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ToxSci Advance Access published online on July 18, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl064
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received May 25, 2006
Accepted July 14, 2006

Environmental Toxicology

Dehydroepiandrosterone Inhibits Complex I of the Mitochondrial Respiratory Chain and is Neurotoxic In Vitro and In Vivo at High Concentrations

Dzhamilja Safiulina 1, Nadezhda Peet 2, Enn Seppet 2, Alexander Zharkovsky 1, and Allen Kaasik 1 *

1 Department of Pharmacology, Centre of Molecular and Clinical Medicine, University of Tartu, Ravila 19, 51014 Tartu, ESTONIA
2 Department of Pathophysiology, Centre of Molecular and Clinical Medicine, University of Tartu, Ravila 19, 51014 Tartu, ESTONIA

* To whom correspondence should be addressed.
Allen Kaasik, E-mail: Allen.Kaasik{at}ut.ee


  Abstract

Dehydroepiandrosterone (DHEA) is widely used as a food supplement and considered to be relatively safe. In animal studies, however, additions of high concentrations of DHEA to the diet have led to hepatotoxicity as well as liver mitochondrial dysfunction. This study was therefore designed to find out whether DHEA is able to inhibit the respiratory activity also in neuronal mitochondria and to reveal whether this leads to functional disturbance in the brain.

Using different mitochondrial substrates, we show here that DHEA suppress the mitochondrial respiration in permeabilized neurons (IC50 13 mikroM) by inhibiting complex I of the mitochondrial electron transport chain. Treatment with DHEA was associated with increased glucose expenditure in intact cultures and led to neuronal death. The latter was most prominent in hypoglycaemic conditions. Mice fed with pellet containing 0.6% DHEA for 3 months showed a significant neuronal loss in the cerebral cortex and hippocampus, a slightly decreased dopamine/dihydroxyphenylacetic acid (DOPAC) ratio, as well as motor impairment. The main conclusion of the present study is that high concentrations of DHEA inhibit complex I of the mitochondrial respiratory chain and are neurotoxic in vitro and in vivo.

Keywords: mitochondria; neurosteroids; neurodegeneration; neurotoxicity; complex I of the mitochondrial electron transport chain, dehydroepiandrosterone.
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