Neuroprotective effects of phytocannabinoid‐based medicines in experimental models of Huntington's disease

Abstract

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.

Sativex-like Combination of Phytocannabinoids is Neuroprotective in Malonate-Lesioned Rats, an Inflammatory Model of Huntington’s Disease: Role of CB1 and CB2 Receptors

“…However, it is important to note that, although SR141716 and AM630, both separately and together, reversed the effects of the Sativex-like combination of Δ 9 -THC-and CBD-enriched botanical extracts, the lowest number of Nissl-stained cells was observed after the treatment with AM630, administered alone or in combination with SR141716. This finding, together with our previously published data showing that CB 2 receptors underwent an upregulation in glial elements located in the striatal parenchyma after malonate, 10 whereas CB 1 receptors underwent a downregulation in the same animal model in the present study (see Figure 4) and also in other models of HD, 8,16 suggests that even though Δ 9 -THC can activate both CB 1 and CB 2 receptors, the CB 2 receptor plays a greater role than the CB 1 receptor in the protection from malonate-induced striatal damage that the Δ 9 -THC-and CBD-enriched botanical extracts produce. …”

“…In a similar way, the Sativex-like combination of phytocannabinoids attenuated the activation of glial elements caused by malonate (i.e., reactive microglia labeled with Iba-1, and astrogliosis labeled with GFAP; see Figure 3), which was particularly abundant and generalized along the whole striatal parenchyma in this experimental model. Lastly, the Sativex-like combination of phytocannabinoids attenuated the malonate-induced up-regulatory responses in iNOS (already described in ref 16) and IGF-1 gene expression in the striatal parenchyma (see Figure 4), whereas it partially recovered the malonate-induced reduction in CB 1 receptors (see Figure 4). These findings support the notion that the combination of both phytocannabinoid-botanical extracts may be effective as a neuroprotective therapy in malonate-lesioned rats as it was previously found when individual cannabinoid agonists (i.e., HU-308) were used in the same HD model.…”

“…Moreover, our previous data showing that, in this proinflammatory model of HD, CB 2 receptors were up-regulated 10 whereas CB 1 receptors were down-regulated (also demonstrated here), as well as our observation that the protective effect of the Sativex-like combination of Δ 9 -THC-and CBDenriched botanical extracts could be blocked by the selective CB 2 receptor antagonist AM630, suggest that CB 2 receptors play a particularly important role in this protective effect, a hypothesis that is also in concordance with the previous literature (see ref 26 for review). Lastly, given that HD is a disorder that is currently poorly managed in the clinic, the present data obtained with malonate-lesioned rats, together with previously published data obtained using an oxidative model of HD, 16 provide a strong justification for mounting clinical trials with cannabinoids that produce positive effects in these preclinical models of HD.…”

“…The Sativex-like combination of phytocannabinoids also protected striatal neurons from death caused by 3NP intoxication and its effects were, as expected, independent of CB 1 and CB 2 receptors. 16 In this Article, 16 we already presented preliminary evidence that the Sativex-like combination of phytocannabinoids might also work in additional models of HD, as it was capable to attenuate malonate-induced iNOS up-regulation in rats lesioned with this neurotoxin, but this was the only parameter analyzed in these rats. 16 The goal of the present study was to corroborate the potential of Sativex-like combination of phytocannabinoids in this model of HD, in which striatal damage is primarily produced by apoptosis and glial activation/inflammatory events, 10 by measuring different histopathological and biochemical parameters that have been more directly related to striatal degeneration in this HD model.…”

“…8−11 This was also the effective dose in our previous study with Sativex-like combination of phytocannabinoids in another HD model. 16 Cannabinoids were prepared in Tween 80-saline solution (1:16) and they were administered i.p. Malonate-lesioned rats administered with vehicle, as well as sham-operated animals, were also included in this experiment.…”