Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer's Disease
Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer's Disease
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DOI：
10.1124/mol.111.071290
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发表时间：
2011-06-01
影响因子：
3.6
通讯作者：
de Ceballos, Maria L.
中科院分区：
文献类型：
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作者：
Maria Martin-Moreno, Ana;Reigada, David;de Ceballos, Maria L.
小胶质细胞活化是阿尔茨海默病（AD）的不变特征。值得注意的是，大麻素通过在体外和体内防止β-淀粉样蛋白（A β）诱导的小胶质细胞活化而具有神经保护作用。另一方面，植物大麻素大麻二酚（CBD）在不同的范例中显示出抗炎特性。在本研究中，我们比较了CBD与其他大麻素对体外小胶质细胞功能的影响以及A β脑室内给药后对小鼠学习行为和细胞因子表达的影响。CBD，（R）-（+）-[2，3-二氢-5-甲基-3-（4-吗啉基甲基）吡咯并-[1，2，3-d，e]-1，4-苯并恶嗪-6-基]-1-萘基甲酮[WIN 55，212 -2（WIN）]，一种混合CB（1）/CB（2）激动剂，和1，1-二甲基丁基-1-脱氧-Delta（9）-四氢大麻酚[JWH-133（JWH）]，一种CB（2）选择性激动剂，浓度依赖性地降低培养的N13小胶质细胞和大鼠原代小胶质细胞中ATP诱导的（400 μ M）细胞内钙（[Ca（2+）]（i））增加。相反，另一种CB（2）激动剂4-[4-（1，1-二甲基庚基）-2，6-二甲氧基苯基]-6，6-二甲基-双环[3.1.1]庚-2-烯-2-甲醇[HU-308（HU）]则无作用。大麻素和腺苷A（2A）受体可能参与CBD的作用。CB（1）和/或CB（2）拮抗剂阻断CBD和WIN-promoted初级小胶质细胞迁移。JWH和HU诱导的迁移仅被CB（2）拮抗剂阻断。所有的大麻素减少脂多糖诱导的亚硝酸盐的产生，这是不敏感的大麻素拮抗作用。最后，CBD和WIN在亚慢性给药3周后，能够阻止β-淀粉样蛋白注射小鼠学习空间导航任务和细胞因子基因表达。总之，CBD能够在体外调节小胶质细胞功能，并在AD体内模型中诱导有益作用。鉴于CBD缺乏精神活性，它可能代表了这种神经系统疾病的新治疗方法。
Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing beta-amyloid (A beta)-induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after A beta intraventricular administration to mice. CBD, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone [WIN 55,212-2 (WIN)], a mixed CB(1)/CB(2) agonist, and 1,1-dimethylbutyl-1-deoxy-Delta(9)-tetrahydrocannabinol [JWH-133 (JWH)], a CB(2)-selective agonist, concentration-dependently decreased ATP-induced (400 mu M) increase in intracellular calcium ([Ca(2+)](i)) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-2-methanol [HU-308 (HU)], another CB(2) agonist, was without effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB(1) and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2) antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in beta-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.