CB2 cannabinoid receptors promote mouse neural stem cell proliferation

Abstract

Neurospheres are clonal cellular aggregates of neural stem/precursor cells that grow in culture as free-floating clusters. Activation of CB1 cannabinoid receptors, which are expressed by these cells, promotes proliferation. In the present study we investigated the expression of CB2 cannabinoid receptors and the effect of exogenous cannabinoids on neural stem/precursor cell proliferation. Neurospheres containing nestin-positive and sn-1 diacylglycerol lipase alpha-positive cells expressed both CB1 and CB2 receptors, which were maintained through several passages. Application of the non-selective cannabinoid agonist (HU-210, 0.5 microM) stimulated bromodeoxyuridine incorporation and neurosphere formation. This action involved both CB1 and CB2 receptors as neurosphere formation was stimulated by either selective CB1 [arachidonyl-2'chloroethylamide/(all Z)-N-(2-cycloethyl)-5,8,11,14-eicosatetraenamide (ACEA), 200 nM and 1 microM] or CB2 (JWH-056, 0.5 microM) agonists. In addition, CB1 or CB2 antagonists (1 microM SR-141716A and SR-144528, respectively) blocked basal proliferation, suggesting that endogenous cannabinoids are implicated in neurosphere proliferation. In addition, cannabinoid agonist-stimulated proliferation was reduced by the Akt translocation inhibitor BML-257 (12.5 microM), suggesting a role for phosphoinositide-3 kinase signalling. Together, our results suggest that cannabinoids stimulate proliferation of neural stem/precursor cells acting on both CB1 and CB2 cannabinoid receptors through a phosphoinositide-3 kinase/Akt pathway.

Loss of Retrograde Endocannabinoid Signaling and Reduced Adult Neurogenesis in Diacylglycerol Lipase Knock-out Mice

“…There is an emerging role for eCB signaling in the regulation of neurogenesis (Aguado et al, 2005;Jiang et al, 2005;Palazuelos et al, 2006;Molina-Holgado et al, 2007). In the adult brain, this is restricted to the lateral wall of the SVZ (Alvarez-Buylla and Garcia-Verdugo, 2002) and the granule cell layer in the DG in the hippocampus (van Praag et al, 2002).…”

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

“…Docosahexaenoic acid; EPA, eicosapentaenoic acid, 2-AG, 2-arachidonylglycerol 4 but have more recently been identified in glia and subsets of neurons the CNS (Onaivi et al, 2012). Activation of cannabinoid receptors stimulates neurogenesis through a mechanism dependent on diacylglycerol lipase (DAGL: the enzyme primarily responsible for the synthesis of 2-AG) and the phosphoinositide-3 kinase ⁄ Akt pathway, an effect more pronounced in older animals (Goncalves et al, 2008;Molina-Holgado et al, 2007).…”

Endocannabinoids via CB1receptors act as neurogenic niche cues during cortical development

“…Neurospheres (non-adherent in vitro culture of NP cells) from embryonic and postnatal development stages express CB 1 receptors and the anandamide (AEA)-degrading enzyme fatty acid amide hydrolase (FAAH), and elevations in their intracellular Ca 2þ concentration increase ECB production [29]. In addition, the CB 2-receptor and diacylglycerol lipase (DAGL), the enzyme responsible for 2AG generation, are also functional in NP cultures [34,35]. AEA and 2-arachidonoylglycerol (2AG) can act therefore in an autocrine or paracrine manner on NPs or surrounding neighbour cells.…”