Inhibitory Effect Of Dehydroepiandrosterone Research Articles

DHEA prevents ribavirin-induced anemia via inhibition of glucose-6-phosphate dehydrogenase

Ribavirin has been widely used for antiviral therapy. Unfortunately, ribavirin-induced anemia is often a cause of limiting or interrupting treatment. Our team has observed that dehydroepiandrosterone (DHEA) has a protective effect against in vitro and in vivo ribavirin-induced hemolysis. The aim of this study was to better understand this effect as well as the underlying mechanism(s).DHEA was able to reduce in vitro intraerythrocytic ATP depletion induced by ribavirin. Only 1% of ATP remained after incubation with ribavirin (2 mM) at 37 °C for 24 h vs. 37% if DHEA (200 μM) was added (p < 0.01). DHEA also helped erythrocytes conserve their size, with a shrinkage of only 10% vs 40% at 24 h with ribavirin alone (p < 0.01), and reduced phosphatidylserine exposure at the outer membrane, i.e. 27% vs 40% at 48 h, (p < 0.05). DHEA also inhibits ribavirin-induced hemolysis, i.e. 34% vs 46.5% at 72 h (p < 0.01).DHEA is an inhibitor of glucose-6-phosphate dehydrogenase (G6PD), a key enzyme in the hexose monophosphate shunt connected to the glycolytic pathway which is the only energy supplier of the red blood cell in the form of ATP. We have confirmed this inhibitory effect in the presence of ribavirin. All these observations suggest that ribavirin-induced hemolysis was initiated by ATP depletion, and that the inhibitory effect of DHEA on G6PD was able to rescue enough ATP to limit this hemolysis. This mechanism could be important for improving the therapeutic management of patients treated with ribavirin.

The inhibitory effect of dehydroepiandrosterone and its derivatives against influenza A virus in vitro and in vivo

The antiviral activity of dehydroepiandrosterone (DHEA) and 21 synthetic derivatives against influenza A virus (IAV) replication was investigated in vitro in cell culture. Our results revealed that three DHEA analogues were potent inhibitors of IAV multiplication in MDCK cells and mainly blocked the post-attachment stage of viral infection. Among these derivatives, one containing a 2-OH-Ph moiety (3i) exhibited the best inhibitory effects against H1N1 and H3N2 IAV in a dose-dependent manner. Moreover, treatment with compound 3i decreased progeny virus yields, viral RNA synthesis and protein expression. Orally administered compound 3i at 25 or 50mg/kg/day for 5days protected mice from lethal A/FM/1/47 (H1N1) challenge by reducing the viral titers in the lungs and promoting survival of infected mice. Our results suggest that DHEA-dihydrazone derivatives may provide promising lead scaffolds for further design and synthesis of potential antiviral agents.

Dehydroepiandrosterone effect on Plasmodium falciparum and its interaction with antimalarial drugs

Dehydroepiandrosterone (DHEA) inhibits glucose 6-phosphate dehydrogenase (G6PDH) of different species and may potentially decrease intracellular glutathione. Therefore, it can have and enhance anti-parasitic action against Plasmodium spp. We evaluated the antiplasmodial activity and the interaction of DHEA with several antimalarial drugs. The inhibitory effect of DHEA on erythrocytic and G6PDH activity and changes in the content of total and reduced gluthatione Plasmodium falciparum content were also evaluated. DHEA showed antiplasmodial activity in vitro, but the potency was low (IC(50) 118.5 μM). DHEA inhibits G6PDH from healthy erythrocyte and decreases GSH content in both erythrocytes and P. falciparum. DHEA did not synergize or antagonize the antiplasmodial effect of several antimalarial drugs. The most important actions of DHEA were the inhibition of G6PDH activity, and the decrease in both P. falciparum and erythrocyte GSH. Since most of the GSH in Plasmodium spp. infected erythrocytes comes from the parasite itself, it is possible that DHEA analogs could act with higher selectivity, better potency, and might interact synergistically with antimalarials drugs.

In vitro antiviral activity of dehydroepiandrosterone, 17 synthetic analogs and ERK modulators against herpes simplex virus type 1

In the present study the in vitro antiviral activity of dehydroepiandrosterone (DHEA) and 17 synthetic derivatives against herpes simplex type 1 (HSV-1) was determined. DHEA, epiandrosterone (EA), two synthetic DHEA analogs and three synthetic EA analogs showed a selective inhibitory effect on HSV in vitro multiplication. DHEA and E2, a synthetic derivative of EA, were not found to be virucidal to cell-free HSV-1 and did not impair virus adsorption or penetration. We determined that treatment with both compounds decreased viral protein synthesis. Moreover, inhibitory effect of DHEA and E2 on extracellular viral titer was stronger than the inhibition found on total viral infectivity, suggesting that the antiherpetic activity of these compounds may also be in part due to an inhibition in virus formation and release.Since DHEA is a known Raf/MEK/ERK signaling pathway activator, we studied the role of this pathway on HSV-1 infection. ERK1/2 phosphorylation was stimulated in HSV-1 infected cultures. UO126, a Raf/MEK/ERK signaling pathway inhibitor, impaired viral multiplication, while anisomycin, an activator of this pathway, enhanced it.Treatment with DHEA 6h before infection enhanced HSV-1 multiplication. On the contrary, pre-treatment with E2, which does not modulate Raf/MEK/ERK signaling pathway, did not produce an increase of viral replication. Taking together these results, the antiviral activity of DHEA seems to occur via a mechanism independent of its ability to modulate ERK phosphorylation.

Inhibitory effect of dehydroepiandrosterone on brain monoamine oxidase activity: In vivo and in vitro studies

Aims To evaluate the acute effect of dehydroepiandrosterone (DHEA) on monoamine oxidase (MAO) activity in the corpus striatum (CS) and the nucleus accumbens (NAc) in vivo and in vitro. Main methods Male Wistar rats received an i.p. injection of DHEA (30, 60 and 120 mg/kg) and MAO activity was assayed by formation of 4-hydroxyquinoline 2 h later. For in vitro studies, DHEA (100 nM–1 mM) was added to brain tissue homogenates to assay MAO activity. Key findings DHEA significantly reduced (− 24%) total MAO activity in the NAc ( F = 8.5, p < 0.001), but not in the CS, at 120 mg/kg dose. No significant difference was observed when MAO A and MAO B activities were independently analyzed. When assayed in vitro, total MAO, MAO A and MAO B activities were reduced by DHEA to 55.7, 28.2 and 54.4% in the NAc and to 71.9, 44.2 and 61.2% in the CS, respectively (IC 50 4.7–56.1 µM). Significance An inhibitory effect of DHEA on MAO activity may be involved in the antidepressant and neuroprotective effects of the steroid. Since MAO inhibition reduces neurodegeneration in clinical trials for Parkinson's disease, our results suggest that DHEA may be useful to treat depression and to prevent neuronal death in this disorder.

Effect of DHEA glutamate release from synaptosomes of rats at different ages.

Dehydroepiandrosterone (DHEA) exerts multiple effects in the central nervous system. Most of them seem to be mediated through their nongenomic actions on neurotransmitter receptors, and these actions occur within seconds or milliseconds. DHEA increases neuronal excitability, enhances neuronal plasticity, and has neuroprotective properties. By investigating glutamate release from synaptosomes of rats at different ages (from 17 days to 12 months), we observed that (i) there is an increase in basal and K(+)-stimulated L-[3H] glutamate release in rats at 12 months old, when compared to other ages; and (ii) there is an inhibitory effect of DHEA on basal L-[3H] glutamate release in 12 months old. This inhibitory effect of DHEA could be related to its reported protective role against excitotoxicity caused by overstimulation of the glutamatergic system and ageing.

Symposium 1. Hormone and longevity. Additional speech. Apoptosis inhibitory effect of Dehydroepiandrosterone (DHEA) and role in longevity.

Symposium 1. Hormone and longevity. Additional speech. Apoptosis inhibitory effect of Dehydroepiandrosterone (DHEA) and role in longevity.

DHEA and the Intracrine Formation of Androgens and Estrogens in Peripheral Target Tissues: Its Role during Aging

Human and some other primates are unique since their adrenals secrete large amounts of dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), which are converted into androstenedione (4-dione) and then into potent androgens and estrogens in peripheral tissues, therefore providing autonomous intracrine control to target tissues that can adjust the formation and metabolism of active sex steroids according to local requirements. Knowledge in this area has recently made rapid progress with the elucidation of the structure of most of the tissue-specific cDNAs and genes that encode the steroidogenic enzymes responsible for the transformation of these inactive precursor steroids into androgens and/or estrogens. It is estimated that 30 to 50% of total androgens in men are synthesized in peripheral intracrine tissues from inactive adrenal precursors while, in women, peripheral estrogen formation is even more important, the best estimate being 75% before menopause and 100% after menopause. The marked reduction in the formation of DHEA-S by the adrenals during aging, especially before the age of 50 years, results in a dramatic fall in the formation of active sex steroids in peripheral target tissues, a situation which is thought to be associated with a long series of age-related decreases such as insulin resistance, obesity, osteoporosis, cardiovascular diseases, loss of muscle mass, cancer and other diseases. We have demonstrated for the first time a series of medically important beneficial effects of DHEA administered for 12 months to post-menopausal women. Most interestingly, the bone mineral density significantly increased. This relatively rapid change was associated with an increase in plasma osteocalcin, a marker of bone formation, while a decrease in bone resorption reflected by a decrease in urinary hydroxyproline excretion was observed in parallel. In addition, the estrogenic stimulation of vaginal cytology in the absence of any sign of stimulatory effect on the endometrium is also of potentially major interest for the prevention and management of menopause. Furthermore, the inhibitory effect of DHEA on the growth of human breast cancer xenografts in vivo in nude mice supports the beneficial use of DHEA as hormone replacement therapy in women.

Dehydroepiandrosterone inhibits the growth of DMBA-induced rat mammary carcinoma via the androgen receptor.

Dehydroepiandrosterone (DHEA) exerts opposite effects on the growth of mammary carcinoma. A stimulatory effect is observed in absence of estrogens, due to interaction of DHEA metabolite(s) with the estrogen receptor (ER); by contrast, in presence of estrogens DHEA inhibits tumor growth. The mechanism underlying the latter DHEA effect, which might be related to activation of the androgen receptor (AR), is poorly understood. Focusing on this point, we measured over a 20 days period the areas of DMBA-induced mammary tumors in rats given DHEA and/or the anti-androgen flutamide (FLU). Results show that DHEA inhibitory effect on the growth of mammary carcinoma is no longer observed when the ARs are blocked by FLU. Data are consistent with an involvement of ARs in the inhibitory effect of DHEA.

Dehydroepiandrosterone markedly inhibits the accumulation of cholesteryl ester in mouse macrophage J774-1 cells

To clarify the antiatherogenic mechanism of action of dehydroepiandrosterone (DHEA), we investigated the effects of DHEA on the accumulation of cholesteryl ester (CE) in cultured mouse macrophage J774-1 cells. The accumulation of CE in J774-1 cells in the presence of acetyl low density lipoprotein (AcLDL) and 10 −5 mol/1 DHEA was significantly reduced to 30% of the control values for 24 h. The marked effect of DHEA was observed as early as 6 h and continued at least for 48 h. This reduction by DHEA was dose-dependent and occurred starting at a DHEA dose of 5 × 10 −7 mol/1 for 24 h. DHEA treatment did not induced any changes in the cell surface binding, cell-association, or degradation of AcLDL. In comparison, the DHEA analogues, 8354 and 8356, which are known to be much stronger inhibitors of glucose 6-phosphate dehydrogenase than DHEA, did not show as marked an effect as DHEA on the accumulation of CE during the first 6 h. However, after 24–48 h of incubation, both 8354 and 8356 caused a marked reduction in the accumulation of CE similar to that observed with DHEA. A quantitative analysis of the cellular cholesterol content revealed that DHEA caused a marked reduction in CE with a concomitant continuous increase in free cholesterol (FC), while the DHEA analogues caused a marked reduction in CE with no change in FC. DHEA demonstrated little inhibitory effect on 25-hydroxycholesterol-driven esterification. Moreover, 10 −5 mol/1 DHEA induced a CE reduction in the foam cells induced by AcLDL. The CE-reducing capacity was also observed in the DHEA analogues. This CE-reducing capacity disappeared, however, when acyl CoA:cholesterol acyltransferase inhibitor, 58-035, was also present. Based on these findings, it can be concluded that the inhibitory effect of DHEA on the CE storage in response to AcLDL can be explained, at least in part, by two mechanisms. First, a recently published mechanism, namely, the inhibitory action of DHEA on lysosomal cholesterol transport, correlates well with the inhibition against foam cell transformation by DHEA in the early phase (at 6 h) observed in our study. With regard to the second mechanism, the CE-reducing capacity of DHEA from CE-laden foam cells, which appears to be related to a decreased cholesteryl ester cycle, may contribute to the inhibitory effect on the CE storage in the late phase (at 24 h and 48 h). These phase-specific inhibitory mechanisms of DHEA on the CE-storage may therefore partly explain the antiatherogenic action of DHEA.

Dehydroepiandrosterone markedly inhibits the accumulation of cholesteryl ester in mouse macrophage J774-1 cells

<h2>Abstract</h2> To clarify the antiatherogenic mechanism of action of dehydroepiandrosterone (DHEA), we investigated the effects of DHEA on the accumulation of cholesteryl ester (CE) in cultured mouse macrophage J774-1 cells. The accumulation of CE in J774-1 cells in the presence of acetyl low density lipoprotein (AcLDL) and 10⁻⁵ mol/1 DHEA was significantly reduced to 30% of the control values for 24 h. The marked effect of DHEA was observed as early as 6 h and continued at least for 48 h. This reduction by DHEA was dose-dependent and occurred starting at a DHEA dose of 5 × 10⁻⁷ mol/1 for 24 h. DHEA treatment did not induced any changes in the cell surface binding, cell-association, or degradation of AcLDL. In comparison, the DHEA analogues, 8354 and 8356, which are known to be much stronger inhibitors of glucose 6-phosphate dehydrogenase than DHEA, did not show as marked an effect as DHEA on the accumulation of CE during the first 6 h. However, after 24–48 h of incubation, both 8354 and 8356 caused a marked reduction in the accumulation of CE similar to that observed with DHEA. A quantitative analysis of the cellular cholesterol content revealed that DHEA caused a marked reduction in CE with a concomitant continuous increase in free cholesterol (FC), while the DHEA analogues caused a marked reduction in CE with no change in FC. DHEA demonstrated little inhibitory effect on 25-hydroxycholesterol-driven esterification. Moreover, 10⁻⁵ mol/1 DHEA induced a CE reduction in the foam cells induced by AcLDL. The CE-reducing capacity was also observed in the DHEA analogues. This CE-reducing capacity disappeared, however, when acyl CoA:cholesterol acyltransferase inhibitor, 58-035, was also present. Based on these findings, it can be concluded that the inhibitory effect of DHEA on the CE storage in response to AcLDL can be explained, at least in part, by two mechanisms. First, a recently published mechanism, namely, the inhibitory action of DHEA on lysosomal cholesterol transport, correlates well with the inhibition against foam cell transformation by DHEA in the early phase (at 6 h) observed in our study. With regard to the second mechanism, the CE-reducing capacity of DHEA from CE-laden foam cells, which appears to be related to a decreased cholesteryl ester cycle, may contribute to the inhibitory effect on the CE storage in the late phase (at 24 h and 48 h). These phase-specific inhibitory mechanisms of DHEA on the CE-storage may therefore partly explain the antiatherogenic action of DHEA.

Dehydroepiandrosterone: Antiglucocorticoid Action in Mice

The acute effect of dehydroepiandrosterone (DHEA) and its conjugate, DHEA-sulfate (DHEA-S) on glucocorticoid action was tested in vivo using male Swiss-Webster mice. The authors found that DHEA and DHEA-S significantly inhibited induction of hepatic tyrosine aminotransferase activity, although the former was more potent. This inhibition was dose- and time-dependent and was not demonstrable with other steroids. The same inhibitory effect of DHEA was seen with kidney tyrosine aminotransferase induction, as well as with liver and kidney ornithine decarboxylase enzyme activity, another glucocorticoid-induced enzyme. The conclusion is that DHEA acts acutely as an antiglucocorticoid and exerts its effect in different glucocorticoid-sensitive systems.