Non‐psychoactive CB2cannabinoid agonists stimulate neural progenitor proliferation

Abstract

Cannabinoids, the active components ofmarijuana and their endogenous counterparts, act onthe brain and many other organs through the widelyexpressed CB1cannabinoid receptor. In contrast, theCB2cannabinoid receptor is abundant in the immunesystem and shows a restricted expression pattern inbrain cells. CB2-selective agonists are, therefore, veryattractive therapeutic agents as they do not causeCB1-mediated psychoactive effects. CB2receptor ex-pression in brain has been partially examined in differ-entiated cells, while its presence and function in neuralprogenitor cells remain unknown. Here we show thatthe CB2receptor is expressed, bothin vitroandin vivo,in neural progenitors from late embryonic stages toadult brain. Selective pharmacological activation of theCB2receptorin vitropromotes neural progenitor cellproliferation and neurosphere generation, an actionthat is impaired in CB2-deficient cells. Accordingly,invivoexperiments evidence that hippocampal progeni-tor proliferation is increased by administration of theCB2-selective agonist HU-308. Moreover, impaired pro-genitor proliferation was observed in CB2-deficientmice both in normal conditions and on kainate-inducedexcitotoxicity. These findings provide a novel physio-logical role for the CB2cannabinoid receptor and opena novel therapeutic avenue for manipulating neuralprogenitor cell fate.—Palazuelos, J., Aguado, T., Egia, A.,Mechoulam, R., Guzma ́n, M., Galve-Roperh, I. Non-psychoactive CB2cannabinoid agonists stimulate neuralprogenitor proliferation.FASEB J.20, E1773–E1779(2006).