Dehydroepiandrosterone and α-estradiol limit the functional alterations of rat brain mitochondria submitted to different experimental stresses

The effects of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), alpha-estradiol and P-estradiol on the main functions of purified rat brain mitochondria were investigated in basal conditions and after being submitted to various stresses including anoxia-reoxygenation, uncoupling and apoptosis, In basal conditions, DHEA (1 muM) and alpha-estradiol (1 muM) inhibited the respiratory control ratio (RCR) from 3.1 to 23 (25%). After anoxia-reoxygenation, DHEA (1 muM) and alpha-estradiol (1 muM) reversed significantly (P < 0.01) the RCR decrease from 1.4 to 2.0 (21.5%) by restoring the state 4. This effect was observed when DHEA was added either before anoxia or before reoxygenation and when alpha-estradiol was added before anoxia. The mitochondrial membranes damaged after the anoxia-reoxygenation were 70 and 50%, respectively, protected by DHEA and alpha-estradiol at 1 muM. They also limited by about 50%, the cytochrome c release induced by the anoxia-reoxgenation. The oxygen consumption of mitochondria in presence of NADH (130 muM) and cytochrome c (5 muM) was significantly inhibited by DHEA and alpha-estradiol with high EC50 of 30 and 22 pM. respectively. At 1 muM, they also inhibited the 10 muM carbonyl cyanide m-chlorophenylhy-drazone-induced uncoupling to about 35% whereas alpha-estradiol only decreased it to 9%. Our results indicated that DHEA and alpha-estradiol partly preserved the mitochondrial functions altered by an anoxia-reoxygenation with a concentration-dependent effect. The mechanism involved was independent of the classical genomic effect of steroids. the antioxidant properties but implicated a direct action on the mitochondrial membranes, (C) 2002 IBRO. Published by Elsevier Science Ltd. All rights reserved.