Neuroprotective Properties of Cannabigerol in Huntington’s Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice

Abstract

Different plant-derived and synthetic cannabinoids have shown to be neuroprotective in experimental models of Huntington’s disease (HD) through cannabinoid receptor-dependent and/or independent mechanisms. Herein, we studied the effects of cannabigerol (CBG), a nonpsychotropic phytocannabinoid, in 2 different in vivo models of HD. CBG was extremely active as neuroprotectant in mice intoxicated with 3-nitropropionate (3NP), improving motor deficits and preserving striatal neurons against 3NP toxicity. In addition, CBG attenuated the reactive microgliosis and the upregulation of proinflammatory markers induced by 3NP, and improved the levels of antioxidant defenses that were also significantly reduced by 3NP. We also investigated the neuroprotective properties of CBG in R6/2 mice. Treatment with this phytocannabinoid produced a much lower, but significant, recovery in the deteriorated rotarod performance typical of R6/2 mice. Using HD array analysis, we were able to identify a series of genes linked to this disease (e.g., symplekin, Sin3a, Rcor1, histone deacetylase 2, huntingtin-associated protein 1, δ subunit of the gamma-aminobutyric acid-A receptor (GABA-A), and hippocalcin), whose expression was altered in R6/2 mice but partially normalized by CBG treatment. We also observed a modest improvement in the gene expression for brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and peroxisome proliferator-activated receptor-γ (PPARγ), which is altered in these mice, as well as a small, but significant, reduction in the aggregation of mutant huntingtin in the striatal parenchyma in CBG-treated animals. In conclusion, our results open new research avenues for the use of CBG, alone or in combination with other phytocannabinoids or therapies, for the treatment of neurodegenerative diseases such as HD.

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Acknowledgments

This work was supported by grants from CIBERNED (CB06/05/0089), MICINN (SAF2009/11847), and CAM (S2011/BMD-2308) to O.S. and S.V., and from MICINN (SAF2010/19292) and MINECO (IPT-2011-0861-900000) to E.M. These agencies had no further role in study design, the collection, analysis and interpretation of data, in the writing of the report, nor in the decision to submit the paper for publication. S.V. was supported by the Complutense University-Predoctoral Program. We are indebted to Yolanda García-Movellán for administrative assistance.

Conflict of interest

C.N. and M.L.B. are employees of VivaCell Biotechnology Spain and they were supported by MINECO IPT-2011-0861-900000 and FEDER-INTERCONNECTA ITC-20111029 grants to VivaCell Biotechnology.

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Correspondence to Eduardo Muñoz or Onintza Sagredo.

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S. Valdeolivas and C. Navarrete share first authorship.

E. Muñoz and O. Sagredo share senior authorship of this study.

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Valdeolivas, S., Navarrete, C., Cantarero, I. et al. Neuroprotective Properties of Cannabigerol in Huntington’s Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice. Neurotherapeutics 12, 185–199 (2015). https://doi.org/10.1007/s13311-014-0304-z

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Key Words

  • Phytocannabinoids
  • cannabigerol
  • Huntington’s disease
  • inflammation
  • neuroprotection