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The translocator protein (TSPO) is an outer mitochondrial membrane protein involved in the transport of cholesterol into the mitochondria, which is the first step for the synthesis of steroid hormones, as well as in the regulation of mitochondrial permeability transition pore opening and apoptosis. Studies have shown that the activation of TSPO may promote neuroprotective actions in experimental models of neurodegeneration and brain injury. In a previous study, our group showed that 4′-chlorodiazepam (4′-CD), a TSPO ligand, was neuroprotective against amyloid-beta (Aβ) in SHSY-5Y neuroblastoma cells. The aim of this study was to evaluate if 4′-CD was also neuroprotective against Aβ in organotypic hippocampal cultures and to identify its mechanisms of action. Aβ decreased the cell viability of organotypic hippocampal cultures, while 4′-CD had a neuroprotective effect when administered at 100 nM and 1000 nM. The neuroprotective effects of 4′-CD against Aβ were associated with an increased expression of superoxide dismutase (SOD). No differences were found in the expression of catalase, glial fibrillary acidic protein, Akt and procaspase-3. In summary, our results show that 4′-CD is neuroprotective against Aβ by a mechanism involving the modulation of SOD protein expression., Bruno D. Arbo received a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Christianne G. Salbego received a CNPq 1C Researcher Productivity Grant. Maria Flávia M. Ribeiro received a CNPq 1D Researcher Productivity Grant.

Translocator protein (TSPO) is an 18kDa protein located at contact sites between the outer and the inner mitochondrial membrane. Numerous studies have associated TSPO with the translocation of cholesterol across the aqueous mitochondrial intermembrane space and the regulation of steroidogenesis, as well as with the control of some other mitochondrial functions, such as mitochondrial respiration, mitochondrial permeability transition pore opening, apoptosis and cell proliferation. In the brain, changes in TSPO expression occur in several neuropathological conditions including neurodegenerative diseases and psychiatric disorders. Furthermore, TSPO ligands have been shown to promote neuroprotection in animal models of brain pathology. At least in some cases, the mechanisms of neuroprotection are associated with modifications in brain steroidogenesis. In addition, regulation of neuroinflammation seems to be a common mechanism in the neuroprotective actions of TSPO ligands in different animal models of brain pathology.

DHEA is a neuroactive steroid, due to its modulatory actions on the central nervous system (CNS). DHEA is able to regulate neurogenesis, neurotransmitter receptors and neuronal excitability, function, survival and metabolism. The levels of DHEA decrease gradually with advancing age, and this decline has been associated with age related neuronal dysfunction and degeneration, suggesting a neuroprotective effect of endogenous DHEA. There are significant sex differences in the pathophysiology, epidemiology and clinical manifestations of many neurological diseases. The aim of this study was to determine whether DHEA can alter glucose metabolism in different structures of the CNS from male and female rats, and if this effect is sex-specific. The results showed that DHEA decreased glucose uptake in some structures (cerebral cortex and olfactory bulb) in males, but did not affect glucose uptake in females. When compared, glucose uptake in males was higher than females. DHEA enhanced the glucose oxidation in both males (cerebral cortex, olfactory bulb, hippocampus and hypothalamus) and females (cerebral cortex and olfactory bulb), in a sex-dependent manner. In males, DHEA did not affect synthesis of glycogen, however, glycogen content was increased in the cerebral cortex and olfactory bulb. DHEA modulates glucose metabolism in a tissue-, dose- and sex-dependent manner to increase glucose oxidation, which could explain the previously described neuroprotective role of this hormone in some neurodegenerative diseases.

This study examined, in the liver of young and old (3- and 24-month-old, respectively) healthy Wistar rats, the in vivo effect of dehydroepiandrosterone (DHEA) (10mg/kg body weight) administered subcutaneously for 5 weeks. Reduced (GSH) and oxidized (GSSG) glutathione levels, glucose-6-phosphate dehydrogenase (G6PDH), glutathione-S-transferase (GST), glutathione peroxidase (GPx) and catalase (CAT) activities, hydrogen peroxide concentration, GST and p-Akt/Akt immunocontent ratio were assessed in hepatic tissue. DHEA treatment significantly increased total glutathione content (17%) and GSH (22%) in 3- and 24-month-old treated groups when compared to control groups. The aging factor increased G6PDH (51%) and GPx (22%) activities as well as the hydrogen peroxide concentration (33%), independently of treatment. DHEA treatment increased p-Akt (54%) and p-Akt/Akt ratio (36%) immunocontents in both treated groups. Increased serum levels of alanine aminotransferase (ALT) in aged rats were reduced by DHEA treatment (34%).

Dehydroepiandrosterone (DHEA) is an endogenous steroid hormone involved in a number of biological actions. This study shows the effects of DHEA on glucose metabolism, hydrogen peroxide and thioredoxin levels in the skeletal muscle of control and diabetic rats. Control and diabetic rats were chronically treated with DHEA (10mg/kg) diluted in oil. Plasma concentration of DHEA and glucose, glucose uptake and oxidation, hydrogen peroxide, GLUT4, Akt and thioredoxin (Trx) was measured in the muscle. Results showed that there was a decrease in blood glucose in diabetic rats, probably linked to an increase in the glucose oxidation by the muscle or glucose uptake by some tissues. Despite the increase in the expression of GLUT4 in DHEA-treated rats, the glucose uptake was only higher in the control rats, showing that the glucose transporter may be present but not functional in the diabetic rats. The low expression of Trx due to diabetes became even lower with DHEA treatment. Although the reduction in blood glucose may be favorable, the decrease in Akt and Trx displays an environment conducive to redox imbalance. Thus, further studies are needed to ascertain the effects of DHEA treatment in diabetic rats.

Dehydroepiandrosterone (DHEA) is an endogenous steroid synthesized mainly in the adrenal cortex. It is known that DHEA is a precursor of sex steroids and that part of its effects depends on its conversion to estrogens and androgens. Sex steroids exert profound and controversial effects on cardiovascular function. Exogenous DHEA can exert a dual effect, antioxidant or prooxidant, depending on the dose and on the tissue specificity [1,2] (F. Celebi, I. Yilmaz, H. Aksoy, M. Gümüs, S. Taysi, D. Oren, Dehydroepiandrosterone prevents oxidative injury in obstructive jaundice in rats, J. Int. Med. Res. 32 (4) (2004) 400-405; S.K. Kim, R.F. Novak, The role of intracellular signaling in insulin-mediated regulation of drug metabolizing enzyme gene and protein expression, Pharmacol. Ther. 113 (1) (2007) 88-120). Akt signaling pathway is one of the anti-proliferative mechanisms of DHEA (Y. Jiang, T. Miyazaki, A. Honda, T. Hirayama, S. Yoshida, N. Tanaka, Y. Matsuzaki, Apoptosis and inhibition of the phosphatidylinositol 3-kinase/Akt signaling pathway in the anti-proliferative actions of dehydroepiandrosterone, J. Gastroenterol. 40 (5) (2005) 490-497). Heart homogenates were prepared to quantify lipid peroxidation (LPO), concentration of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), 4-hydroxy-2-nonenal (HNE) and p-Akt/Akt ratio, and the activities of those antioxidant enzymes. When administrated to male Wistar rats in short-term (6 or 24h) intraperitoneally, DHEA produced significant differences in some parameters of oxidative stress in rat hearts among the distinct doses (1, 10, and 50mg/kg) used. The results here presented, regarding 6 and 24h oxidative stress status, have shown that DHEA injections promoted a prooxidant answer in healthy Wistar rat hearts.

Dehydroepiandrosterone (DHEA) is a steroid synthesized in adrenal cortex as well as in the nervous system. DHEA effects on central nervous system (CNS) have been associated with several brain functions such as marked neurotrophic and neuroprotective activity. DHEA plasma concentration decreases steadily with aging and studies have reported an inverse correlation between levels of DHEA and neurological diseases age-associated. Nonetheless, its mechanisms of action are not yet fully understood. Akt signaling pathway is one protein kinase which has been related to be DHEA modulated. The goal of this study was to investigate whether short-term (6 or 24h) or chronic (5 weeks) DHEA treatment modulates Akt in CNS of adult (3 months) and aged (18 and 24 months) healthy rats. Hypothalamus and hippocampus homogenates were prepared to quantify total-Akt and phosphorylated Akt at Ser(473) (pAkt). The results here presented have shown that acute (50mg/kg) and chronic (10mg/kg) DHEA injections modulate total and pAkt levels. This effect was dose and time-dependent as well as age and tissue-dependent. In addition, the age variable also intervenes on total and pAkt levels expression independently of DHEA treatment.