Stochastic time-concentration activity models for cytotoxicity in 3D brain cell cultures.

Détails

Ressource 1Télécharger: BIB_1C9FA7FAAB0D.P001.pdf (1039.51 [Ko])
Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_1C9FA7FAAB0D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Stochastic time-concentration activity models for cytotoxicity in 3D brain cell cultures.
Périodique
Theoretical Biology and Medical Modelling
Auteur(s)
Renner M., Zurich M.G., Kopp-Schneider A.
ISSN
1742-4682 (Electronic)
ISSN-L
1742-4682
Statut éditorial
Publié
Date de publication
2013
Volume
10
Pages
19
Langue
anglais
Notes
Publication types: Journal Article Publication Status: epublish
Résumé
BACKGROUND: In vitro aggregating brain cell cultures containing all types of brain cells have been shown to be useful for neurotoxicological investigations. The cultures are used for the detection of nervous system-specific effects of compounds by measuring multiple endpoints, including changes in enzyme activities. Concentration-dependent neurotoxicity is determined at several time points.
METHODS: A Markov model was set up to describe the dynamics of brain cell populations exposed to potentially neurotoxic compounds. Brain cells were assumed to be either in a healthy or stressed state, with only stressed cells being susceptible to cell death. Cells may have switched between these states or died with concentration-dependent transition rates. Since cell numbers were not directly measurable, intracellular lactate dehydrogenase (LDH) activity was used as a surrogate. Assuming that changes in cell numbers are proportional to changes in intracellular LDH activity, stochastic enzyme activity models were derived. Maximum likelihood and least squares regression techniques were applied for estimation of the transition rates. Likelihood ratio tests were performed to test hypotheses about the transition rates. Simulation studies were used to investigate the performance of the transition rate estimators and to analyze the error rates of the likelihood ratio tests. The stochastic time-concentration activity model was applied to intracellular LDH activity measurements after 7 and 14 days of continuous exposure to propofol. The model describes transitions from healthy to stressed cells and from stressed cells to death.
RESULTS: The model predicted that propofol would affect stressed cells more than healthy cells. Increasing propofol concentration from 10 to 100 μM reduced the mean waiting time for transition to the stressed state by 50%, from 14 to 7 days, whereas the mean duration to cellular death reduced more dramatically from 2.7 days to 6.5 hours.
CONCLUSION: The proposed stochastic modeling approach can be used to discriminate between different biological hypotheses regarding the effect of a compound on the transition rates. The effects of different compounds on the transition rate estimates can be quantitatively compared. Data can be extrapolated at late measurement time points to investigate whether costs and time-consuming long-term experiments could possibly be eliminated.
Pubmed
Web of science
Open Access
Oui
Création de la notice
26/07/2013 16:43
Dernière modification de la notice
20/08/2019 12:53
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