Preclinical investigation of β-caryophyllene as a therapeutic agent in an experimental murine model of Dravet syndrome

Dravet Syndrome (DS) is caused by mutations in the Scn1a gene encoding the α1 subunit of the sodium channel Nav1.1, which results in febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved for the management of seizures in DS patients, but it appears to be also active against associated comorbidities. In this new study, we have investigated β-caryophyllene (BCP), a cannabinoid with terpene structure that appears to also have a broad-spectrum profile, as a useful therapy against both seizuring activity and progression of associated comorbidities. This has been studied in heterozygous conditional knock-in mice carrying a missense mutation (A1783V) in Scn1a gene expressed exclusively in neurons of the Central Nervous System (Syn-Cre/Scn1aWT/A1783V), using two experimental approaches. In the first approach, an acute treatment with BCP was effective against seizuring activity induced by pentylenetetrazole (PTZ) in wildtype (Scn1aWT/WT) and also in Syn-Cre/Scn1aWT/A1783V mice, with these last animals having a greater susceptibility to PTZ. Such benefits were paralleled by a BCP-induced reduction in PTZ-induced reactive astrogliosis (labelled with GFAP) and microgliosis (labelled with Iba-1) in the prefrontal cortex and the hippocampal dentate gyrus, which were visible in both wildtype (Scn1aWT/WT) and Syn-Cre/Scn1aWT/A1783V mice. In the second approach, both genotypes were treated repeatedly with BCP to investigate its effects on several DS comorbidities. Thus, BCP corrected important behavioural abnormalities of Syn-Cre/Scn1aWT/A1783V mice (e.g. delayed appearance of hindlimb grasp reflex, induction of clasping response, motor hyperactivity, altered social interaction and memory impairment), attenuated weight loss, and slightly delayed premature mortality. Again, these benefits were paralleled by a BCP-induced reduction in reactive astrogliosis and microgliosis in the prefrontal cortex and the hippocampal dentate gyrus typical of Syn-Cre/Scn1aWT/A1783V mice. In conclusion, BCP was active in Syn-Cre/Scn1aWT/A1783V mice against seizuring activity (acute treatment) and against several comorbidities (repeated treatment), in both cases in association with its capability to reduce glial reactivity in areas related to these behavioural abnormalities. This situates BCP in a promising position for further preclinical evaluation towards a close translation to DS patients

Uso la plataforma H5P de creación de contenido interactivo como herramienta para la creación de un laboratorio de bioquímica virtual e interactivo

En este proyecto de innovación docente está diseñado para que el alumnado se acerque a un laboratorio de bioquímica virtual e interactivo y conozca los diferentes métodos y técnicas experimentales que se utilizan en ciertos análisis clínicos

Diseño de la asignatura de Bioquímica del Grado de Fisioterapia: elaboración de materiales para el aprendizaje a través de la clase invertida

Sección Deptal. de Bioquímica y Biología Molecular (Medicina)Fac. de MedicinaFALSEsubmitte

Puesta en marcha del curso on line “Envejecimiento y enfermedades neurodegenerativas” en la plataforma Miriadax

Este informe detalla los objetivos, actividades y métodos llevados a cabo durante la ejecución de un proyecto de innovación docente que tiene como objetivo implementar un curso online en abierto sobre las enfermedades neurodegenerativas y el envejecimiento

Possible therapeutic applications of cannabis in the neuropsychopharmacology field

Cannabis use induces a plethora of actions on the CNS via its active chemical ingredients, the so-called phytocannabinoids. These compounds have been frequently associated with the intoxicating properties of cannabis preparations. However, not all phytocannabinoids are psychotropic, and, irrespective of whether they are psychotropic or not, they have also shown numerous therapeutic properties. These properties are mostly associated with their ability to modulate the activity of an intercellular communication system, the so-called endocannabinoid system, which is highly active in the CNS and has been found altered in many neurological disorders. Specifically, this includes the neuropsychopharmacology field, with diseases such as schizophrenia and related psychoses, anxiety-related disorders, mood disorders, addiction, sleep disorders, post-traumatic stress disorder, anorexia nervosa and other feeding-related disorders, dementia, epileptic syndromes, as well as autism, fragile X syndrome and other neurodevelopment-related disorders. Here, we gather, from a pharmacological and biochemical standpoint, the recent advances in the study of the therapeutic relevance of the endocannabinoid system in the CNS, with especial emphasis on the neuropsychopharmacology field. We also illustrate the efforts that are currently being made to investigate at the clinical level the potential therapeutic benefits derived from elevating or inhibiting endocannabinoid signaling in animal models of neuropsychiatric disorders.Depto. de Bioquímica y Biología MolecularFac. de Ciencias QuímicasFac. de MedicinaTRUEpu

Disease-modifying effects of cannabidiol, β-caryophyllene and their combination in Syn1-Cre/Scn1aWT/A1783V mice, a preclinical model of Dravet syndrome

Cannabidiol (CBD) has been recently approved as an antiseizure agent in Dravet Syndrome (DS), a pediatric epileptic encephalopathy, but CBD could also be active against associated comorbidities. Such associated comorbidities were also attenuated by the sesquiterpene β-caryophyllene (BCP). Here, we have compared the efficacy of both compounds and further initiated the analysis of a possible additive effect between both compounds in relation with these comorbidities using two experimental approaches. The first experiment was aimed at comparing the benefits of CBD and BCP, including their combination in conditional knock-in Scn1a-A1783V mice, an experimental model of DS, treated since the postnatal day 10th to 24th. As expected, DS mice showed impairment in limb clasping, delay in the appearance of hindlimb grasp reflex and additional behavioural disturbances (e.g., hyperactivity, cognitive deterioration, social interaction deficits). This behavioural impairment was associated with marked astroglial and microglial reactivities in the prefrontal cortex and the hippocampal dentate gyrus. BCP and CBD administered alone were both able to partially attenuate the behavioural disturbances and the glial reactivities, with apparently greater efficacy against glial reactivities obtained with BCP, whereas superior effects in a few specific parameters were obtained when both compounds were combined. In the second experiment, we investigated this additive effect in cultured BV2 cells treated with BCP and/or CBD and stimulated with LPS. As expected, addition of LPS induced a marked increase in several inflammation-related markers (e.g., TLR4, COX-2, iNOS, catalase, TNF-α, IL-1β), as well as elevated Iba-1 immunostaining. Treatment with BCP or CBD attenuated these elevations, but, again and in general, superior results were obtained when both cannabinoids were combined. In conclusion, our results support the interest to continue investigating the combination of BCP and CBD to improve the therapeutic management of DS in relation with their disease- modifying properties.Centro de Investigación Biomédica en Red enfermedades neurodegenerativasMinisterio de Ciencia, Innovación y Universidades (España)Depto. de Bioquímica y Biología MolecularFac. de MedicinaTRUEpubAPC financiada por la UC

Effects of a Sativex-Like Combination of Phytocannabinoids on Disease Progression in R6/2 Mice, an Experimental Model of Huntington’s Disease

Several cannabinoids afforded neuroprotection in experimental models of Huntington’s disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆9-tetrahydrocannabinol (∆9-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex®, is beneficial in R6/2 mice (a transgenic model of HD), as it was previously shown to have positive effects in neurotoxin-based models of HD. We recorded the progression of neurological deficits and the extent of striatal deterioration, using behavioral, in vivo imaging, and biochemical methods in R6/2 mice and their corresponding wild-type mice. The mice were daily treated, starting at 4 weeks after birth, with a Sativex-like combination of phytocannabinoids (equivalent to 3 mg/kg weight of pure CBD + ∆9-THC) or vehicle. R6/2 mice exhibited the characteristic deterioration in rotarod performance that initiated at 6 weeks and progressed up to 10 weeks, and elevated clasping behavior reflecting dystonia. Treatment with the Sativex-like combination of phytocannabinoids did not recover rotarod performance, but markedly attenuated clasping behavior. The in vivo positron emission tomography (PET) analysis of R6/2 animals at 10 weeks revealed a reduced metabolic activity in the basal ganglia, which was partially attenuated by treatment with the Sativex-like combination of phytocannabinoids. Proton nuclear magnetic resonance spectroscopy (H+-MRS) analysis of the ex vivo striatum of R6/2 mice at 12 weeks revealed changes in various prognostic markers reflecting events typically found in HD patients and animal models, such as energy failure, mitochondrial dysfunction, and excitotoxicity. Some of these changes (taurine/creatine, taurine/N-acetylaspartate, and N-acetylaspartate/choline ratios) were completely reversed by treatment with the Sativex-like combination of phytocannabinoids. A Sativex-like combination of phytocannabinoids administered to R6/2 mice at the onset of motor symptoms produced certain benefits on the progression of striatal deterioration in these mice, which supports the interest of this cannabinoid-based medicine for the treatment of disease progression in HD patients

Cannabinoid signalling in the immature brain: Encephalopathies and neurodevelopmental disorders

The endocannabinoid system exerts a crucial neuromodulatory role in many brain areas that is essential for proper regulation of neuronal activity. The role of cannabinoid signalling controlling neuronal activity in the adult brain is also evident when considering its contribution to adult brain insults or neurodegenerative diseases. In the context of brain genetic or acquired encephalopathies administration of cannabinoid-based molecules has demonstrated to exert symptomatic relief and hence, they are proposed as new potential therapeutic compounds. This review article summarizes the main evidences indicating the beneficial action of cannabinoid-derived molecules in preclinical models of neonatal hypoxia/ischemic damage. In a second part, we discuss the available evidences of therapeutic actions of cannabidiol in children with refractory epilepsy syndromes. Finally, we discuss the current view of cannabinoid signalling mechanisms active in the immature brain that affect in neural cell fate and can contribute to long-term neural cell plasticity.Ministerio de Economía y Competitividad (MINECO)/Fondo Europeo de desarrollo Regional (FEDER)Comunidad de MadridInstituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional (FEDER)GW Research LtdUniversidad Complutense de Madrid (UCM)/Banco de SantanderDepto. de Bioquímica y Biología MolecularFac. de Ciencias BiológicasTRUEpu

Education during the pandemic, a tool for the future

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 el que pretendemos evaluar el efecto que ha tenido la situación pandémica global derivada de la COVID-19 sobre la docencia universitaria, enmarcada dentro de los departamentos de Bioquímica y Biología Molecular de la Facultad de Medicina y Psicobiología y Metodología en CIencias del Comportamiento, de la Facultad de Psicología. Esto nos permitirá buscar diferencias entre las medidas implementadas en diferentes centros y entre varios grados impartidos en el área de las Ciencias de la Salud, pero con un diferente componente práctico, como serían los grados de Medicina, Bioquímica, Fisiología, Podología o Psicología.Depto. de Bioquímica y Biología MolecularFac. de MedicinaFALSEsubmitte

eSTEM - Estudio para el avance en la diversidad e inclusión de estudiantes embarazadas en grados experimentales

Depto. de Química InorgánicaDepto. de Química AnalíticaDepto. de Química OrgánicaDepto. de Química FísicaFac. de Ciencias QuímicasFALSEsubmitte