Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease

Authors

  • Onintza Sagredo,

    1. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain
    2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universidad Complutense, Madrid, Spain
    3. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Facultad de Medicina, Universidad Complutense, Madrid, Spain
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    • O. Sagredo and M.R. Pazos contributed equally to this work.

  • M. Ruth Pazos,

    1. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain
    2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universidad Complutense, Madrid, Spain
    3. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Facultad de Medicina, Universidad Complutense, Madrid, Spain
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    • O. Sagredo and M.R. Pazos contributed equally to this work.

  • Valentina Satta,

    1. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain
    2. Department of Neuroscience, University of Cagliari, Cagliari, Italy
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  • José A. Ramos,

    1. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense, Madrid, Spain
    2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universidad Complutense, Madrid, Spain
    3. Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Facultad de Medicina, Universidad Complutense, Madrid, Spain
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  • Roger G. Pertwee,

    1. School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
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  • Javier Fernández-Ruiz

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

We studied whether combinations of botanical extracts enriched in either Δ9-tetrahydrocannabinol (Δ9-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington's disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ9-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ9-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB1 receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ9-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB1 and CB2 receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ9-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies. © 2011 Wiley-Liss, Inc.

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