Role of endogenous cannabinoids in the control of basal ganglia activity

The cannabinoid system is a novel intercellular signaling system that plays a prominent role, among others, in the control of basal ganglia function. This finding can be concluded from the data obtained in different series of anatomical, biochemical, electrophysiological and pharmacological studies. These data demonstrated: (i) that the basal ganglia contain high levels of endocannabinoids and their receptors, mainly including the cannabinoid CB1 receptor subtype but also a related receptor type, the vanilloid TRPV1 receptor; (ii) that the activation or the blockade of this system produces important changes in motor behavior, changes that are originated as a consequence of interactions of the cannabinoid system with various classic neurotransmitters such as GABA, dopamine or glutamate; and (iii) the occurrence of marked changes in specific elements of the cannabinoid signaling system in various basal ganglia disorders, with emphasis in the induction/upregulation of the cannabinoid CB2 receptor subtype. This large evidence relating endocannabinoids and their receptors to the function of the basal ganglia, both in the healthy and the pathological brain, has provided support for the idea that cannabinoid-based medicines, with selectivity for different targets of the cannabinoid signaling system (synthetic enzymes, receptors, inactivation system), might have therapeutic potential to alleviate symptoms and/or provide neuroprotection in basal ganglia disorders, in particular Parkinson´s disease and Huntington´s chorea. The present chapter will review the knowledge on this issue trying to establish the future lines for the research on the therapeutic potential of the cannabinoid signaling system in basal ganglia disorders.peer-reviewe

Aumentando la presencia de la UCM en los MOOCs: Puesta en marcha de un curso online sobre neurociencia

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

Neuropathological Characterization of a Dravet Syndrome Knock-In Mouse Model Useful for Investigating Cannabinoid Treatments

Dravet syndrome (DS) is an epileptic syndrome caused by mutations in the Scn1a gene encoding the alpha 1 subunit of the sodium channel Nav1.1, which is associated with febrile seizures that progress to severe tonic-clonic seizures and associated comorbidities. Treatment with cannabidiol has been approved to reduce seizures in DS, but it may also be active against these comorbidities. The aim of this study was to validate a new mouse model of DS having lower mortality than previous models, which may serve to further evaluate therapies for the long-term comorbidities. This new model consists of heterozygous conditional knock-in mice carrying a missense mutation (A1783V) in Scn1a gene expressed exclusively in neurons of the CNS (Syn-Cre/Scn1a(WT/A1783V)). These mice have been used here to determine the extent and persistence of the behavioral deterioration in different postnatal days (PND), as well as to investigate the alterations that the disease produces in the endocannabinoid system and the contribution of inflammatory events and impaired neurogenesis in the pathology. Syn-Cre/Scn1a(WT/A1783V) mice showed a strong reduction in hindlimb grasp reflex at PND10, whereas at PND25, they presented spontaneous convulsions and a greater susceptibility to pentylenetetrazole-induced seizures, marked hyperactivity, deficient spatial working memory, lower levels of anxiety, and altered social interaction behavior. These differences disappeared at PND40 and PND60, except the changes in social interaction and anxiety. The analysis of CNS structures associated with these behavioral alterations revealed an elevated glial reactivity in the prefrontal cortex and the dentate gyrus. This was associated in the dentate gyrus with a greater cell proliferation detected with Ki67 immunostaining, whereas double-labeling analyses identified that proliferating cells were GFAP-positive suggesting failed neurogenesis but astrocyte proliferation. The analysis of the endocannabinoid system of Syn-Cre/Scn1a(WT/A1783V) mice confirmed reductions in CB1 receptors and MAGL and FAAH enzymes, mainly in the cerebellum but also in other areas, whereas CB2 receptors became upregulated in the hippocampus. In conclusion, Syn-Cre/Scn1a(WT/A1783V) mice showed seizuring susceptibility and several comorbidities (hyperactivity, memory impairment, less anxiety, and altered social behavior), which exhibited a pattern of age expression similar to DS patients. Syn-Cre/Scn1a(WT/A1783V) mice also exhibited greater glial reactivity and a reactive response in the neurogenic niche, and regional changes in the status of the endocannabinoid signaling, events that could contribute in behavioral impairmentThis work was supported by grants from CIBERNED (CB06/05/0089) and MICIU (RTI2018-098885-B-100) to JF-R, Proyectos de Investigacion en Salud, Instituto de Salud Carlos III (PI20/00773) to OS, and Spanish Ministry of Economy and Competitiveness (MINECO; SAF-2015-70866-R, with FEDER Funds) to JE. These agencies had no further role in study design, collection, analysis and interpretation of the data, in the writing of the report, or in the decision to submit the paper for publication. CA is a predoctoral fellow supported by the FPU-Programme (FPU16/04768). The authors are indebted to Yolanda Garcia-Movellan for administrative assistanc

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

Experiencia sobre la evaluación continua a través de Campus Virtual

Los métodos digitales están adquiriendo cada vez más importancia dentro del proceso de aprendizaje por las ventajas que aportan y por la demanda de los alumnos. Sin embargo, uno de los retos más complicados que se nos plantean con los nuevos planes docentes es llegar a conseguir un método efectivo de evaluación continua sobre el trabajo de los alumnos. Es por lo tanto, importante el realizar experiencias encaminadas a desarrollar diferentes estrategias que lo permitan, aprovechando las herramientas que aportan las nuevas plataformas digitales

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

Editorial: Cannabinoids as potential treatment for neurological diseases

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