Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons

Jonathan E. Hood, Jerry W. Jenkins, Dejan Milatovic, Lu Rongzhu, Michael Aschner

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Mefloquine is an effective antimalarial that can cause adverse neurological events including headache, nausea, fatigue, insomnia, anxiety and depression. In this study, we examined the oxidative stress response in primary rat cortical neurons treated with mefloquine by quantifying oxidative stress markers glutathione (GSH) and F2-isoprostanes (F2-isoPs). Furthermore, we examined whether mefloquine induces synaptodendritic degeneration of primary rat cortical neurons. GSH was quantified in cortical neurons after 24-h treatment with mefloquine (0, 1, 5, 10μM) using monochlorobimane. F2-isoPs were quantified in cortical neurons after 24-h treatment with mefloquine (0, 1, 5, 10μM) using a stable isotope dilution method with detection by gas chromatography/mass spectrometry and selective ion monitoring. The concentration dependent decrease in GSH and the concomitant increase of F2-isoPs indicates the presence of oxidative stress in primary rat cortical neurons treated with mefloquine. Following a 24-h treatment with mefloquine, primary rat cortical neurons (0, 5, 10μM) were fixed with 4% paraformaldehyde. Images from eight optical sections covering a distance of 2.88μm on the z-axis were acquired using a confocal laser scanning unit. Traced images were analyzed with NeuroExplorer, a neurophysiological data analysis package. Mefloquine induces a concentration dependent decrease in the number of spines per neuron and the spine density, suggesting that mefloquine induced oxidative stress may be associated with the synaptodendritic degeneration. Together with previous work, there is strong evidence that a relationship exists between calcium homeostasis disruption, ER stress response, the oxidative stress response, and neurodegeneration. Understanding how oxidative stress alters the morphology of cortical neurons treated with mefloquine will provide further insight into the mechanism(s) related to clinically observed adverse neurological events.

Original languageEnglish (US)
Pages (from-to)518-523
Number of pages6
JournalNeuroToxicology
Volume31
Issue number5
DOIs
StatePublished - Sep 1 2010
Externally publishedYes

Keywords

  • Glutathione
  • Isoprostane
  • Mefloquine
  • Neurodegeneration
  • Oxidative stress

ASJC Scopus subject areas

  • Neuroscience(all)
  • Toxicology

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