title: Antidepressants inhibit proton currents and tumor necrosis factor-α production in BV2 microglial cells.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, 221 Heuksuk-Dong, Dongjak-Gu, Seoul 156-756, Republic of Korea. jinhos@cau.ac.kr
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Song
authors.forename: William
authors.initials: W
authors.lastname: Marszalec
authors.forename: Li
authors.initials: L
authors.lastname: Kai
authors.forename: Jay Z
authors.initials: JZ
authors.lastname: Yeh
authors.forename: Toshio
authors.initials: T
authors.lastname: Narahashi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001703:Biophysics; D002461:Cell Line, Transformed; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006863:Hydrogen-Ion Concentration; D008070:Lipopolysaccharides / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D011522:Protons; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D011522:Protons; D014409:Tumor Necrosis Factor-alpha