Non-psychoactive CB sub(2) cannabinoid agonists stimulate neural progenitor proliferation

Cannabinoids, the active components of marijuana and their endogenous counterparts, act on the brain and many other organs through the widely expressed CB sub(1) cannabinoid receptor. In contrast, the CB sub(2) cannabinoid receptor is abundant in the immune system and shows a restricted expression pattern in brain cells. CB sub(2)-selective agonists are, therefore, very attractive therapeutic agents as they do not cause CB sub(1)-mediated psychoactive effects. CB sub(2) 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 CB sub(2) receptor is expressed, both in vitro and in vivo, in neural progenitors from late embryonic stages to adult brain. Selective pharmacological activation of the CB sub(2) receptor in vitro promotes neural progenitor cell proliferation and neurosphere generation, an action that is impaired in CB sub(2)-deficient cells. Accordingly, in vivo experiments evidence that hippocampal progenitor proliferation is increased by administration of the CB sub(2)-selective agonist HU-308. Moreover, impaired progenitor proliferation was observed in CB sub(2)-deficient mice both in normal conditions and on kainate-induced excitotoxicity. These findings provide a novel physiological role for the CB sub(2) cannabinoid receptor and open a novel therapeutic avenue for manipulating neural progenitor cell fate.