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Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's disease

Authors

  • Onintza Sagredo,

    1. Departamento de Bioquímica y Biología Molecular and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain
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    • Onintza Sagredo, Sara González, and Ilia Aroyo contributed equally to this study.

  • Sara González,

    1. Departamento de Bioquímica y Biología Molecular and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain
    Current affiliation:
    1. Department of Neurology, Albert Einstein College of Medicine, Rose F. Kennedy Center, 1410 Pelham Pkwy S, Rm 401, Bronx, New York 10461, USA
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  • Ilia Aroyo,

    1. Departamento de Bioquímica y Biología Molecular and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain
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    • Onintza Sagredo, Sara González, and Ilia Aroyo contributed equally to this study.

  • María Ruth Pazos,

    1. Departamento de Bioquímica y Biología Molecular and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain
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  • Cristina Benito,

    1. Laboratorio de Investigación and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Fundación Hospital Alcorcón, 28922 Madrid, Spain
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  • Isabel Lastres-Becker,

    1. Departamento de Bioquímica y Biología Molecular and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain
    Current affiliation:
    1. Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Departamento de Bioquímica, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
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  • Juan P. Romero,

    1. Laboratorio de Investigación and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Fundación Hospital Alcorcón, 28922 Madrid, Spain
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  • Rosa M. Tolón,

    1. Laboratorio de Investigación and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Fundación Hospital Alcorcón, 28922 Madrid, Spain
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  • Raphael Mechoulam,

    1. Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University, Jerusalem 91120, Israel
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  • Emmanuel Brouillet,

    1. Neuronal Death Group, URA CEA-CNRS 2210, Service Hospitalier Frédéric Joliot, DRM, DSV, CEA, 91401 Orsay Cedex, France
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  • Julián Romero,

    1. Laboratorio de Investigación and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Fundación Hospital Alcorcón, 28922 Madrid, Spain
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  • Javier Fernández-Ruiz

    Corresponding author
    1. Departamento de Bioquímica y Biología Molecular and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain
    • Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University, 28040 Madrid, Spain
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Abstract

Cannabinoid agonists might serve as neuroprotective agents in neurodegenerative disorders. Here, we examined this hypothesis in a rat model of Huntington's disease (HD) generated by intrastriatal injection of the mitochondrial complex II inhibitor malonate. Our results showed that only compounds able to activate CB2 receptors were capable of protecting striatal projection neurons from malonate-induced death. That CB2 receptor agonists are neuroprotective was confirmed by using the selective CB2 receptor antagonist, SR144528, and by the observation that mice deficient in CB2 receptor were more sensitive to malonate than wild-type animals. CB2 receptors are scarce in the striatum in healthy conditions, but they are markedly upregulated after the lesion with malonate. Studies of double immunostaining revealed a significant presence of CB2 receptors in cells labeled with the marker of reactive microglia OX-42, and also in cells labeled with GFAP (a marker of astrocytes). We further showed that the activation of CB2 receptors significantly reduced the levels of tumor necrosis factor-α (TNF-α) that had been increased by the lesion with malonate. In summary, our results demonstrate that stimulation of CB2 receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB2 receptors would be upregulated in response to the lesion. Activation of these receptors would reduce the generation of proinflammatory molecules like TNF-α. Altogether, our results support the hypothesis that CB2 receptors could constitute a therapeutic target to slowdown neurodegeneration in HD. © 2008 Wiley-Liss, Inc.

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