Dehydroepiandrosterone protects hippocampal neurons against neurotoxin-induced cell death: mechanism of action.

Dehydroepiandrosterone (DHEA), an adrenal cortex hormone secreted in large quantities in humans, protects cells of the clonal mouse hippocampal cell line HT-22 against the excitatory amino acid glutamate (5 mM), and amyloid beta-protein (2 microM) toxicity in a dose-dependent manner with optimum protection obtained at 5 microM concentration of DHEA. The protective effects of DHEA appear to be specific in that other related steroids and metabolites of DHEA, such as 5-androstene-3beta,17beta-diol, etiocholan-3alpha-ol-17-one, etiocholan-3beta-ol-17-one, testosterone, and 5alpha-androstane-3, 17-dione, offered no protection even at 50 microM concentrations. In addition, using immunocytochemical techniques, we observed that 20 hr of treatment with 5 mM glutamate remarkably increased glucocorticoid receptor (GR) nuclear localization in neuronal cells. Interestingly, 5 microM DHEA treatment for 24 hr, followed by 5 mM glutamate treatment for 20 hr almost completely reversed the copious nuclear localization of GR observed by glutamate treatment alone. Results obtained suggest that DHEA protects hippocampal neurons, at least in part, by its antiglucocorticoid action via decreasing hippocampal cells nuclear GR levels.

Antibacterial and immunostimulating casein-derived substances from milk: casecidin, isracidin peptides.

Apart from immunoglobulin A and G antibodies and plasma cells, milk also contains antibiotic/host protective peptides that are of value not only for maintenance of its nutritional integrity but also for protection of the newborn and, possibly, protection of the lactating mother. Among the first such peptides identified with casecidin; following chymosin digestion of casein at pH 6 or 7, casecidin inhibited in vitro staphylococci, sarcina, Bacillus subtilis, Diplococcus pneumoniae and Streptococcus pyogenes. Inhibition occurred at high concentrations, in vitro, compared with commercial antibiotics, and thus interest in casecidin languished. Work with casecidin was followed by investigation of a related refined non-immunogenic product of chymosin digestion of alpha s1-casein. This product consisted of the N -terminal segment (1-23) of alpha s1-casein B, named "isracidin", and was significantly effective in vivo at concentrations that were competitive with known antibiotics, as seen in the protection of mice against lethal infection by Staphylococcus aureus strain Smith. Field trials showed that injection of isracidin into the udder gave protection against mastitis in sheep and cows. Isracidin was both therapeutic and prophylactic and responses to its therapeutic effect produced long-term immune resistance. Isracidin protected mice against Candida albicans, by stimulation of both phagocytosis and immune responses. However, like other recently described milk-derived peptides, despite its clinical value, isracidin was overlooked because of the lack of commercial interest in the 1970s and early 1980s, in host-mediated non-specific resistance as a therapeutic approach to infection. Another problem that impeded commercial interest was the isomeric variation in isracidin peptides seen on a large-scale batch production for commercial use. It is hoped that this review of previous studies of the activity of isracidin action will revive interest in milk as an antibiotic source.

Review of the biology of Quercetin and related bioflavonoids.

The French paradox is a dietary anomaly which has focused attention on the Mediterranean diet. Epidemiological studies revealed that this diet, replete in flavonoid-rich foods (Allium and Brassica vegetables, and red wine), correlated with the increased longevity and decreased incidence of cardiovascular disease seen in these populations. The most frequently studied flavonoid, quercetin, has been shown to have biological properties consistent with its sparing effect on the cardiovascular system. Quercetin and other flavonoids have been shown to modify eicosanoid biosynthesis (antiprostanoid and anti-inflammatory responses), protect low-density lipoprotein from oxidation (prevent atherosclerotic plaque formation), prevent platelet aggregation (antithrombic effects), and promote relaxation of cardiovascular smooth muscle (antihypertensive, antiarrhythmic effects). In addition, flavonoids have been shown to have antiviral and carcinostatic properties. However, flavonoids are poorly absorbed from the gut and are subject to degradation by intestinal micro-organisms. The amount of quercetin that remains biologically available may not be of sufficient concentration, theoretically, to explain the beneficial effects seen with the Mediterranean diet. The role of flavonoids may transcend their presence in food. The activity of flavonoids as inhibitors of reverse transcriptase suggests a place for these compounds in the control of retrovirus infections, such as acquired immunodeficiency syndrome (AIDS). In addition to specific effects, the broad-modulating effects of flavonoids as antioxidants, inhibitors of ubiquitous enzymes (ornithine carboxylase, protein kinase, calmodulin), and promoters of vasodilatation and platelet disaggregation can serve as starting material for drug development programmes.

Glucocorticoids enhance the potency of Schwann cell mitogens.

Previous studies have documented that cultured Schwann cells require serum-containing medium to respond maximally to mitogens. We now report that Schwann cells are able to proliferate to a mitogenic response in a serum-free defined medium termed oligodendrocyte defined media (ODM). Glucocorticoids are the essential component of ODM which allow Schwann cell proliferation in the serum-free medium. Charcoal treatment of the fetal calf serum decreases the mitogenic potency of the axolemma-enriched fraction (AEF) by 50%. The addition of 2 microM hydrocortisone to charcoal-treated fetal calf serum restores 75% of the lost mitogenicity. These observations are consistent with the view that glucocorticoids present in fetal calf serum are potent co-mitogens essential for AEF-induced Schwann cell proliferation. The synthetic glucocorticoid, dexamethasone, is a more potent co-mitogen than hydrocortisone, with a maximal effect at concentrations less than 10 nM. In contrast, other steroids including aldosterone, progesterone, testosterone, and 17 beta-estradiol have no effect on enhancing the mitogenic response of Schwann cells to the AEF. The glucocorticoid antagonists RU 486 and dehydroepiandrosterone (DHEA), but not the antiestrogenic compound tamoxifen, block AEF-induced Schwann cell proliferation. These results suggest that glucocorticoid-induced Schwann cell proliferation is mediated through a glucocorticoid receptor (GR) mechanism. We detected immunoreactivity to the GR in the cytoplasm, but not in the nuclei of Schwann cells grown in ODM lacking dexamethasone. The addition of 100 nM dexamethasone to these cultures resulted in immunoreactivity in the nucleus. This data suggests that glucocorticoids working through the GR are potent co-mitogens for Schwann cell proliferation.

Pineal control of aging: effect of melatonin and pineal grafting on aging mice.

Dark-cycle, night administration of the pineal hormone melatonin in drinking water to aging mice (15 months of age) prolongs survival of BALB/c females from 23.8 to 28.1 months and preserves aspects of their youthful state. Similar results were seen in New Zealand Black females beginning at 5 months and C57BL/6 males beginning at 19 months. As melatonin is produced in circadian fashion from the pineal, we grafted pineals from young 3- to 4-month-old donors into the thymus of 20-month-old syngeneic C57BL/6 male recipients, and a 12% increase in survival was induced. Prolongation of survival was also seen on pineal transplant to the thymus in C57BL/6, BALB/cJ, and hybrid female mice at 16, 19, and 22 months. In all studies, the endogenous pineal of grafted mice was left in situ. Pineal grafted aged mice display a remarkable maintenance of thymic structure and cellularity. Preservation of T-cell-mediated function, despite age, as measured by response to oxazolone is seen. Other evidence suggests that melatonin and/or pineal-related factors could produce their effects through an influence on thyroid function. These data indicate that pineal influences have a place in the physiologic regulation of aging.

Dehydroepiandrosterone prevents dexamethasone-induced hypertension in rats.

Dehydroepiandrosterone (DHEA) is an endogenous steroid having a wide variety of biological and biochemical effects. In the present study, we have examined the role of DHEA on various rodent models of experimental hypertension. Sprague-Dawley rats were given subcutaneous injections of 1.5 mg dexamethasone every alternate day, resulting in an increase in systolic blood pressure within 1 wk. Interestingly, administration of a pharmacological dose of 1.5, 3, or 7.5 mg DHEA along with dexamethasone prevented dexamethasone-induced hypertension in a dose-dependent manner. DHEA had no effect on the hypertension induced by deoxycorticosterone acetate (DOCA)-salt administration using uninephrectomized rats or on the genetic model of spontaneously hypertensive rats. Dexamethasone administration resulted in a significant weight loss in rats, which was not prevented by simultaneous administration of DHEA. These results indicate that dexamethasone-mediated weight loss may involve mechanisms separate from its hypertensive action. Dexamethasone treatment resulted in a significant decrease in food consumption that was not reversed by DHEA. It is concluded that DHEA at doses above physiological levels when given subcutaneously has no effect on DOCA-salt or a genetic model of hypertension but has a beneficial effect on dexamethasone-induced hypertension.

RU 486: how abortion politics have impacted on a potentially useful drug of broad medical application.

PIP: RU-486 or mifepristone is best known as an antiprogestin and an abortifacient, but it has broad medical applicability. The drug is also a potent blocker of corticosteroid receptors, and it has shown promise in the treatment of breast cancer, inoperable meningioma, and cushing's disease. Cushing's is a model for the symptomatology of aging which may involve enhanced response to corticosteroid. RU-486 has reversed the osteoporosis, thinning of skin, muscle atrophy, obesity, adult onset diabetes, depression, hypertension, and immunosuppression associated with this disease. RU-486 may be of value in aiding cervical dilation, lactation, and the treatment of endometriosis. In addition, breast, bowel, kidney tumors, hepatomas, endometrial cancer, and fibrosarcomas can show corticosteroid dependency, suggesting that RU-486 may have clinical value against inoperable tumors. In a preliminary 1987 phase I study, in estrogen-positive, chemotherapy-refractory breast cancer patients in Montpelier, France, Ru-486 produced objective tumor regression (6 of 22) that was prolonged (3 months) in 4 patients. Clinical relief of bone pain was observed in 7 of 23 patients with a decline in carcinoembryonic antigen (CEA) tumor makers in 8 patients. Growing in vitro data also show that RU-486 can directly inhibit breast cancer cell proliferation. RU-486 has application for HIV infection, based on data that there is a serum factor in AIDS patients that enhances corticosteroid lympholysis. IN addition, the immune restorative action of RU-486 suggests that it could counteract the immunosuppression seen in aging, in cancer, or in viral or stress-related disease, which has recently focused clinical attention on its potential in the treatment of senile dementia and depression. Scientific conferences and workshops are needed to alert scientists, physicians, and the public to the potential medical benefits of this drug.^ieng

Mechanism(s) of cytoprotective and anti-inflammatory activity of PGB1 oligomers: PGBx has potent anti-phospholipase A2 and anti-oxidant activity.

We postulate that the anti-PLA2 and anti-oxidant activities may account for the broad spectrum protective effects of PGBx that were previously described. These dual properties are demonstrable in vitro, in situ and in vivo, and would have profound effects on stabilization of membrane structure and function, which in turn, would protect organelles, cells, tissues, and organs from inflammation and injury, and possibly alter patterns of aging involving senescence and cell death.

Protection against acute lethal viral infections with the native steroid dehydroepiandrosterone (DHEA).

A significant protective effect of a native adrenal steroid, dehydroepiandrosterone (DHEA), was demonstrated in studies of two lethal viral infection models in mice: systemic coxsackievirus B4 and herpes simplex type 2 encephalitis. The steroid was active either by long-term feeding or by a single subcutaneous injection. A closely related steroid, etiocholanolone, was not protective in these models. Histopathological analysis, leukocyte counts, and numbers of spleen antibody forming cells in the coxsackievirus B4 model suggests that DHEA functions by maintaining or potentiating the immune competence of mice otherwise depressed by viral infection. DHEA was not effective in genetically immunodeficient HRS/J hr/hr mice and did not demonstrate antiviral activity in vitro. While the molecular basis for DHEA's effect on the immune system is not known, studies by others suggest that it may counteract the stress related immunosuppressive effects of glucocorticoids stimulated by viral infection. Because DHEA is a native steroid that has been used clinically with minimal side effects, the utility of DHEA in the therapeutic modulation of acute and chronic viral infections including the acquired immune deficiency syndrome deserves intensive study.