Estudio de la eficacia terapéutica de nuevos derivados de cannabigerol y cannabidiol en esclerosis múltiple

Tesis doctoral inédita, leída en la Universidad Autónoma de Madrid, Facultad de Medicina,Departamento de Anatomía, Histología y Neurociencia. Fecha de lectura: 15 de abril de 2016La esclerosis múltiple, la causa más común de discapacidad neurológica en adultos jóvenes, es una enfermedad autoinmune compleja con componente neuroinflamatorio, caracterizada por la infiltración de leucocitos en el sistema nervioso central, la desmielinización y el daño axonal. A pesar de ser la enfermedad desmielinizante más común del sistema nervioso central, aún no existe una terapia satisfactoria, especialmente en las formas de EM primaria-progresiva y durante la fase secundaria de la enfermedad. Por ello, existe una clara necesidad de investigación para el desarrollo de agentes terapéuticos capaces de disminuir el desarrollo de este trastorno progresivo. Los fitocannabinoides son compuestos químicos presentes en la planta Cannabis sativa. Muchos de ellos no presentan efectos psicotrópicos, y se consideran de especial interés para el tratamiento de enfermedades del SNC. Entre estos fitocannabinoides sin efectos psicoactivos cabe destacar el cannabidiol y cannabigerol, entre otros. Su acción antiinflamatoria está medidada por los receptores CB clásicos, y se ha demostrado que los receptores PPAR también pueden estar involucrados en estos efectos, presentando un potencial terapéutico para el tratamiento de enfermedades con un componente inflamatorio. Se han desarrollado una serie de nuevos derivados de cannabigerol (VCE-003, VCE-003.2 y VCE-006) y de cannabidiol (VCE-004.8), cuyas modificaciones en su estructura química hacen que presenten mayor afinidad que los compuestos de origen por los receptores CB2 y PPARγ, exhibiendo una actividad dual por los mismos. Los resultados obtenidos en esta tesis doctoral muestran que VCE-003 y VCE-004.8 son compuestos que reducen la muerte neuronal y ejercen efectos antiinflamatorios en cultivos celulares. Asimismo, actúan como agentes inmunomoduladores que activan los receptores CB2 y PPARγ en dos modelos de esclerosis múltiple, tanto en la encefalomielitis murina inducida por el virus de Theiler como en la encefalomielitis autoinmune experimental. Además, estos compuestos reducen la infiltración de linfocitos T CD4 y disminuyen la activación microglial en la médula espinal. Ambos compuestos preservan la estructura de las vainas de mielina y contribuyen a la reducción del daño axonal . Su agonismo por los receptores CB2 y PPARγ hace que se postulen como unos prometedores agentes antiinflamatorios y neuroprotectores para el posible tratamiento de la EM.Multiple sclerosis, the most common cause of neurological disability in young adults, is a complex autoimmune disease characterized by neuroinflammation as reflected by the presence of leukocyte infiltrates into the central nervous system, the loss of myelin and the axonal damage in both the brain and the spinal cord. Despite multiple sclerosis prevalence, no satisfactory therapy has been found for MS, particularly for the variants primary-progressive and the secondary phase. There is a clear need for the development of novel agents able to stop the development of this progressive disorder. Non-psychotropic phytocannabinoids are considered of special interest as novel therapeutic agents in CNS diseases. These include cannabidiol and cannabigerol, among others. Besides their effects through the classical CB receptors, PPARγ receptors have been shown to be involved the attenuation neuroinflammation by these compounds, showing a therapeutic potential for the treatment of inflammatory diseases. We have developed a series of new cannabigerol (VCE-003, VCE-003.2 and VCE-006) and cannabidiol derivatives (VCE-004.8) that show CB2 and PPARγ receptors affinity. The findings of this doctoral thesis show that VCE-003 and VCE-004.8 are compounds that reduce neuronal death and exert anti-inflammatory effects in cell cultures. Moreover, these compounds act as immunomodulatory agents targeting CB2 and PPARγ receptors in two models of multiple sclerosis, Theiler's murine encephalomyelitis virus-induced demyelinating disease and experimental autoimmune encephalomyelitis. Furthermore, these compounds reduce CD4 T cells infiltrates and diminish microglial activation, preserve myelin sheets structure and reduce axonal damage in the spinal cord. Their dual affinity for CB2 and PPARγ receptors is critical for their consideration as a novel anti-inflammatory and neuroprotective compounds for the treatment of several inflammatory diseases, such as multiple sclerosis

Use of PV plants monitoring to characterize PV arrays power

PV plants require a monitorization of their electrical parameters to achieve its best performance. Lately, it is more and more common that SCADA systems monitor currents and voltages even of every single string. These measurements which use to be stored instantaneously with a frequency like the one established on inverters and energy meters (usually each 10, 15, 20 or 60 minutes) are useful to detect faults. Unfortunately, it is not taken advantage of them to characterize the PV arrays. A better option would be to exploit this monitoring capability not only to detect operation failures, but also to characterize the PV strings/arrays. In order to implement this characterization it is needed to use the adequate devices to measure voltages and currents and determine which should be the optimal frequency to store data, depending on they are instantaneous or mean values. This paper presents the results of the DC monitoring of a grid-connected PV array of 5.8 kWp, installed on the headquarters of the Instituto de Energía Solar of the Universidad Politécnica de Madrid (IES-UPM), located in the Campus Sur of Vallecas (Madrid), which allows characterizing the PV arrays power. To study the relation between sampling frequency and its impact in the accuracy of the power averages each 1’, 5’, 10, and 15’ have been calculated from instantaneous measurements, and they have been analysed to evaluate which is the more adequate sampling rate for instantaneous and mean values

Outdoors measurements of pv module efficiency and temperature coefficients

Performance of a PV installation depends critically on the modules behaviour. That is the reason why a good estimation of energy production of a PV installation relies not only on the goodness of the module power characterization at standard test conditions, but also on the goodness of the characterisation of the module behaviour related to the variation of irradiance and temperature. So, it is closer to the reality running a simulation exercise of energy production with the actual values measured outdoors than with the values obtained from datasheets. This paper presents a device specifically implemented to measure outdoors the power of modules at standard test conditions, as well as their efficiency variation with irradiance and their temperature coefficients. Results of measurements with this device are also reported

Brain innate immunity in the regulation of neuroinflammation: therapeutic strategies by modulating cd200-cd200r interaction involve the cannabinoid system

The central nervous system (CNS) innate immune response includes an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons that is involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the CNS are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) and Alzheimer´s disease (AD) being primary examples. Hence, it is important to identify the key regulatory mechanisms involved in the control of CNS innate immunity and which could be harnessed to explore novel therapeutic avenues. Neuroimmune regulatory proteins (NIReg) such as CD95L, CD200, CD47, sialic acid, complement regulatory proteins (CD55, CD46, fH, C3a), HMGB1, may control the adverse immune responses in health and diseases. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury as well as an adverse inflammatory response in acute and chronic settings. We will herein provide new emphasis on the role of the pair CD200-CD200R in MS and its experimental models: experimental autoimmune encephalomyelitis (EAE) and Theiler?s virus induced demyelinating disease (TMEV-IDD). The interest of the cannabinoid system as inhibitor of inflammation prompt us to introduce our findings about the role of endocannabinoids (eCBs) in promoting CD200-CD200 receptor (CD200R) interaction and the benefits caused in TMEV-IDD. Finally, we also review the current data on CD200-CD200R interaction in AD, as well as, in the aging brain.Fil: Hernangómez, Miriam. Consejo Superior de Investigaciones Cientificas; EspañaFil: Carrillo Salinas, Francisco. Consejo Superior de Investigaciones Cientificas; EspañaFil: Mecha, Miriam. Consejo Superior de Investigaciones Cientificas; EspañaFil: Correa, Fernando Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina; ArgentinaFil: Mestre, Leyre. Consejo Superior de Investigaciones Cientificas; EspañaFil: Loría, Frida. Consejo Superior de Investigaciones Cientificas; EspañaFil: Feliú, Ana. Consejo Superior de Investigaciones Cientificas; EspañaFil: Docagne, Fabian. Inserm; FranciaFil: Guaza, Carmen. Consejo Superior de Investigaciones Cientificas; Españ

A Cannabigerol Derivative Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis

Phytocannabinoids that do not produce psychotropic effects are considered of special interest as novel therapeutic agents in CNS diseases. A cannabigerol quinone, the compound VCE-003, has been shown to alleviate symptoms in a viral model of multiple sclerosis (MS). Hence, we studied T cells and macrophages as targets for VCE-003 and its efficacy in an autoimmune model of MS. Proliferation, cell cycle, expression of activation markers was assessed by FACs in human primary T cells, and cytokine and chemokine production was evaluated. Transcription was studied in Jurkat cells and RAW264.7 cells were used to study the effects of VCE-003 on IL-17-induced macrophage polarization to a M1 phenotype. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG35–55) immunization and spinal cord pathology was assessed by immunohistochemistry. Neurological impairment was evaluated using disease scores. We show here that VCE-003 inhibits CD3/CD28-induced proliferation, cell cycle progression and the expression of the IL-2Rα and ICAM-1 activation markers in human primary T cells. VCE-003 inhibits the secretion of Th1/Th17 cytokines and chemokines in primary murine T cells, and it reduces the transcriptional activity of the IL-2, IL-17 and TNFα promoters induced by CD3/CD28. In addition, VCE-003 and JWH-133, a selective CB2 agonist, dampened the IL-17-induced polarization of macrophages to a pro-inflammatory M1 profile. VCE-003 also prevented LPS-induced iNOS expression in microglia. VCE-003 ameliorates the neurological defects and the severity of MOG-induced EAE in mice through CB2 and PPARγ receptor activation. A reduction in cell infiltrates, mainly CD4+ T cells, was observed, and Th1 and Th17 responses were inhibited in the spinal cord of VCE-003-treated mice, accompanied by weaker microglial activation, structural preservation of myelin sheets and reduced axonal damage. This study highlights the therapeutic potential of VCE-003 as an agent for the treatment of human immune diseases with both inflammatory and autoimmune components

How oral probiotics affect the severity of an experimental model of progressive multiple sclerosis? Bringing commensal bacteria into the neurodegenerative process

A growing number of studies support that the bidirectional interactions between the gut microbiota, the immune system and the CNS are relevant for the pathophysiology of MS. Several studies have reported alterations in the gut microbiome of MS patients. In addition, a variety of studies in animal models of MS have suggested that specific members of the gut commensal microbiota can exacerbate or ameliorate neuroinflammation. Probiotics represent oral nontoxic immunomodulatory agents that would exert benefits when using in combination with current MS therapy. Here we investigate the effect of Vivomixx on the gut microbiome and central and peripheral immune responses in a murine model of primary progressive MS. Vivomixx administration was associated with increased abundance of many taxa such as Bacteroidetes, Actinobacteria, Tenericutes and TM7. This was accompanied by a clear improvement of the motor disability of Theiler's virus infected mice; in the CNS Vivomixx reduced microgliosis, astrogliosis and leukocyte infiltration. Notably, the presence of Breg cells (CD19 + CD5 + CD1d high) in the CNS was enhanced by Vivomixx, and while spinal cord gene expression of IL-1β and IL-6 was diminished, the probiotic promoted IL-10 gene expression. One of the most significant findings was the increased plasma levels of butyrate and acetate levels in TMEV-mice that received Vivomixx. Peripheral immunological changes were subtle but interestingly, the probiotic restricted IL-17 production by Th17-polarized CD4 + T-cells purified from the mesenteric lymph nodes of Theiler's virus infected mice. Our data reinforce the beneficial effects of oral probiotics that would be coadjuvant treatments to current MS therapies

Chromenopyrazole, a Versatile Cannabinoid Scaffold with in Vivo Activity in a Model of Multiple Sclerosis

A combination of molecular modeling and structure activity relationship studies has been used to fine-tune CB2 selectivity in the chromenopyrazole ring, a versatile CB1/CB2 cannabinoid scaffold. Thus, a series of 36 new derivatives covering a wide range of structural diversity has been synthesized, and docking studies have been performed for some of them. Biological evaluation of the new compounds includes, among others, cannabinoid binding assays, functional studies, and surface plasmon resonance measurements. The most promising compound [43 (PM226)], a selective and potent CB2 agonist isoxazole derivative, was tested in the acute phase of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a well established animal model of primary progressive multiple sclerosis. Compound 43 dampened neuroinflammation by reducing microglial activation in the TMEV

Rationale and design of the Concordance study between FFR and iFR for the assessment of lesions in the left main coronary artery. The ILITRO-EPIC-07 Trial

Introduction and objectives: Patients with left main coronary artery (LMCA) stenosis have been excluded from the trials that support the non-inferiority of the instantaneous wave-free ratio (iFR) compared to the fractional flow reserve (FFR) in the decision-making process of coronary revascularization. This study proposes to prospectively assess the concordance between the two indices in LMCA lesions and to validate the iFR cut-off value of 0.89 for clinical use. Methods: National, prospective, and observational multicenter registry of 300 consecutive patients with intermediate lesions in the LMCA (angiographic stenosis, 25% to 60%. A pressure gudiewire study and determination of the RFF and the iFR will be performed: in the event of a negative concordant result (FFR > 0.80/iFR > 0.89), no treatment will be performed; in case of a positive concordant result (FFR 0.80/iFR 0.89), an intravascular echocardiography will be performed and revascularization will be delayed if the minimum lumen area is > 6 mm(2). The primary clinical endpoint will be a composite of cardiovascular death, LMCA lesion-related non-fatal infarction or need for revascularization of the LMCA lesion at 12 months. Conclusions: Confirm that an iFR-guided decision-making process in patients with intermediate LMCA stenosis is clinically safe and would have a significant clinical impact. Also, justify its systematic use when prescribing treatment in these potentially high-risk patients

World-Wide FINGERS Network: A global approach to risk reduction and prevention of dementia

© 2020 The Authors. Alzheimer\u27s & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer\u27s Association Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late-onset dementia, including Alzheimer\u27s disease (AD), indicates a potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World-Wide FINGERS (WW-FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW-FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at-risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW-FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies