A Biophysical Model for Cytotoxic Cell Swelling

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Abstract

We present a dynamic biophysical model to explain neuronal swelling underlying cytotoxic edema in conditions of low energy supply, as observed in cerebral ischemia. Our model contains Hodgkin—Huxley-type ion currents, a recently discovered voltage-gated chloride flux through the ion exchanger SLC26A11, active KCC2-mediated chloride extrusion, and ATP-dependent pumps. The model predicts changes in ion gradients and cell swelling during ischemia of various severity or channel blockage with realistic timescales. We theoretically substantiate experimental observations of chloride influx generating cytotoxic edema, while sodium entry alone does not. We show a tipping point of Na+/K+-ATPase functioning, where below cell volume rapidly increases as a function of the remaining pump activity, and a Gibbs–Donnan-like equilibrium state is reached. This precludes a return to physiological conditions even when pump strength returns to baseline. However, when voltage-gated sodium channels are temporarily blocked, cell volume and membrane potential normalize, yielding a potential therapeutic strategy.
Original languageUndefined
Pages (from-to)11881-11890
Number of pages10
JournalJournal of neuroscience
Volume36
Issue number47
DOIs
Publication statusPublished - 23 Nov 2016

Keywords

  • cytotoxic edema
  • EWI-27480
  • ATP
  • IR-103047
  • Electrodiffusion
  • osmosis
  • METIS-320829
  • Gibbs–Donnan equilibrium

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