title: VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington's disease.
abstract: Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARγ. We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPARγ. We have now generated a non-thiophilic VCE-003 derivative named VCE-003.2 that preserves the ability to activate PPARγ and analyzed its neuroprotective activity. This compound exerted a prosurvival action in progenitor cells during neuronal differentiation, which was prevented by a PPARγ antagonist, without affecting neural progenitor cell proliferation. In addition, VCE-003.2 attenuated quinolinic acid (QA)-induced cell death and caspase-3 activation and also reduced mutant huntingtin aggregates in striatal cells. The neuroprotective profile of VCE-003.2 was analyzed using in vivo models of striatal neurodegeneration induced by QA and 3-nitropropionic acid (3NP) administration. VCE-003.2 prevented medium spiny DARPP32(+) neuronal loss in these Huntington's-like disease mice models improving motor deficits, reactive astrogliosis and microglial activation. In the 3NP model VCE-003.2 inhibited the upregulation of proinflammatory markers and improved antioxidant defenses in the brain. These data lead us to consider VCE-003.2 to have high potential for the treatment of Huntington's disease (HD) and other neurodegenerative diseases with neuroinflammatory traits.
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra, Colmenar Viejo, km. 9100, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular I, Universidad Complutense, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Díaz-Alonso
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra, Colmenar Viejo, km. 9100, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular I, Universidad Complutense, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Paraíso-Luna
authors.affiliation: VivaCell Biotechnology España, Córdoba, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Navarrete
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Del Río
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Cantarero
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Palomares
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra, Colmenar Viejo, km. 9100, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular I, Universidad Complutense, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Aguareles
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra, Colmenar Viejo, km. 9100, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.|Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular III, Universidad Complutense, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.affiliation: VivaCell Biotechnology España, Córdoba, Spain.
authors.forename: María Luz
authors.initials: ML
authors.lastname: Bellido
authors.affiliation: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Pollastro
authors.affiliation: Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Spain.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.affiliation: Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ctra, Colmenar Viejo, km. 9100, Madrid, Spain.|Departamento de Bioquímica y Biología Molecular I, Universidad Complutense, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: Galve-Roperh
authors.affiliation: Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006816:Huntington Disease / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology*; D051381:Rats
chemical_list: D002186:Cannabinoids; D018696:Neuroprotective Agents; D011809:Quinones; C581223:VCE-003; C037036:cannabigerol