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CB2 cannabinoid receptors promote mouse neural stem cell proliferation

Authors

  • Francisco Molina-Holgado,

    1. The Wolfson Centre for Age-Related Diseases, King's College London, Hodking Building, Guy's Campus, London SE1 1UL, UK
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  • Ana Rubio-Araiz,

    1. Laboratory of Neuroinflammation, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain [Research Unit associated to Instituto Cajal (CSIC), Madrid, Spain]
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  • Daniel García-Ovejero,

    1. Laboratory of Neuroinflammation, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain [Research Unit associated to Instituto Cajal (CSIC), Madrid, Spain]
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  • Robert J. Williams,

    1. The Wolfson Centre for Age-Related Diseases, King's College London, Hodking Building, Guy's Campus, London SE1 1UL, UK
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  • Jonathan D. Moore,

    1. The Wolfson Centre for Age-Related Diseases, King's College London, Hodking Building, Guy's Campus, London SE1 1UL, UK
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  • Ángel Arévalo-Martín,

    1. Laboratory of Neuroinflammation, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain [Research Unit associated to Instituto Cajal (CSIC), Madrid, Spain]
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  • Oscar Gómez-Torres,

    1. Laboratory of Neuroinflammation, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain [Research Unit associated to Instituto Cajal (CSIC), Madrid, Spain]
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  • Eduardo Molina-Holgado

    1. Laboratory of Neuroinflammation, Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain [Research Unit associated to Instituto Cajal (CSIC), Madrid, Spain]
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Dr Francisco Molina-Holgado, as above.
E-mail: francisco.molina-holgado@kcl.ac.uk

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 α-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 µm) 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 µm] or CB2 (JWH-056, 0.5 µm) agonists. In addition, CB1 or CB2 antagonists (1 µm 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 µm), 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.

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