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Thioxanthenes, chlorprothixene and flupentixol inhibit proton currents in BV2 microglial cells

Jiwon Kim1, Jin-Ho Song1

  • 1Department of Pharmacology, College of Medicine, Chung-Ang University, 84 Heukseok-Ro, Dongjak-Gu, Seoul 06974, Republic of Korea.

European Journal of Pharmacology
|March 7, 2016
PubMed

Insights

Thioxanthene antipsychotics like chlorprothixene and flupentixol reduce damaging reactive oxygen species by inhibiting voltage-gated proton channels in microglia. This finding may explain their antioxidant effects in neurodegenerative diseases.

Area of Science:

  • Neuropharmacology
  • Cellular Neuroscience
  • Oxidative Stress Research

Background:

  • Microglia-mediated inflammation and reactive oxygen species (ROS) contribute to neurodegeneration.
  • NADPH oxidase activity, sustained by voltage-gated proton channels, is a key source of ROS in microglia.
  • Thioxanthene antipsychotics possess anti-inflammatory and antioxidant properties.

Purpose of the Study:

  • To investigate the effects of chlorprothixene and flupentixol on proton currents in microglial cells.
  • To determine if inhibition of proton channels by these drugs contributes to their antioxidant effects.

Main Methods:

  • Whole-cell patch-clamp electrophysiology was used to record proton currents in BV2 microglial cells.
  • Concentration-dependent inhibition of proton currents by chlorprothixene and flupentixol was assessed.
  • Kinetic properties and voltage-dependence of proton currents were analyzed in the presence of chlorprothixene.

Main Results:

  • Both chlorprothixene and flupentixol inhibited proton currents in a concentration-dependent manner.
  • Chlorprothixene demonstrated an IC50 of 1.7μM, while flupentixol had an IC50 of 6.6μM.
  • Chlorprothixene slowed both activation and deactivation kinetics of proton currents and shifted activation voltage.

Conclusions:

  • Chlorprothixene and flupentixol inhibit voltage-gated proton channels in microglia.
  • Inhibition of these proton channels likely contributes to the observed antioxidant effects of thioxanthene antipsychotics.
  • This mechanism offers a potential therapeutic avenue for neurodegenerative diseases characterized by oxidative stress.
Keywords:
ChlorprothixeneFlupentixolMicrogliaProton channelThioxanthenes

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