TY - JOUR
T1 - Mefloquine induces oxidative stress and neurodegeneration in primary rat cortical neurons
AU - Hood, Jonathan E.
AU - Jenkins, Jerry W.
AU - Milatovic, Dejan
AU - Rongzhu, Lu
AU - Aschner, Michael
PY - 2010/9
Y1 - 2010/9
N2 - 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.
AB - 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.
KW - Glutathione
KW - Isoprostane
KW - Mefloquine
KW - Neurodegeneration
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=77956226033&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77956226033&partnerID=8YFLogxK
U2 - 10.1016/j.neuro.2010.05.005
DO - 10.1016/j.neuro.2010.05.005
M3 - Article
C2 - 20562019
AN - SCOPUS:77956226033
SN - 0161-813X
VL - 31
SP - 518
EP - 523
JO - Neurotoxicology
JF - Neurotoxicology
IS - 5
ER -