Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity
Identifieur interne : 003819 ( Main/Exploration ); précédent : 003818; suivant : 003820Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity
Auteurs : Javier Palazuelos [Espagne] ; Tania Aguado [Espagne] ; M. Ruth Pazos [Espagne] ; Boris Julien [Espagne] ; Carolina Carrasco [Espagne] ; Eva Resel [Espagne] ; Onintza Sagredo [Espagne] ; Cristina Benito [Espagne] ; Julián Romero [Espagne] ; I Igo Azcoitia [Espagne] ; Javier Fernández-Ruiz [Espagne] ; Manuel Guzmán [Espagne] ; Ismael Galve-Roperh [Espagne]Source :
- Brain [ 0006-8950 ] ; 2009-11.
Abstract
Cannabinoid-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.
Url:
DOI: 10.1093/brain/awp239
Affiliations:
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xml:lang="fr">Espagne</country><wicri:regionArea>3 Department of Biochemistry and Molecular Biology III, School of Medicine, Complutense University, 28040 Madrid</wicri:regionArea><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Benito, Cristina" sort="Benito, Cristina" uniqKey="Benito C" first="Cristina" last="Benito">Cristina Benito</name><affiliation wicri:level="1"><country xml:lang="fr">Espagne</country><wicri:regionArea>1 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)</wicri:regionArea></affiliation><affiliation wicri:level="2"><country xml:lang="fr">Espagne</country><wicri:regionArea>4 Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, 28922 Madrid</wicri:regionArea><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Romero, Julian" sort="Romero, Julian" uniqKey="Romero J" first="Julián" last="Romero">Julián Romero</name><affiliation wicri:level="1"><country xml:lang="fr">Espagne</country><wicri:regionArea>1 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)</wicri:regionArea></affiliation><affiliation wicri:level="2"><country xml:lang="fr">Espagne</country><wicri:regionArea>4 Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, 28922 Madrid</wicri:regionArea><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Azcoitia, I Igo" sort="Azcoitia, I Igo" uniqKey="Azcoitia I" first="I Igo" last="Azcoitia">I Igo Azcoitia</name><affiliation wicri:level="2"><country xml:lang="fr">Espagne</country><wicri:regionArea>5 Department of Cell Biology, School of Biology, Complutense University, 28040 Madrid</wicri:regionArea><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Fernandez Ruiz, Javier" sort="Fernandez Ruiz, Javier" uniqKey="Fernandez Ruiz J" first="Javier" last="Fernández-Ruiz">Javier Fernández-Ruiz</name><affiliation wicri:level="1"><country xml:lang="fr">Espagne</country><wicri:regionArea>1 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)</wicri:regionArea></affiliation><affiliation wicri:level="2"><country xml:lang="fr">Espagne</country><wicri:regionArea>3 Department of Biochemistry and Molecular Biology III, School of Medicine, Complutense University, 28040 Madrid</wicri:regionArea><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Guzman, Manuel" sort="Guzman, Manuel" uniqKey="Guzman M" first="Manuel" last="Guzmán">Manuel Guzmán</name><affiliation wicri:level="1"><country xml:lang="fr">Espagne</country><wicri:regionArea>1 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)</wicri:regionArea></affiliation><affiliation wicri:level="2"><country xml:lang="fr">Espagne</country><wicri:regionArea>2 Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid</wicri:regionArea><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Galve Roperh, Ismael" sort="Galve Roperh, Ismael" uniqKey="Galve Roperh I" first="Ismael" last="Galve-Roperh">Ismael Galve-Roperh</name><affiliation wicri:level="1"><country xml:lang="fr">Espagne</country><wicri:regionArea>1 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED)</wicri:regionArea></affiliation><affiliation wicri:level="2"><country xml:lang="fr">Espagne</country><wicri:regionArea>2 Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid</wicri:regionArea><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Espagne</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Brain</title><idno type="ISSN">0006-8950</idno><idno type="eISSN">1460-2156</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-11">2009-11</date><biblScope unit="volume">132</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="3152">3152</biblScope><biblScope unit="page" to="3164">3164</biblScope></imprint><idno type="ISSN">0006-8950</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0006-8950</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">Cannabinoid-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.</div></front></TEI><affiliations><list><country><li>Espagne</li></country><region><li>Communauté de Madrid</li></region></list><tree><country name="Espagne"><noRegion><name sortKey="Palazuelos, Javier" sort="Palazuelos, Javier" uniqKey="Palazuelos J" first="Javier" last="Palazuelos">Javier Palazuelos</name></noRegion><name sortKey="Aguado, Tania" sort="Aguado, Tania" uniqKey="Aguado T" first="Tania" last="Aguado">Tania Aguado</name><name sortKey="Aguado, Tania" sort="Aguado, Tania" uniqKey="Aguado T" first="Tania" last="Aguado">Tania Aguado</name><name sortKey="Azcoitia, I Igo" sort="Azcoitia, I Igo" uniqKey="Azcoitia I" first="I Igo" last="Azcoitia">I Igo Azcoitia</name><name sortKey="Benito, Cristina" sort="Benito, Cristina" uniqKey="Benito C" first="Cristina" last="Benito">Cristina Benito</name><name sortKey="Benito, Cristina" sort="Benito, Cristina" uniqKey="Benito C" first="Cristina" last="Benito">Cristina Benito</name><name sortKey="Carrasco, Carolina" sort="Carrasco, Carolina" uniqKey="Carrasco C" first="Carolina" last="Carrasco">Carolina Carrasco</name><name sortKey="Carrasco, Carolina" sort="Carrasco, Carolina" uniqKey="Carrasco C" first="Carolina" last="Carrasco">Carolina Carrasco</name><name sortKey="Fernandez Ruiz, Javier" sort="Fernandez Ruiz, Javier" uniqKey="Fernandez Ruiz J" first="Javier" last="Fernández-Ruiz">Javier Fernández-Ruiz</name><name sortKey="Fernandez Ruiz, Javier" sort="Fernandez Ruiz, Javier" uniqKey="Fernandez Ruiz J" first="Javier" last="Fernández-Ruiz">Javier Fernández-Ruiz</name><name sortKey="Galve Roperh, Ismael" sort="Galve Roperh, Ismael" uniqKey="Galve Roperh I" first="Ismael" last="Galve-Roperh">Ismael Galve-Roperh</name><name sortKey="Galve Roperh, Ismael" sort="Galve Roperh, Ismael" uniqKey="Galve Roperh I" first="Ismael" last="Galve-Roperh">Ismael Galve-Roperh</name><name sortKey="Galve Roperh, Ismael" sort="Galve Roperh, Ismael" uniqKey="Galve Roperh I" first="Ismael" last="Galve-Roperh">Ismael Galve-Roperh</name><name sortKey="Guzman, Manuel" sort="Guzman, Manuel" uniqKey="Guzman M" first="Manuel" last="Guzmán">Manuel Guzmán</name><name sortKey="Guzman, Manuel" sort="Guzman, Manuel" uniqKey="Guzman M" first="Manuel" last="Guzmán">Manuel Guzmán</name><name sortKey="Julien, Boris" sort="Julien, Boris" uniqKey="Julien B" first="Boris" last="Julien">Boris Julien</name><name sortKey="Julien, Boris" sort="Julien, Boris" uniqKey="Julien B" first="Boris" last="Julien">Boris Julien</name><name sortKey="Palazuelos, Javier" sort="Palazuelos, Javier" uniqKey="Palazuelos J" first="Javier" last="Palazuelos">Javier Palazuelos</name><name sortKey="Pazos, M Ruth" sort="Pazos, M Ruth" uniqKey="Pazos M" first="M. Ruth" last="Pazos">M. Ruth Pazos</name><name sortKey="Pazos, M Ruth" sort="Pazos, M Ruth" uniqKey="Pazos M" first="M. Ruth" last="Pazos">M. Ruth Pazos</name><name sortKey="Resel, Eva" sort="Resel, Eva" uniqKey="Resel E" first="Eva" last="Resel">Eva Resel</name><name sortKey="Resel, Eva" sort="Resel, Eva" uniqKey="Resel E" first="Eva" last="Resel">Eva Resel</name><name sortKey="Romero, Julian" sort="Romero, Julian" uniqKey="Romero J" first="Julián" last="Romero">Julián Romero</name><name sortKey="Romero, Julian" sort="Romero, Julian" uniqKey="Romero J" first="Julián" last="Romero">Julián Romero</name><name sortKey="Sagredo, Onintza" sort="Sagredo, Onintza" uniqKey="Sagredo O" first="Onintza" last="Sagredo">Onintza Sagredo</name><name sortKey="Sagredo, Onintza" sort="Sagredo, Onintza" uniqKey="Sagredo O" first="Onintza" last="Sagredo">Onintza Sagredo</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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