We have investigated whether a 1:1 combination 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, is neuroprotective in
Huntington's disease (HD), using an experimental model of this disease generated by unilateral lesions of the striatum with the mitochondrial complex II inhibitor
malonate. This toxin damages striatal neurons by mechanisms that primarily involve apoptosis and microglial activation. We monitored the extent of this damage and the possible preservation of the striatal parenchyma by treatment with a
Sativex-like combination of phytocannabinoids using different histological and
biochemical markers. Results were as follows: (i)
malonate increased the volume of
edema measured by in vivo NMR imaging and the
Sativex-like combination of phytocannabinoids partially reduced this increase; (ii)
malonate reduced the number of Nissl-stained cells, while enhancing the number of degenerating cells stained with FluoroJade-B, and the
Sativex-like combination of phytocannabinoids reversed both effects; (iii)
malonate caused a strong glial activation (i.e., reactive microglia labeled with Iba-1, and
astrogliosis labeled with GFAP) and the
Sativex-like combination of phytocannabinoids attenuated both responses; and (iv)
malonate increased the expression of
inducible nitric oxide synthase and the
neurotrophin IGF-1, and both responses were attenuated after the treatment with the
Sativex-like combination of phytocannabinoids. We also wanted to establish whether targets within the
endocannabinoid system (i.e., CB(1) and CB(2) receptors) are involved in the beneficial effects induced in this model by the
Sativex-like combination of phytocannabinoids. This we did using selective antagonists for both receptor types (i.e.,
SR141716 and
AM630) combined with the
Sativex-like phytocannabinoid combination. Our results indicated that the effects of this combination are blocked by these antagonists and hence that they do result from an activation of both CB(1) and CB(2) receptors. In summary, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine
Sativex as a
neuroprotective agent capable of delaying signs of
disease progression in a proinflammatory model of HD, which adds to previous data obtained in models priming oxidative mechanisms of striatal injury. However, the interest here is that, in contrast with these previous data, we have now obtained evidence that both CB(1) and CB(2) receptors appear to be involved in the effects produced by a
Sativex-like phytocannabinoid combination, thus stressing the broad-spectrum properties of
Sativex that may combine activity at the CB(1) and/or CB(2) receptors with
cannabinoid receptor-independent actions.