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

• Published in: Brain (London, England : 1878) Vol. 132; no. 11; pp. 3152 - 3164
• Main Authors: Palazuelos, Javier, Aguado, Tania, Pazos, M. Ruth, Julien, Boris, Carrasco, Carolina, Resel, Eva, Sagredo, Onintza, Benito, Cristina, Romero, Julián, Azcoitia, Iñigo, Fernández-Ruiz, Javier, Guzmán, Manuel, Galve-Roperh, Ismael
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2009
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Biological and medical sciences; Biomarkers - metabolism; cannabinoid; Corpus Striatum - cytology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; excitotoxicity; Humans; Huntingtin Protein; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington Disease - physiopathology; Huntington's disease; Magnetic Resonance Imaging; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; microglia; Microglia - metabolism; Minocycline - pharmacology; Nerve Degeneration - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; neurodegeneration; Neurology; Neuroprotective Agents - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Quinolinic Acid - pharmacology; Receptor, Cannabinoid, CB2 - genetics; Receptor, Cannabinoid, CB2 - metabolism; Rotarod Performance Test; Seizures - physiopathology; neurodegeneration; Huntington's disease; excitotoxicity; microglia; cannabinoid; Nervous system diseases; Toxicity; Excitotoxicity; Central nervous system disease; Huntington disease; Degenerative disease; CB2 cannabinoid receptor; Genetic disease; Cerebral disorder; Extrapyramidal syndrome
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awp239

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.