Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation
Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation
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DOI：
10.1096/fj.06-6164fje
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发表时间：
2006-11-01
期刊：
影响因子：
4.8
通讯作者：
Galve-Roperh, Ismael
中科院分区：
文献类型：
--
作者：
Palazuelos, Javier;Aguado, Tania;Galve-Roperh, Ismael
大麻素是大麻及其内源性对应物的活性成分，通过广泛表达的CB 1大麻素受体作用于大脑和许多其他器官。相比之下，CB 2大麻素受体在免疫系统中丰富，并在脑细胞中显示出有限的表达模式。因此，CB 2选择性激动剂是非常有吸引力的治疗剂，因为它们不引起CB 1介导的精神活性作用。CB 2受体在脑中的表达已在分化细胞中部分检测，而其在神经祖细胞中的存在和功能仍不清楚。在这里，我们表明，CB 2受体的表达，在体外和体内，在神经祖细胞从胚胎晚期到成年大脑。体外CB 2受体的选择性药理学激活促进神经祖细胞增殖和神经球生成，这一作用在CB 2缺陷细胞中受损。因此，体内实验证明海马祖细胞增殖通过施用CB 2选择性激动剂HU-308而增加。此外，在正常条件下和红藻氨酸诱导的兴奋性毒性下，在CB 2缺陷小鼠中观察到祖细胞增殖受损。这些发现为CB 2大麻素受体提供了一种新的生理作用，并为操纵神经祖细胞命运开辟了一条新的治疗途径。
Cannabinoids, the active components of marijuana and their endogenous counterparts, act on the brain and many other organs through the widely expressed CB1 cannabinoid receptor. In contrast, the CB2 cannabinoid receptor is abundant in the immune system and shows a restricted expression pattern in brain cells. CB2-selective agonists are, therefore, very attractive therapeutic agents as they do not cause CB1-mediated psychoactive effects. CB2 receptor expression in brain has been partially examined in differentiated cells, while its presence and function in neural progenitor cells remain unknown. Here we show that the CB2 receptor is expressed, both in vitro and in vivo, in neural progenitors from late embryonic stages to adult brain. Selective pharmacological activation of the CB2 receptor in vitro promotes neural progenitor cell proliferation and neurosphere generation, an action that is impaired in CB2-deficient cells. Accordingly, in vivo experiments evidence that hippocampal progenitor proliferation is increased by administration of the CB2-selective agonist HU-308. Moreover, impaired progenitor proliferation was observed in CB2-deficient mice both in normal conditions and on kainate-induced excitotoxicity. These findings provide a novel physiological role for the CB2 cannabinoid receptor and open a novel therapeutic avenue for manipulating neural progenitor cell fate.