We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-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 Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in
malonate-lesioned rats. The administration of Δ(9)-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 CB(1) 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 Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the
antioxidant and CB(1) and CB(2) 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 Δ(9)-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.