Digoxin Induces Human Astrocyte Reaction In Vitro.
Astrocytes
Astrogliosis
Energy metabolism
Glycolysis
Neuroinflammation
Neurotoxicity
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Jan 2023
Jan 2023
Historique:
received:
22
06
2022
accepted:
21
09
2022
pubmed:
13
10
2022
medline:
21
12
2022
entrez:
12
10
2022
Statut:
ppublish
Résumé
Astrocyte reaction is a complex cellular process involving astrocytes in response to various types of CNS injury and a marker of neurotoxicity. It has been abundantly studied in rodents but relatively poorly in human cells due to limited access to the brain. Astrocytes play important roles in cerebral energy metabolism and are also key players in neuroinflammation. Astroglial metabolic and inflammatory changes have been reported with age, leading to the hypothesis that mitochondrial metabolism and inflammatory responses are interconnected. However, the relationship between energy metabolism and astrocyte reactivity in the context of neurotoxicity is not known. We hypothesized that changes in energy metabolism of astrocytes will be coupled to their activation by xenobiotics. Astrocyte reaction and associated energy metabolic changes were assessed by immunostaining, gene expression, proteomics, metabolomics, and extracellular flux analyses after 24 h of exposure of human ReN-derived astrocytes to digoxin (1-10 µM) or TNFα (30 ng/ml) used as a positive control. Strong astrocytic reaction was observed, accompanied by increased glycolysis at low concentrations of digoxin (0.1 and 0.5 µM) and after TNFα exposure, suggesting that increased glycolysis may be a common feature of reactive astrocytes, independent of the triggering molecule. In conclusion, whether astrocyte activation is triggered by cytokines or a xenobiotic, it is strongly tied to energy metabolism in human ReN-derived astrocytes. Increased glycolysis might be considered as an endpoint to detect astrocyte activation by potentially neurotoxic compounds in vitro. Finally, ReN-derived astrocytes may help to decipher mechanisms of neurotoxicity in ascertaining the ability of chemicals to directly target astrocytes.
Identifiants
pubmed: 36223047
doi: 10.1007/s12035-022-03057-1
pii: 10.1007/s12035-022-03057-1
pmc: PMC9758102
doi:
Substances chimiques
Digoxin
73K4184T59
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
84-97Subventions
Organisme : Swiss Center for Applied Human Toxicology (SCAHT)
ID : CP3
Informations de copyright
© 2022. The Author(s).
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