Delta-9-tetrahydrocannabinol accumulation, metabolism and cell-type-specific adverse effects in aggregating brain cell cultures

Autor: Florianne Monnet-Tschudi, Nicolas Perret, Paul Honegger, Arno Hazekamp, Marie-Gabrielle Zurich, Christian Giroud, Patrice Mangin
Rok vydání: 2007
Předmět:
Cannabinoid receptor
Receptor
Cannabinoid
CB1/agonists
Pharmacology
Toxicology
Mass Spectrometry
GTP Phosphohydrolases
Receptor
Cannabinoid
CB2
Receptor
Cannabinoid
CB1
Choline O-Acetyltransferase/metabolism
Pregnancy
Cannabinoids/metabolism
Cannabinoid receptor type 2
Dronabinol
Receptor
Cells
Cultured
Chromatography
High Pressure Liquid
Tetrahydrocannabinol/analysis/metabolism/toxicity
Cell Aggregation
Neurons
Glutamate Decarboxylase
Reverse Transcriptase Polymerase Chain Reaction
Brain
Reference Standards
Brain/cytology/pathology
medicine.anatomical_structure
Toxicity
Female
Cell Aggregation/drug effects
Neuroglia
Astrocyte
Agonist
medicine.drug_class
Tumor Necrosis Factor-alpha/biosynthesis
Biology
Choline O-Acetyltransferase
mental disorders
L-Lactate Dehydrogenase/metabolism
medicine
Animals
L-Lactate Dehydrogenase
Cannabinoids
Interleukin-6
Tumor Necrosis Factor-alpha
organic chemicals
ddc:614.1
Neuroglia/drug effects
Interleukin-6/biosynthesis
Neurons/drug effects
Glutamate Decarboxylase/metabolism
Rats
Immunology
Solvents
Cholinergic
Receptor
Cannabinoid
CB2/agonists
Neuron
GTP Phosphohydrolases/metabolism
Zdroj: Toxicology and Applied Pharmacology, Vol. 228, No 1 (2008) pp. 8-16
ISSN: 0041-008X
Popis: Despite the widespread use of Cannabis as recreational drug or as medicine, little is known about its toxicity. The accumulation, metabolism and toxicity of THC were analyzed 10 days after a single treatment, and after repeated exposures during 10 days. Mixed-cell aggregate cultures of fetal rat telencephalon were used as in vitro model, as well as aggregates enriched either in neurons or in glial cells. It was found that THC accumulated preferentially in neurons, and that glia-neuron interactions decreased THC accumulation. The quantification of 11-OH-THC and of THC-COOH showed that brain aggregates were capable of THC metabolism. No cell-type difference was found for the metabolite 11-OH-THC, whereas the THC-COOH content was higher in mixed-cell cultures. No cell death was found at THC concentrations of 2 microM in single treatment and of 1 microM and 2 microM in repeated treatments. Neurons, and particularly GABAergic neurons, were most sensitive to THC. Only the GABAergic marker was affected after the single treatment, whereas the GABAergic, cholinergic and astrocytic markers were decreased after the repeated treatments. JWH 015, a CB2 receptor agonist, showed effects similar to THC, whereas ACEA, a CB1 receptor agonist, had no effect. The expression of the cytokine IL-6 was upregulated 48 h after the single treatment with 5 microM of THC or JWH 015, whereas the expression of TNF-alpha remained unchanged. These results suggest that the adverse effects of THC were related either to THC accumulation or to cannabinoid receptor activation and associated with IL-6 upregulation.
Databáze: OpenAIRE
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