Cannabinoid CB2receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's disease

Publisher Website
Google Scholar
Abstract
Cannabinoid agonists might serve as neuroprotective agents in neurodegenerative disorders. Here, we examined this hypothesis in a rat model of Huntington's disease (HD) generated by intrastriatal injection of the mitochondrial complex II inhibitor malonate. Our results showed that only compounds able to activate CB2receptors were capable of protecting striatal projection neurons from malonate‐induced death. That CB2receptor agonists are neuroprotective was confirmed by using the selective CB2receptor antagonist, SR144528, and by the observation that mice deficient in CB2receptor were more sensitive to malonate than wild‐type animals. CB2receptors are scarce in the striatum in healthy conditions, but they are markedly upregulated after the lesion with malonate. Studies of double immunostaining revealed a significant presence of CB2receptors in cells labeled with the marker of reactive microglia OX‐42, and also in cells labeled with GFAP (a marker of astrocytes). We further showed that the activation of CB2receptors significantly reduced the levels of tumor necrosis factor‐α (TNF‐α) that had been increased by the lesion with malonate. In summary, our results demonstrate that stimulation of CB2receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB2receptors would be upregulated in response to the lesion. Activation of these receptors would reduce the generation of proinflammatory molecules like TNF‐α. Altogether, our results support the hypothesis that CB2receptors could constitute a therapeutic target to slowdown neurodegeneration in HD.