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Brain Advance Access originally published online on October 5, 2009
Brain 2009 132(11):3152-3164; doi:10.1093/brain/awp239
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© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Javier Palazuelos1,2, Tania Aguado1,2, M. Ruth Pazos1,3, Boris Julien1,2, Carolina Carrasco1,2, Eva Resel1,2, Onintza Sagredo1,3, Cristina Benito1,4, Julián Romero1,4, Iñigo Azcoitia5, Javier Fernández-Ruiz1,3, Manuel Guzmán1,2 and Ismael Galve-Roperh1,2

1 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain 2 Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain 3 Department of Biochemistry and Molecular Biology III, School of Medicine, Complutense University, 28040 Madrid, Spain 4 Laboratorio de Apoyo a la Investigación, Hospital Universitario Fundación Alcorcón, 28922 Madrid, Spain 5 Department of Cell Biology, School of Biology, Complutense University, 28040 Madrid, Spain

Correspondence to: Ismael Galve-Roperh, Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain E-mail: igr{at}quim.ucm.es Correspondence may also be addressed to: Manuel Guzmán, Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain E-mail: mgp{at}bbm1.ucm.es

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.

Key Words: cannabinoid; microglia; Huntington's disease; excitotoxicity; neurodegeneration

Abbreviations: BrdU, 5-bromo-2'-deoxyuridine; DARPP32, dopamine- and cyclic AMP-regulated phosphoprotein; ECB, endocannabinoid; GFAP, glial fibrillary acidic protein; iNOS, inducible nitric oxide synthase; MRI, magnetic resonance imaging; PBS, phosphate buffered saline; WT, wild-type

Received March 27, 2009. Revised July 28, 2009. Accepted August 3, 2009.


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