title: Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington's disease: role of CB1 and CB2 receptors.
abstract: 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.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Centro deInvestigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), and Instituto Ramón y Cajal deInvestigación Sanitaria (IRYCIS), Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Valdeolivas
authors.forename: Valentina
authors.initials: V
authors.lastname: Satta
authors.forename: Roger G
authors.initials: RG
authors.lastname: Pertwee
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.forename: Onintza
authors.initials: O
authors.lastname: Sagredo
mesh_terms: D000818:Animals; D002185:Cannabidiol; D002186:Cannabinoids / Q000008:administration & dosage; D004195:Disease Models, Animal; D013759:Dronabinol; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008314:Malonates / Q000633:toxicity*; D008517:Phytotherapy / Q000379:methods; D010936:Plant Extracts / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000502:physiology*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000502:physiology*
chemical_list: D002186:Cannabinoids; D004338:Drug Combinations; D008314:Malonates; D010936:Plant Extracts; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D002185:Cannabidiol; D013759:Dronabinol; C030290:malonic acid; C587251:nabiximols