Stochastic time-concentration activity models for in vitro neurotoxicity

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 of enzyme activities. Concentration-dependent neurotoxicity is determined at several time points.A Markov model is set up to describe dynamics of brain cell populations exposed to potentially neurotoxic compounds. Brain cells are assumed to be either in a healthy or stressed state and only stressed cells are susceptible to cell death. Cells may switch between these states or die with concentration-dependent transition rates. Since cell numbers are not directly measurable, intracellular lactate dehydrogenase (LDH) activity is used as a surrogate. Assuming that changes in cell numbers are proportional to changes in intracellular LDH activity, stochastic enzyme activity models are derived. Maximum likelihood and least squares regression techniques are applied for estimation of the transition rates. Likelihood ratio tests are performed to test hypotheses about the transition rates. Simulation studies are 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 is applied to intracellular LDH activity measurements after 7 and 14 days of continuous exposure to propofol. The model des...
Source: Theoretical Biology and Medical Modelling - Category: Biomedical Science Authors: Source Type: research