Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's disease
✍ Scribed by Onintza Sagredo; Sara González; Ilia Aroyo; María Ruth Pazos; Cristina Benito; Isabel Lastres-Becker; Juan P. Romero; Rosa M. Tolón; Raphael Mechoulam; Emmanuel Brouillet; Julián Romero; Javier Fernández-Ruiz
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 629 KB
- Volume
- 57
- Category
- Article
- ISSN
- 0894-1491
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✦ Synopsis
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 CB 2 receptors were capable of protecting striatal projection neurons from malonateinduced death. That CB 2 receptor agonists are neuroprotective was confirmed by using the selective CB 2 receptor antagonist, SR144528, and by the observation that mice deficient in CB 2 receptor were more sensitive to malonate than wild-type animals. CB 2 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 CB 2 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 CB 2 receptors significantly reduced the levels of tumor necrosis factor-a (TNF-a) that had been increased by the lesion with malonate. In summary, our results demonstrate that stimulation of CB 2 receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB 2 receptors would be upregulated in response to the lesion. Activation of these receptors would reduce the generation of proinflammatory molecules like TNF-a. Altogether, our results support the hypothesis that CB 2 receptors could constitute a therapeutic target to slowdown neurodegeneration in HD. V V C 2008 Wiley-Liss, Inc.
Onintza Sagredo, Sara Gonz alez, and Ilia Aroyo contributed equally to this study.