Antidepressants inhibit proton currents and tumor necrosis factor-α production in BV2 microglial cells

Jin Ho Song*, William Marszalec, Li Kai, Jay Z. Yeh, Toshio Narahashi

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Proton channels are gated by voltage and pH gradients, and play an important role in the microglial production of pro-inflammatory cytokines, which are known to be suppressed by antidepressants. In the present study we tested the hypothesis that cytokine inhibition by antidepressants is due to an inhibitory action on proton currents by comparing their effects on tumor necrosis factor-α production with the effects on the proton currents in BV2 murine microglial cells. Imipramine, amitriptyline, desipramine and fluoxetine potently and reversibly inhibited proton currents at micromolar concentrations at an intracellular/extracellular pH gradient of 5.5/7.3. Raising extracellular pH to 8.3 sped up the rate and enhanced the extent of block whereas raising intracellular pH to 6.3 reduced the blocking potency of imipramine. These results support a mechanism where the uncharged drug form penetrates the cell membrane, and the charged form blocks the proton channel from the internal side of membrane. This mode of action was corroborated by an experiment with imipraminium, a permanently charged quaternary derivative, which showed far less block compared to imipramine. The lipopolysaccharide-induced release of tumor necrosis factor-α was inhibited by imipramine at concentrations comparable to those inhibiting the proton current. These results support the hypothesis that tumor necrosis factor-α inhibition by imipramine is related to its inhibitory effects on proton channels.

Original languageEnglish (US)
Pages (from-to)15-23
Number of pages9
JournalBrain research
Volume1435
DOIs
StatePublished - Jan 30 2012

Keywords

  • Antidepressant
  • Imipramine
  • Microglia
  • Proton channel
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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