Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's disease

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 CB₂ receptors were capable of protecting striatal projection neurons from malonate‐induced death. That CB₂ receptor agonists are neuroprotective was confirmed by using the selective CB₂ receptor antagonist, SR144528, and by the observation that mice deficient in CB₂ receptor were more sensitive to malonate than wild‐type animals. CB₂ receptors 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 CB₂ receptors 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 CB₂ receptors 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 CB₂ receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB₂ receptors 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 CB₂ receptors could constitute a therapeutic target to slowdown neurodegeneration in HD. © 2008 Wiley‐Liss, Inc.