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Pharmacological activation of CB2 receptors counteracts the deleterious effect of ethanol on cell proliferation in the main neurogenic zones of the adult rat brain.

Rivera P, Blanco E, Bindila L, Alen F, Vargas A, Rubio L, Pavón FJ, Serrano A, Lutz B, Rodríguez de Fonseca F, Suárez J - Front Cell Neurosci (2015)

Bottom Line: Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations.Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus.JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ.

View Article: PubMed Central - PubMed

Affiliation: UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga-Hospital Universitario Regional de Málaga Málaga, Spain.

ABSTRACT
Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations. Cannabinoid receptor agonists promote adult neural progenitor cell (NPC) proliferation. We evaluated the protective effects of the selective CB1 receptor agonist ACEA, the selective CB2 receptor agonist JWH133 and the fatty-acid amide-hydrolase (FAAH) inhibitor URB597, which enhances endocannabinoid receptor activity, on NPC proliferation in rats with forced consumption of ethanol (10%) or sucrose liquid diets for 2 weeks. We performed immunohistochemical and stereological analyses of cells expressing the mitotic phosphorylation of histone-3 (phospho-H3+) and the replicating cell DNA marker 5-bromo-2'-deoxyuridine (BrdU+) in the main neurogenic zones of adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ) and hypothalamus. Animals were allowed ad libitum ethanol intake (7.3 ± 1.1 g/kg/day) after a controlled isocaloric pair-feeding period of sucrose and alcoholic diets. Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus. The treatments (URB597, ACEA, JWH133) exerted a differential increase in alcohol consumption over time, but JWH133 specifically counteracted the deleterious effect of ethanol on NPC proliferation in the SVZ and SGZ, and ACEA reversed this effect in the SGZ only. JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ. These results indicated that the specific activation of CB2 receptors rescued alcohol-induced impaired NPC proliferation, which is a potential clinical interest for the risk of neural damage in alcohol dependence.

No MeSH data available.


Related in: MedlinePlus

Quantification of the proportion of cells labeled with BrdU that expressed phospho-H3 in the SVZ (A), SGZ (B), and hypothalamus (C) of vehicle, ACEA and JWH133-treated rats fed with sucrose and ethanol diets. Bars represent the percentage of labeled cells in each experimental group. (D–U) BrdU and phospho-H3 co-expression in the rat brain. High-resolution confocal laser scanning photomicrographs showing the labeling of BrdU (green) and phospho-H3 (red) in the SVZ, SGZ, and hypothalamus of vehicle, ACEA and JWH133-treated rats fed with sucrose (left panel) and ethanol (right panel) diets. The arrowheads indicate co-expression. Scale bars are included in the left-upper images.
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Figure 5: Quantification of the proportion of cells labeled with BrdU that expressed phospho-H3 in the SVZ (A), SGZ (B), and hypothalamus (C) of vehicle, ACEA and JWH133-treated rats fed with sucrose and ethanol diets. Bars represent the percentage of labeled cells in each experimental group. (D–U) BrdU and phospho-H3 co-expression in the rat brain. High-resolution confocal laser scanning photomicrographs showing the labeling of BrdU (green) and phospho-H3 (red) in the SVZ, SGZ, and hypothalamus of vehicle, ACEA and JWH133-treated rats fed with sucrose (left panel) and ethanol (right panel) diets. The arrowheads indicate co-expression. Scale bars are included in the left-upper images.

Mentions: We evaluated the percentage of BrdU+ cells showing a precursor (GFAP or phospho-H3 expression) or mature neuronal (β3-tubulin) phenotype to characterize the neural proliferating cells in the main neurogenic zones of ACEA- and JWH133-treated rats. We detected a very low number and a lack of BrdU+ cells expressing the mitotic marker phospho-H3 in the SVZ and hypothalamus, respectively (Figures 5A,C). In contrast, alcohol-exposed rats treated with JWH133, but not the other treatments, exhibited BrdU+ cells that expressed phospho-H3 in the SGZ (Figure 5B). Representative images of BrdU and phospho-H3 labeling in the SVZ, SGZ, and hypothalamus of each experimental group are shown in Figures 5D–U.


Pharmacological activation of CB2 receptors counteracts the deleterious effect of ethanol on cell proliferation in the main neurogenic zones of the adult rat brain.

Rivera P, Blanco E, Bindila L, Alen F, Vargas A, Rubio L, Pavón FJ, Serrano A, Lutz B, Rodríguez de Fonseca F, Suárez J - Front Cell Neurosci (2015)

Quantification of the proportion of cells labeled with BrdU that expressed phospho-H3 in the SVZ (A), SGZ (B), and hypothalamus (C) of vehicle, ACEA and JWH133-treated rats fed with sucrose and ethanol diets. Bars represent the percentage of labeled cells in each experimental group. (D–U) BrdU and phospho-H3 co-expression in the rat brain. High-resolution confocal laser scanning photomicrographs showing the labeling of BrdU (green) and phospho-H3 (red) in the SVZ, SGZ, and hypothalamus of vehicle, ACEA and JWH133-treated rats fed with sucrose (left panel) and ethanol (right panel) diets. The arrowheads indicate co-expression. Scale bars are included in the left-upper images.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4587308&req=5

Figure 5: Quantification of the proportion of cells labeled with BrdU that expressed phospho-H3 in the SVZ (A), SGZ (B), and hypothalamus (C) of vehicle, ACEA and JWH133-treated rats fed with sucrose and ethanol diets. Bars represent the percentage of labeled cells in each experimental group. (D–U) BrdU and phospho-H3 co-expression in the rat brain. High-resolution confocal laser scanning photomicrographs showing the labeling of BrdU (green) and phospho-H3 (red) in the SVZ, SGZ, and hypothalamus of vehicle, ACEA and JWH133-treated rats fed with sucrose (left panel) and ethanol (right panel) diets. The arrowheads indicate co-expression. Scale bars are included in the left-upper images.
Mentions: We evaluated the percentage of BrdU+ cells showing a precursor (GFAP or phospho-H3 expression) or mature neuronal (β3-tubulin) phenotype to characterize the neural proliferating cells in the main neurogenic zones of ACEA- and JWH133-treated rats. We detected a very low number and a lack of BrdU+ cells expressing the mitotic marker phospho-H3 in the SVZ and hypothalamus, respectively (Figures 5A,C). In contrast, alcohol-exposed rats treated with JWH133, but not the other treatments, exhibited BrdU+ cells that expressed phospho-H3 in the SGZ (Figure 5B). Representative images of BrdU and phospho-H3 labeling in the SVZ, SGZ, and hypothalamus of each experimental group are shown in Figures 5D–U.

Bottom Line: Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations.Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus.JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ.

View Article: PubMed Central - PubMed

Affiliation: UGC Salud Mental, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga-Hospital Universitario Regional de Málaga Málaga, Spain.

ABSTRACT
Chronic alcohol exposure reduces endocannabinoid activity and disrupts adult neurogenesis in rodents, which results in structural and functional alterations. Cannabinoid receptor agonists promote adult neural progenitor cell (NPC) proliferation. We evaluated the protective effects of the selective CB1 receptor agonist ACEA, the selective CB2 receptor agonist JWH133 and the fatty-acid amide-hydrolase (FAAH) inhibitor URB597, which enhances endocannabinoid receptor activity, on NPC proliferation in rats with forced consumption of ethanol (10%) or sucrose liquid diets for 2 weeks. We performed immunohistochemical and stereological analyses of cells expressing the mitotic phosphorylation of histone-3 (phospho-H3+) and the replicating cell DNA marker 5-bromo-2'-deoxyuridine (BrdU+) in the main neurogenic zones of adult brain: subgranular zone of dentate gyrus (SGZ), subventricular zone of lateral ventricles (SVZ) and hypothalamus. Animals were allowed ad libitum ethanol intake (7.3 ± 1.1 g/kg/day) after a controlled isocaloric pair-feeding period of sucrose and alcoholic diets. Alcohol intake reduced the number of BrdU+ cells in SGZ, SVZ, and hypothalamus. The treatments (URB597, ACEA, JWH133) exerted a differential increase in alcohol consumption over time, but JWH133 specifically counteracted the deleterious effect of ethanol on NPC proliferation in the SVZ and SGZ, and ACEA reversed this effect in the SGZ only. JWH133 also induced an increased number of BrdU+ cells expressing neuron-specific β3-tubulin in the SVZ and SGZ. These results indicated that the specific activation of CB2 receptors rescued alcohol-induced impaired NPC proliferation, which is a potential clinical interest for the risk of neural damage in alcohol dependence.

No MeSH data available.


Related in: MedlinePlus