimentos y Ciencias Ambientales). Desde el inicio de la andadura como equipo docente en el año 2015, el grupo ha participado en dos Proyectos de Innovación Educativa (PIE) subvencionados por la UPV/EHU (PIE nº 40 y nº 96). Estos proyectos están dirigidos a ayudar al alumnado a desarrollar, de una manera eficaz, las competencias específicas y transversales propias de cada Grado y a conseguir que se involucren en su propio aprendizaje. En ambos proyectos se ha incidido en la  importancia de trabajar en equipos multidisciplinares, apostando por la utilización de metodologías de aprendizaje activo. En el primero de ellos (PIE nº 40; 2015-2017), se planteó la participación activa del alumnado en la resolución de casos clínicos complejos que requieren un abordaje multidisciplinar para garantizar la asistencia integral al paciente. En el segundo proyecto (PIE nº 96; 2018-2020), se llevó a cabo un abordaje multidisciplinar de temas relacionados con la salud biomédica y científica desde distintos Grados, y posterior divulgación enfocada a diferentes sectores de la sociedad. Los resultados obtenidos tras el desarrollo de ambos proyectos han sido muy alentadores, y alumnado, profesorado y personas externas colaboradoras han valorado muy positivamente la experiencia, que ha quedado reflejada en varias publicaciones y comunicaciones a congresos

Multidisciplinary approach and social diffusion of a health problem

La universidad debe ser capaz de formar profesionales preparados para afrontar desafíos que requieran un abordaje multidisciplinar, así como para transmitir de forma clara y comprensible problemas sanitarios de interés para la sociedad, por ejemplo, mediante el uso de redes sociales. Este trabajo planteó un escenario complejo dentro del ámbito sanitario, como es el uso racional de los antibióticos, para que equipos multidisciplinares de alumnado de distintos grados reflexionaran de manera conjunta sobre diversas cuestiones. Como resultado, el alumnado desarrolló un blog que reflejaba las soluciones a los escenarios planteados relacionados con el tema, utilizando un lenguaje divulgativo para conseguir la concienciación de la ciudadanía sobre este problema no solo sanitario sino también ambiental. La evaluación de esta actividad fue altamente satisfactoria tanto en lo relativo a la propia elaboración del blog (máxima puntuación en 7 de los 9 ítems evaluados) así como en la pregunta de respuesta individual incluida en el examen final (96% del alumnado consiguió la máxima calificación) o en la defensa oral de su trabajo (100% del alumnado consiguió la máxima calificación). De esta manera, el alumnado tomó conciencia de la importancia del trabajo multidisciplinar, así como de la difusión del conocimiento adquirido. Además, se consiguió trabajar y evaluar competencias tanto específicas como transversales adquiridas en los diferentes Grados.The university must be able to train professionals prepared to face challenges that require a multidisciplinary approach, as well as to transmit health problems of interest to society in a clear and understandable way, for example, through the use of social networks. This work posed a complex scenario within the health field, such as the rational use of antibiotics, for multidisciplinary teams of students from different degrees to reflect together on various issues. As a result, the students developed a blog that reflected the solutions to the scenarios raised related to the topic, using an informative language to raise public awareness of this problem, not only health but also environmental. The evaluation of this activity was highly satisfactory both in terms of the development of the blog itself (maximum score in 7 of the 9 items evaluated) as well as in the individual response question included in the final exam (96% of the students obtained the maximum score) or in the oral defense of their work (100% of the students obtained the maximum score). In this way, students became aware of the importance of multidisciplinary work, as well as of the dissemination of the knowledge acquired. In addition, it was possible to work and evaluate both specific and transversal competencies acquired in the different Degrees