1. Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration
- Author
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Elena García-Taboada, Eduardo Muñoz, Carmen Navarrete, Raquel Bajo-Grañeras, José Aguareles, Juan Paraíso-Luna, Andrea Ruiz-Calvo, Manuel Guzmán, Daniel García-Rincón, Belén Palomares, Ismael Galve-Roperh, [Aguareles,J, Paraíso-Luna,J, Bajo-Grañeras,R, Ruiz-Calvo,A, García-Rincón,D, García-Taboada,E, Guzmán,M, Galve-Roperh,I] Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. [Aguareles,J, Galve-Roperh,I] Departamento de Bioquímica y Biología Molecular and Instituto Universitario de Investigación Neuroquímica, Universidad Complutense, Madrid, Spain. [Aguareles,J, Galve-Roperh,I] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Palomares,B, Muñoz,E] Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain. [Palomares,B, Muñoz,E] Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain. [Palomares,B, Muñoz,E] Hospital Universitario Reina Sofía, Córdoba, Spain. [Navarrete,C] Emerald Health Pharmaceuticals, San Diego, USA., This work was supported by the MINECO grant RTC-2015-3364 to EM and IGR cofounded by the European Development Regional Fund in the Framework of the Operative Program 'Reinforcement of research, technological development and innovation'. IGR was also supported by grant PI15–00310 and PI18–00941 cofinanced by the European Development Regional Fund 'A way to achieve Europe' and EM by the MINECO grant SAF2017–87701-R. JA and JPL were supported by FPI and FPU program fellowship (Ministerio de Educación, Cultura y Deporte) and DGR by Fundación Tatiana de Guzmán el Bueno. BP is a predoctoral fellow supported by the i-PFIS program, Instituto de Salud Carlos III (IFI15/00022, and European Social Fund 'Investing in your future').
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0301 basic medicine ,Neurogénesis ,Bioquímica ,Huntingtin ,Cannabigerol ,Peroxisome proliferator-activated receptors ,Cognitive Neuroscience ,Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Differentiation::Neurogenesis [Medical Subject Headings] ,Neurogenesis ,Subventricular zone ,Cardiología ,Medium spiny neuron ,Neuroprotection ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Receptors, Cytoplasmic and Nuclear::Peroxisome Proliferator-Activated Receptors [Medical Subject Headings] ,PPAR ,lcsh:RC346-429 ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neuroblast ,Diseases::Nervous System Diseases::Neurodegenerative Diseases [Medical Subject Headings] ,medicine ,Neurodegeneration ,Receptores activados del proliferador del peroxisoma ,Cannabinoid ,lcsh:Neurology. Diseases of the nervous system ,Chemistry ,Research ,Neurodegenerative diseases ,Proteína huntingtina ,medicine.disease ,Enfermedades neurodegenerativas ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Cannabinoides ,Neurology (clinical) ,030217 neurology & neurosurgery ,Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Terpenes::Cannabinoids [Medical Subject Headings] ,medicine.drug - Abstract
Background The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1 receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids. Methods We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro. Results Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis. Conclusions The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration. Electronic supplementary material The online version of this article (10.1186/s40035-019-0148-x) contains supplementary material, which is available to authorized users.
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- 2019