Abstract
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.
Highlights
In the adult brain, generation of new neurons is restricted to discrete areas including the subventricular zone and the subgranular zone of the dentate gyrus [1, 2]
Neural Progenitor Proliferation—To investigate the mechanism involved in the regulation of neural progenitors (NPs) upon excitotoxicity, we cultured
The response of hippocampal NPs was analyzed at different growth factors that are involved in the time points by quantifying the number of cells in the sub- regulation of NP cell proliferation [1, 2] and that have been granular zone of the dentate gyrus expressing the endoge- shown to cross-talk with the eCB system [15, 26, 27]
Summary
Factor-deprived chemically defined medium supplemented with 1% fetal calf serum and the action of 500 nM KA or 20. CB1Ϫ/Ϫ mice (8 weeks old) and their respective wild-type littermates were treated with vehicle or KA (15 mg/kg, intraperitoneal), injected with 50 monoclonal anti-nestin and anti-Sox antibodies as well as mg/kg of BrdUrd daily for 5 days, and perfused 1, 7, or 30 days polyclonal anti-musashi-1 antibody were from Chemicon later (n ϭ 4, n ϭ 4, n ϭ 6 for each group, respectively). The following PCR conditions were used for most of the analyzed genes: 35 cycles (30 s at pFIrGoUlifReEra3t.ioEnxcwitoastoqxuicaintyti-fiienddubcyeddenteeurmrainl pinrgogKei-n6i7tϩorcperlolsliifnertahteiosnubisgirmanpualiarredzoinneCBo1f-tdheefidcieennttamteicgey.rAu,sNinP wild-type (white bars) and CB1Ϫ/Ϫ (black bars) mice after 1 or 7 days (left and right, respectively) of vehicle (Veh) or KA treatment. The absolute number of positive cells was quantified considering the total hippocampal volume as determined by the sum of the areas of sampled sections multiplied by the distances between them. In vivo data were analyzed by an unpaired Student t test
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