The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis.
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 CB1+ bFGF+ 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.
Aguado
Tania
T
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.
Romero
Eva
E
Monory
Krisztina
K
Palazuelos
Javier
J
Sendtner
Michael
M
Marsicano
Giovanni
G
Lutz
Beat
B
Guzmán
Manuel
M
Galve-Roperh
Ismael
I
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D006624:Hippocampus; D007608:Kainic Acid / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009498:Neurotoxins / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects
D009498:Neurotoxins; D043884:Receptor, Cannabinoid, CB1; D016222:Fibroblast Growth Factor 2; D007608:Kainic Acid