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Our results showed that only compounds able to activate CB<jats:sub>2<\/jats:sub>receptors were capable of protecting striatal projection neurons from malonate\u2010induced death. That CB<jats:sub>2<\/jats:sub>receptor agonists are neuroprotective was confirmed by using the selective CB<jats:sub>2<\/jats:sub>receptor antagonist, SR144528, and by the observation that mice deficient in CB<jats:sub>2<\/jats:sub>receptor were more sensitive to malonate than wild\u2010type animals. CB<jats:sub>2<\/jats:sub>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<jats:sub>2<\/jats:sub>receptors in cells labeled with the marker of reactive microglia OX\u201042, and also in cells labeled with GFAP (a marker of astrocytes). We further showed that the activation of CB<jats:sub>2<\/jats:sub>receptors significantly reduced the levels of tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) that had been increased by the lesion with malonate. In summary, our results demonstrate that stimulation of CB<jats:sub>2<\/jats:sub>receptors protect the striatum against malonate toxicity, likely through a mechanism involving glial cells, in particular reactive microglial cells in which CB<jats:sub>2<\/jats:sub>receptors would be upregulated in response to the lesion. Activation of these receptors would reduce the generation of proinflammatory molecules like TNF\u2010\u03b1. Altogether, our results support the hypothesis that CB<jats:sub>2<\/jats:sub>receptors could constitute a therapeutic target to slowdown neurodegeneration in HD. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/glia.20838","type":"journal-article","created":{"date-parts":[[2008,12,31]],"date-time":"2008-12-31T19:43:51Z","timestamp":1230752631000},"page":"1154-1167","source":"Crossref","is-referenced-by-count":175,"title":["Cannabinoid CB<sub>2<\/sub>receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's 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