Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity

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dc.contributor.authorPalazuelos Diego, Javier
dc.contributor.authorAguado Sánchez, Tania
dc.contributor.authorPazos, Ruth
dc.contributor.authorJulien, Boris
dc.contributor.authorCarrasco, Carolina
dc.contributor.authorResel, Eva
dc.contributor.authorSagredo Ezquioga, Onintza
dc.contributor.authorBenito, Cristina
dc.contributor.authorRomero, Julián
dc.contributor.authorAzcoitia Elías, Íñigo
dc.contributor.authorFernández Ruiz, José Javier
dc.contributor.authorGuzmán Pastor, Manuel
dc.contributor.authorGalve Roperh, Ismael
dc.date.accessioned2023-12-20T13:54:46Z
dc.date.available2023-12-20T13:54:46Z
dc.date.issued2009
dc.description.abstractCannabinoid-derived drugs are promising agents for the development of novel neuroprotective strategies. Activation of neuronal CB1 cannabinoid receptors attenuates excitotoxic glutamatergic neurotransmission, triggers prosurvival signalling pathways and palliates motor symptoms in animal models of neurodegenerative disorders. However, in Huntington's disease there is a very early downregulation of CB1 receptors in striatal neurons that, together with the undesirable psychoactive effects triggered by CB1 receptor activation, foster the search for alternative pharmacological treatments. Here, we show that CB2 cannabinoid receptor expression increases in striatal microglia of Huntington's disease transgenic mouse models and patients. Genetic ablation of CB2 receptors in R6/2 mice, that express human mutant huntingtin exon 1, enhanced microglial activation, aggravated disease symptomatology and reduced mice lifespan. Likewise, induction of striatal excitotoxicity in CB2 receptor-deficient mice by quinolinic acid administration exacerbated brain oedema, microglial activation, proinflammatory-mediator state and medium-sized spiny neuron degeneration. Moreover, administration of CB2 receptor-selective agonists to wild-type mice subjected to excitotoxicity reduced neuroinflammation, brain oedema, striatal neuronal loss and motor symptoms. Studies on ganciclovir-induced depletion of astroglial proliferation in transgenic mice expressing thymidine kinase under the control of the glial fibrillary acidic protein promoter excluded the participation of proliferating astroglia in CB2 receptor-mediated actions. These findings support a pivotal role for CB2 receptors in attenuating microglial activation and preventing neurodegeneration that may pave the way to new therapeutic strategies for neuroprotection in Huntington's disease as well as in other neurodegenerative disorders with a significant excitotoxic component.en
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Ciencias Biológicas
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Ciencia, Innovación y Universidades (España)
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipMedical Research Foundation (Francia)
dc.description.sponsorshipUniversidad Complutense de Madrid
dc.description.statuspub
dc.identifier.citationJavier Palazuelos, Tania Aguado, M. Ruth Pazos, Boris Julien, Carolina Carrasco, Eva Resel, Onintza Sagredo, Cristina Benito, Julián Romero, Iñigo Azcoitia, Javier Fernández-Ruiz, Manuel Guzmán, Ismael Galve-Roperh, Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity, Brain, Volume 132, Issue 11, November 2009, Pages 3152–3164,
dc.identifier.doi10.1093/brain/awp239
dc.identifier.essn1460-2156
dc.identifier.issn0006-8950
dc.identifier.officialurlhttps://doi.org/10.1093/brain/awp239
dc.identifier.urihttps://hdl.handle.net/20.500.14352/91606
dc.issue.number11
dc.journal.titleBrain
dc.language.isoeng
dc.page.final3164
dc.page.initial3152
dc.publisherOxford University Press
dc.relation.projectID(SAF2009-08403, SAF2009-11847 , SAF2007-61565)
dc.relation.projectID(S-SAL-2006/261 , 950344)
dc.rights.accessRightsrestricted access
dc.subject.cdu577.1
dc.subject.cdu577.2
dc.subject.cdu616.8
dc.subject.keywordCannabinoid
dc.subject.keywordMicroglia
dc.subject.keywordHuntington's disease
dc.subject.keywordExcitotoxicity
dc.subject.keywordNeurodegeneration
dc.subject.ucmBiología molecular (Biología)
dc.subject.ucmBioquímica (Biología)
dc.subject.ucmNeurociencias (Medicina)
dc.subject.unesco2403 Bioquímica
dc.subject.unesco2415 Biología Molecular
dc.subject.unesco2490 Neurociencias
dc.titleMicroglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicityen
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number132
dspace.entity.typePublication
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