title: Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity.
abstract: Cannabinoid-derived drugs are promising agents for the development of novel neuroprotective strategies. Activation of neuronal CB(1) 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 CB(1) receptors in striatal neurons that, together with the undesirable psychoactive effects triggered by CB(1) receptor activation, foster the search for alternative pharmacological treatments. Here, we show that CB(2) cannabinoid receptor expression increases in striatal microglia of Huntington's disease transgenic mouse models and patients. Genetic ablation of CB(2) 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 CB(2) receptor-deficient mice by quinolinic acid administration exacerbated brain oedema, microglial activation, proinflammatory-mediator state and medium-sized spiny neuron degeneration. Moreover, administration of CB(2) 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 CB(2) receptor-mediated actions. These findings support a pivotal role for CB(2) 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.
authors.affiliation: Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Palazuelos
authors.forename: Tania
authors.initials: T
authors.lastname: Aguado
authors.forename: M Ruth
authors.initials: MR
authors.lastname: Pazos
authors.forename: Boris
authors.initials: B
authors.lastname: Julien
authors.forename: Carolina
authors.initials: C
authors.lastname: Carrasco
authors.forename: Eva
authors.initials: E
authors.lastname: Resel
authors.forename: Onintza
authors.initials: O
authors.lastname: Sagredo
authors.forename: Cristina
authors.initials: C
authors.lastname: Benito
authors.forename: Julián
authors.initials: J
authors.lastname: Romero
authors.forename: Iñigo
authors.initials: I
authors.lastname: Azcoitia
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.forename: Manuel
authors.initials: M
authors.lastname: Guzmán
authors.forename: Ismael
authors.initials: I
authors.lastname: Galve-Roperh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology; D009410:Nerve Degeneration / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017378:Quinolinic Acid / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D045442:Rotarod Performance Test; D012640:Seizures / Q000503:physiopathology
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D043885:Receptor, Cannabinoid, CB2; D017378:Quinolinic Acid; D008911:Minocycline