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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

Effects of the repeated administration of URB597 (0.3 mg/kg), ACEA (3 mg/kg), and JWH133 (0.2 mg/kg) on cells that contained the replicating cell DNA marker 5-bromo-2′-deoxyuridine (BrdU+) in the SVZ (A), SGZ (B), and hypothalamus (C) of adult rats with sucrose and alcohol consumption. The data were expressed as the percentage of positive cells per area (mm2) relative to the control group (vehicle-treated sucrose-fed group). The histograms represents the mean + s.e.m. (n = 6). Bonferroni's test: *P < 0.05, **P < 0.01, ***P < 0.001 vs. sucrose-vehicle group; #P < 0.05, ###P < 0.001 vs. ethanol-vehicle group. (D–Z′) Representative microphotographs showing low and high (insets) magnification views of the typical clustering of newborn cells containing the BrdU labeling (arrowheads) in the SGZ, SVZ, and hypothalamus of vehicle, URB597, ACEA, and JWH133-treated rats fed with sucrose (left panel) and ethanol (right panel) diets. Scale bars are included in each image.
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Figure 4: Effects of the repeated administration of URB597 (0.3 mg/kg), ACEA (3 mg/kg), and JWH133 (0.2 mg/kg) on cells that contained the replicating cell DNA marker 5-bromo-2′-deoxyuridine (BrdU+) in the SVZ (A), SGZ (B), and hypothalamus (C) of adult rats with sucrose and alcohol consumption. The data were expressed as the percentage of positive cells per area (mm2) relative to the control group (vehicle-treated sucrose-fed group). The histograms represents the mean + s.e.m. (n = 6). Bonferroni's test: *P < 0.05, **P < 0.01, ***P < 0.001 vs. sucrose-vehicle group; #P < 0.05, ###P < 0.001 vs. ethanol-vehicle group. (D–Z′) Representative microphotographs showing low and high (insets) magnification views of the typical clustering of newborn cells containing the BrdU labeling (arrowheads) in the SGZ, SVZ, and hypothalamus of vehicle, URB597, ACEA, and JWH133-treated rats fed with sucrose (left panel) and ethanol (right panel) diets. Scale bars are included in each image.

Mentions: Bonferroni analyses for multiple comparisons indicated that ethanol induced a decrease in the percentage of BrdU+ cells in the SVZ (*P < 0.05), SGZ (***P < 0.001), and hypothalamus (*P < 0.05; Figures 4A–C). JWH133 increased the percentage of BrdU+ cells in the SVZ and SGZ of sucrose- and ethanol-fed rats (Figures 4A,B). ACEA and JWH133 increased the percentage of BrdU+ cells in the hypothalamus of sucrose-fed rats (Figure 4C). ACEA increased the percentage of BrdU+ cells in the SVZ, SGZ, and hypothalamus of ethanol-fed rats (#P < 0.05; Figures 4A–C). Representative images of the labeling in the SVZ, SGZ, and hypothalamus of each experimental group are shown in Figures 4D–Z′.


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)

Effects of the repeated administration of URB597 (0.3 mg/kg), ACEA (3 mg/kg), and JWH133 (0.2 mg/kg) on cells that contained the replicating cell DNA marker 5-bromo-2′-deoxyuridine (BrdU+) in the SVZ (A), SGZ (B), and hypothalamus (C) of adult rats with sucrose and alcohol consumption. The data were expressed as the percentage of positive cells per area (mm2) relative to the control group (vehicle-treated sucrose-fed group). The histograms represents the mean + s.e.m. (n = 6). Bonferroni's test: *P < 0.05, **P < 0.01, ***P < 0.001 vs. sucrose-vehicle group; #P < 0.05, ###P < 0.001 vs. ethanol-vehicle group. (D–Z′) Representative microphotographs showing low and high (insets) magnification views of the typical clustering of newborn cells containing the BrdU labeling (arrowheads) in the SGZ, SVZ, and hypothalamus of vehicle, URB597, ACEA, and JWH133-treated rats fed with sucrose (left panel) and ethanol (right panel) diets. Scale bars are included in each image.
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Figure 4: Effects of the repeated administration of URB597 (0.3 mg/kg), ACEA (3 mg/kg), and JWH133 (0.2 mg/kg) on cells that contained the replicating cell DNA marker 5-bromo-2′-deoxyuridine (BrdU+) in the SVZ (A), SGZ (B), and hypothalamus (C) of adult rats with sucrose and alcohol consumption. The data were expressed as the percentage of positive cells per area (mm2) relative to the control group (vehicle-treated sucrose-fed group). The histograms represents the mean + s.e.m. (n = 6). Bonferroni's test: *P < 0.05, **P < 0.01, ***P < 0.001 vs. sucrose-vehicle group; #P < 0.05, ###P < 0.001 vs. ethanol-vehicle group. (D–Z′) Representative microphotographs showing low and high (insets) magnification views of the typical clustering of newborn cells containing the BrdU labeling (arrowheads) in the SGZ, SVZ, and hypothalamus of vehicle, URB597, ACEA, and JWH133-treated rats fed with sucrose (left panel) and ethanol (right panel) diets. Scale bars are included in each image.
Mentions: Bonferroni analyses for multiple comparisons indicated that ethanol induced a decrease in the percentage of BrdU+ cells in the SVZ (*P < 0.05), SGZ (***P < 0.001), and hypothalamus (*P < 0.05; Figures 4A–C). JWH133 increased the percentage of BrdU+ cells in the SVZ and SGZ of sucrose- and ethanol-fed rats (Figures 4A,B). ACEA and JWH133 increased the percentage of BrdU+ cells in the hypothalamus of sucrose-fed rats (Figure 4C). ACEA increased the percentage of BrdU+ cells in the SVZ, SGZ, and hypothalamus of ethanol-fed rats (#P < 0.05; Figures 4A–C). Representative images of the labeling in the SVZ, SGZ, and hypothalamus of each experimental group are shown in Figures 4D–Z′.

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