ToxSci Advance Access originally published online on July 18, 2006
Toxicological Sciences 2006 93(2):348-356; doi:10.1093/toxsci/kfl064
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Dehydroepiandrosterone Inhibits Complex I of the Mitochondrial Respiratory Chain and is Neurotoxic In Vitro and In Vivo at High Concentrations
* Department of Pharmacology, and Department of Pathophysiology, Centre of Molecular and Clinical Medicine, University of Tartu, 51014 Tartu, Estonia
Received May 25, 2006; accepted July 14, 2006
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 suppresses the mitochondrial respiration in permeabilized neurons (half maximal inhibitory concentration 13µM) 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 hypoglycemic 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 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.
Key Words: mitochondria; neurosteroids; neurodegeneration; neurotoxicity; complex I of the mitochondrial electron transport chain; dehydroepiandrosterone.