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J. Biol. Chem., Vol. 282, Issue 33, 23892-23898, August 17, 2007

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The CB₁ Cannabinoid Receptor Mediates Excitotoxicity-induced Neural Progenitor Proliferation and Neurogenesis^*

Tania Aguado¹, Eva Romero², Krisztina Monory, Javier Palazuelos, Michael Sendtner^¶, Giovanni Marsicano^||, Beat Lutz, Manuel Guzmán, and Ismael Galve-Roperh³

From the Department of Biochemistry and Molecular Biology I, School of Biology, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Complutense University, 28040 Madrid, Spain, the Department of Physiological Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 6, 55099 Mainz, Germany, the ^¶Institute of Clinical Neurobiology, Würzburg University, Versbacher Str. 5, 97078 Würzburg, Germany, and the ^||U862 INSERM, Institute Francois Magendie, 146, rue Léo Saignat, 33076 Bordeaux, France

Endocannabinoids are lipid signaling mediators that exert an important neuromodulatory role and confer neuroprotection in several types of brain injury. Excitotoxicity and stroke can induce neural progenitor (NP) proliferation and differentiation as an attempt of neuroregeneration after damage. Here we investigated the mechanism of hippocampal progenitor cell engagement upon excitotoxicity induced by kainic acid administration and the putative involvement of the CB₁ cannabinoid receptor in this process. Adult NPs express kainate receptors that mediate proliferation and neurosphere generation in vitro via CB₁ cannabinoid receptors. Similarly, in vivo studies showed that excitotoxicity-induced hippocampal NPs proliferation and neurogenesis are abrogated in CB₁-deficient mice and in wild-type mice administered with the selective CB₁ antagonist rimonabant (N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazolecarboxamide; SR141716). Kainate stimulation increased basic fibroblast growth factor (bFGF) expression in cultured NPs in a CB₁-dependent manner as this response was prevented by rimonabant and mimicked by endocannabinoids. Likewise, in vivo analyses showed that increased hippocampal expression of bFGF, as well as of brain-derived neurotrophic factor and epidermal growth factor, occurs upon excitotoxicity and that CB₁ receptor ablation prevents this induction. Moreover, excitotoxicity increased the number of CB ⁺₁bFGF⁺ cells, and this up-regulation preceded NP proliferation. In summary, our results show the involvement of the CB₁ cannabinoid receptor in NP proliferation and neurogenesis induced by excitotoxic injury and support a role for bFGF signaling in this process.

Received for publication, January 24, 2007 , and in revised form, May 4, 2007.

^* This work was supported by grants from Comunidad Autónoma de Madrid (Grants S-SAL/0261/2006 and 950344), Fundación de Investigación Médica Mutua Madrileña Automovilística, Santander Complutense (Grant PR27/05-13988), Deutsche Forschungsgemeinschaft (Grant LU755-4), and the AVENIR Program of INSERM (in partnership with the Fondation Betten-court-Schueller). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two supplemental tables and a figure.

¹ Supported by Comunidad Autónoma de Madrid.

² Present address: AVENIR INSERM, Institute Francois Magendie, 146, rue Léo Saignat, 33076 Bordeaux, France.

³ To whom correspondence should be addressed. Tel.: 34-913944668; Fax: 34-913944672; E-mail: igr{at}quim.ucm.es.

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