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Non-psychoactive CB₂ cannabinoid agonists stimulate neural progenitor proliferation

Javier Palazuelos^*, Tania Aguado^*, Ainara Egia^*, Raphael Mechoulam, Manuel Guzmán^*,1,2 and Ismael Galve-Roperh^*,1,2

^* Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain;

Department of Medicinal Chemistry and Natural Products, School of Pharmacy, The Hebrew University, Jerusalem, Israel

²Correspondence: Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain. E-mail: igr{at}quim.ucm.esmgp{at}bbm1.ucm.es

ABSTRACT

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.—Palazuelos, J., Aguado, T., Egia, A., Mechoulam, R., Guzmán, M., Galve-Roperh, I. Non-psychoactive CB₂ cannabinoid agonists stimulate neural progenitor proliferation.

This article has been cited by other articles:

				J. Palazuelos, N. Davoust, B. Julien, E. Hatterer, T. Aguado, R. Mechoulam, C. Benito, J. Romero, A. Silva, M. Guzman, et al. The CB2 Cannabinoid Receptor Controls Myeloid Progenitor Trafficking: INVOLVEMENT IN THE PATHOGENESIS OF AN ANIMAL MODEL OF MULTIPLE SCLEROSIS J. Biol. Chem., May 9, 2008; 283(19): 13320 - 13329. [Abstract] [Full Text] [PDF]

				T. Aguado, E. Romero, K. Monory, J. Palazuelos, M. Sendtner, G. Marsicano, B. Lutz, M. Guzman, and I. Galve-Roperh The CB1 Cannabinoid Receptor Mediates Excitotoxicity-induced Neural Progenitor Proliferation and Neurogenesis J. Biol. Chem., August 17, 2007; 282(33): 23892 - 23898. [Abstract] [Full Text] [PDF]

				I. Galve-Roperh, T. Aguado, J. Palazuelos, and M. Guzman The Endocannabinoid System and Neurogenesis in Health and Disease Neuroscientist, April 1, 2007; 13(2): 109 - 114. [Abstract] [PDF]