title: Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: relevance for Huntington's disease.
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 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-alpha (TNF-alpha) 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-alpha. Altogether, our results support the hypothesis that CB2 receptors could constitute a therapeutic target to slowdown neurodegeneration in HD.
authors.affiliation: Departamento de Bioquímica y Biología Molecular and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Onintza
authors.initials: O
authors.lastname: Sagredo
authors.forename: Sara
authors.initials: S
authors.lastname: González
authors.forename: Ilia
authors.initials: I
authors.lastname: Aroyo
authors.forename: María Ruth
authors.initials: MR
authors.lastname: Pazos
authors.forename: Cristina
authors.initials: C
authors.lastname: Benito
authors.forename: Isabel
authors.initials: I
authors.lastname: Lastres-Becker
authors.forename: Juan P
authors.initials: JP
authors.lastname: Romero
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Tolón
authors.forename: Raphael
authors.initials: R
authors.lastname: Mechoulam
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: Julián
authors.initials: J
authors.lastname: Romero
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001892:Camphanes / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002491:Central Nervous System Agents / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects*; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D001892:Camphanes; D002186:Cannabinoids; D002491:Central Nervous System Agents; D008314:Malonates; D018696:Neuroprotective Agents; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D014409:Tumor Necrosis Factor-alpha; C119325:arachidonyl-2-chloroethylamide; C402416:HU 308; C030290:malonic acid