Abstract
Pharmacological brain slice experiments are complicated by the need to ensure adequate drug delivery deep into the healthy layers of the tissue. Because tissue slices have no blood supply, this is achieved solely by passive drug diffusion. The aim of this study was to determine whether pharmacokinetic/pharmacodynamic (PKPD) modeling could be adapted to estimate drug diffusion times in neocortical brain slices. No-magnesium seizure-like event (SLE) activity was generated in 41 slices (400 μm). Two anesthetic agents, etomidate (24 μM, n = 14) and thiopental (250 μM, n = 14), and magnesium ions (n = 13) were delivered to effect reversible reductions in SLE frequency. Concentration-effect hysteresis loops were collapsed using a first order rate constant model and equilibrium half-lives (t1/2Ke0) derived. The t1/2Ke0 values obtained were consistent with expectations. The median (range) t1/2Ke0 of 83.1 (19.4–330.1) min for etomidate is in keeping with its known slow diffusion into brain slice tissue. Values for etomidate and thiopental (111.8 (27.8–198.0) min) were similar, while magnesium had a significantly faster equilibration rate (t1/2Ke0 of 26.1 (8.6–77.0) min) compared to the anesthetics, as expected for a simple ion. In conclusion, PKPD modeling is a simple and practical method that can be applied to brain slice experiments for investigating drug diffusion characteristics.
Highlights
Characterisation of drug effects in in vitro brain slice experiments is complicated by the absence of a blood supply to the tissue
Because substances diffuse at different rates according to their physicochemical properties, it can be difficult to know how long to expose the tissue in order to achieve drug penetration into the healthiest layers of the slice—approximately the middle 100 μm for a 400 μm thick slice [1]
No-magnesium seizure-like event (SLE) activity was generated in 41 slices from 14 mice
Summary
Characterisation of drug effects in in vitro brain slice experiments is complicated by the absence of a blood supply to the tissue. This means that drugs must be delivered to the tissue by passive diffusion via the perfusion solution. Measuring drug concentrations in tissue slicesnecessitates methodologies that are time consuming and complex and cannot realistically be applied to each and every drug one may want to test. This motivated us to explore alternative, simpler approaches for estimating drug diffusion in brain slice tissue. By applying Fick’s law of diffusion (stating that the rate of equilibration of a substance is proportional to its concentration gradient), it is possible to calculate the equilibration half-time (t1/2Ke0)—a measure of the time required for a substance to reach half of its equilibrated concentration at the tissue recording site
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