Palazuelos Javier, Aguado Tania, Egia Ainara, Mechoulam Raphael, Guzmán Manuel, Galve-Roperh Ismael
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain.
FASEB J. 2006 Nov;20(13):2405-7. doi: 10.1096/fj.06-6164fje. Epub 2006 Oct 2.
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.
大麻素是大麻的活性成分及其内源性类似物，它们通过广泛表达的CB1大麻素受体作用于大脑和许多其他器官。相比之下，CB2大麻素受体在免疫系统中大量存在，而在脑细胞中呈现出受限的表达模式。因此，CB2选择性激动剂是非常有吸引力的治疗药物，因为它们不会引起CB1介导的精神活性作用。CB2受体在大脑中的表达已在分化细胞中进行了部分研究，但其在神经祖细胞中的存在和功能仍然未知。在这里，我们表明CB2受体在体外和体内均在从胚胎后期到成年大脑的神经祖细胞中表达。体外对CB2受体的选择性药理激活促进神经祖细胞增殖和神经球生成，而这一作用在CB2缺陷细胞中受损。相应地，体内实验证明，给予CB2选择性激动剂HU-308可增加海马祖细胞增殖。此外，在正常条件下以及在海藻酸诱导的兴奋性毒性作用下，在CB2缺陷小鼠中均观察到祖细胞增殖受损。这些发现为CB2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。
