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 receptordependent 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), insulinlike growth factor-1 (IGF-1), and peroxisome proliferatoractivated 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 CBGtreated 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.

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…CBD was very active in animal models characterized by mitochondrial damage, oxidative stress and calpain activation, such as rats intoxicated with the complex II inhibitor 3-nitropropionate [136], yet it was inactive in proinflammatory models like malonate-lesioned rats [134]. CBG was neuroprotective in 3-nitropropionate-lesioned and R6/2 mice [137]. Based on these beneficial effects, CBD combined with Δ 9 -THC, as in the cannabinoid-based medicine Sativex (GWPharma), has also been studied in animal models of HD given the wide spectrum of pharmacological actions produced by this combination.…”

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…In CBGtreated animals, an increase in the gene expression for brain-derived neurotrophic factor (BDNF), insulin-like growth factor I (IGF-I), and PPAR␥, and a small reduction in the aggregation of mutant huntingtin, were observed, thus opening the possibility of it being used for the treatment of HD (863).…”

The bright side of psychoactive substances: cannabinoid-based drugs in motor diseases

“…On a final note, also the beneficial effect of the phytocannabinoids Δ properties have been supposed to be responsible of their beneficial action [79,80]. Controversial results were obtained by using phytocannabinoids [68,73,81], and improvements of hyperkinesia and behavioral alterations have been reported in clinical trials with nabilone [82]. Unfortunately, a recent phase II clinical trial with Sativex® was unsuccessful [83] probably due to short treatment period and low dose administered.…”

“…Unfortunately, a recent phase II clinical trial with Sativex® was unsuccessful [83] probably due to short treatment period and low dose administered. More recently, cannabigerol (CBG), another phytocannabinoid with non-psychotropic profile, was investigated in both R6/2 and 3NP-lesioned mice models of HD [81]. CBG preserved striatal neurons death as well as neurological deterioration and improved motor deficits, although these effects were much more evident in 3NP-lesioned mice than in R6/2 mice.…”

“…CBG preserved striatal neurons death as well as neurological deterioration and improved motor deficits, although these effects were much more evident in 3NP-lesioned mice than in R6/2 mice. Since CBG exhibited poor affinity for CB 1 and/or CB 2 receptors, the mechanisms responsible for the beneficial effects of CBG in HD await to be better investigated [81].…”