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July 2011

Characterization of the convulsant action of pregnenolone sulfate.

Pregnenolone sulfate (PS) is an endogenous neurosteroid synthesized by glial cells, which acts as a potent convulsant when injected intracerebroventricularly and intraperitoneally. PS is found in relatively high concentrations in the hippocampus. But its convulsant action in the hippocampus has not been characterized. A range of PS doses were infused directly into the right hippocampus of 42 rats, which were subsequently monitored for behavioral and electrographic seizures. At the highest dose (4 micromol), PS produced status epilepticus (SE) and severe behavioral convulsions. As the dose of PS was reduced, the fraction of rats having SE diminished (ED50 for SE = 2.7 micromol). At doses lower than 300 nmol, PS infusion produced discrete electrographic seizures (ED50 = 68 nmol) associated with mild behavioral seizures. Both the behavioral seizure score (BSS) and the total number of seizures during the observation period changed in a dose-dependent manner. In separate experiments in cultured hippocampal neurons, PS enhanced NMDA-evoked whole-cell currents (EC50 = 16 microM). The results demonstrate that the hippocampus is highly sensitive to the convulsant effects of PS and that the enhancement of NMDA currents could contribute to the convulsant action of PS.

Neuropharmacology. 2004 May;46(6):856-64

Associated hormonal declines in aging: DHEAS.

DHEA and its sulfate prohormone DHEAS are the most abundant circulating adrenal steroid hormones in humans. DHEA exerts its actions on peripheral target tissues either indirectly, following its conversion to androgens, estrogens or both, or directly, as a steroid hormone interacting with either a nuclear or a membrane receptor. In humans, DHEA shows a characteristic pattern of secretion throughout life. Serum DHEA concentrations decline with advancing age and vary with gender, ethnicity, and environmental factors. Epidemiological studies show an inverse relationship between plasma DHEA(S) levels in men and age-related illnesses, including cardiovascular and metabolic diseases, immune disorders, malignancies, and neurological dysfunction. This has generated great interest on the putative role of DHEA in age-associated illnesses. Administration of DHEA to rats and mice reduces visceral fat accumulation, and improves insulin resistance in experimental models of diet-induced obesity and/or type 2 diabetes. In addition, recent studies in vitro have shown that DHEA has the capacity to improve endothelial function by increasing nitric oxide (NO) synthesis. Replacement of DHEA in patients with adrenal insufficiency has been shown to exert beneficial effects on well-being, mood, and sexuality. By contrast, in healthy individuals, the physiological age-associated decline in circulating DHEA(S) per se does not justify DHEA supplementation, since the effects of this hormone on metabolic abnormalities, endothelial function in vivo, and cardiovascular events are contradictory. However, these results do not exclude the possibility that DHEA treatment may prove beneficial in specific subgroups of elderly subjects.

J Endocrinol Invest. 2005;28(3 Suppl):85-93

Uses of DHEA in aging and other disease states.

Dehydro-3-epiandrosterone is a steroid hormone synthesized in large quantities by the adrenal gland whose physiologic role remains unclear. The effects of DHEA could be estrogenic or androgenic, depending on the hormonal milieu. Low levels of DHEA are associated with aging, cardiovascular disease in men, and an increased risk of pre-menopausal breast and ovarian cancer. High levels of DHEA might increase the risk of postmenopausal breast cancer. Therapeutically DHEA might be useful for improving psychological well-being in the elderly, reducing disease activity in people with mild to moderate systemic lupus erythematosus and myotonic dystrophy, improving mood in those clinically depressed, and improving various parameters in women with adrenal insufficiency. Although many other claims have been made for DHEA in diverse conditions, such as aging, dementia, and AIDS, no well-designed clinical trials have clearly substantiated the utility and safety of long-term DHEA supplementation.

Ageing Res Rev. 2002 Feb;1(1):29-41

Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus.

Age-dependent cognitive impairments have been correlated with functional and structural modifications in the hippocampal formation. In particular, the brain endogenous steroid pregnenolone-sulfate (Preg-S) is a cognitive enhancer whose hippocampal levels have been linked physiologically to cognitive performance in senescent animals. However, the mechanism of its actions remains unknown. Because neurogenesis is sensitive to hormonal influences, we examined the effect of Preg-S on neurogenesis, a novel form of plasticity, in young and old rats. We demonstrate that in vivo infusion of Preg-S stimulates neurogenesis and the expression of the polysialylated forms of NCAM, PSA-NCAM, in the dentate gyrus of 3- and 20-month-old rats. These influences on hippocampal plasticity are mediated by the modulation of the gamma-aminobutyric acid receptor complex A (GABA(A)) receptors present on hippocampal neuroblasts. In vitro, Preg-S stimulates the division of adult-derived spheres suggesting a direct influence on progenitors. These data provide evidence that neurosteroids represent one of the local secreted signals controlling hippocampal neurogenesis. Thus, therapies which stimulate neurosteroidogenesis could preserve hippocampal plasticity and prevent the appearance of age-related cognitive disturbances.

Neurobiol Aging. 2005 Jan;26(1):103-14

Pregnenolone, dehydroepiandrosterone, and their sulfate and fatty acid esters in the rat brain.

The rat brain contains large amounts of pregnenolone (P) and dehydroepiandrosterone (D) arising from local biosynthetic pathways. We have devised a procedure for the measurement of both “neurosteroids” either unconjugated or released from their sulfate (S) or fatty acid (L) esters. The measurements were performed at the acrophase of the circadian variation of neurosteroids, and confirmed the large accumulation of P (25 +/- 8 ng/g, mean +/- SD) and of PS (19 +/- 6 ng/g) and DS (2.1 +/- 0.5 ng/g) in the brain of adult male rats. We found that fatty acid esters constitute the major species of neurosteroids in brain (PL 46 +/- 14, and DL 36 +/- 7 ng/g, in adult males). The levels of P and DS were increased by daily injection of vehicle to intact males, whereas castration, without or with testosterone or estradiol supplementation (2 mg daily for 7 days), did not produce a significant change of neurosteroids concentrations. Measurements of neurosteroids had not been previously reported in cyclic females. The levels of P, PL, and DS were identical in proestrous females and in intact males, whereas PS (26 +/- 6 ng/g) and DL (50 +/- 16 ng/g) were increased in females. Compared to proestrous females, diestrous females had lower levels of PS (19 +/- 6 ng/g), DS (1.7 +/- 0.4 ng/g), and PL (43 +/- 19 ng/g). These differences suggested a modulatory role of ovarian secretions on the metabolism of neurosteroids.

Steroids. 1989 Sep;54(3):287-97

Endogenous neuroprotective factors: neurosteroids.

Neurosteroids are a group of steroid hormones synthesized by the brain in the presence of steroidogenic enzymes. Specific neurosteroids modulate function of several receptors, and also regulate growth of neurons, myelinization and synaptogenesis in the central nervous system. Some neurosteroids have been shown to display neuroprotective properties, which may have important implications for their potential use in the treatment of various neuropathologies such as: age-dependent dementia, stroke, epilepsy, spinal cord injury, Alzheimer’s disease (AD), Parkinson’s disease (PD) and Niemann-Pick type C disease (NP-C). This paper focuses on neuroprotection afforded by neurosteroids.

Pharmacol Rep. 2006 May-Jun;58(3):335-40

Pregnenolone sulphate attenuates AMPA cytotoxicity on rat cortical neurons.

Neuroactive steroids can modulate brain excitability by interaction with several neurotransmitter receptor-associated channels. These compounds may thus exert profound influences on excitotoxic injury, i.e. neuronal cell death triggered by over-activation of glutamate receptors. It has been reported that pregnenolone sulphate (PS) and pregnenolone hemisuccinate (PHS) augment N-methyl-D-aspartate (NMDA) neurotoxicity in rat cultured neurons. Here we show that the effects of neuroactive steroids on AMPA cytotoxicity display features distinct from those on NMDA cytotoxicity. Concomitant application of PS (30-300 microm) attenuated, rather than augmented, AMPA neurotoxicity in cortical slice cultures in a concentration-dependent manner, whereas various other steroids including pregnenolone and PHS had no effect. Inhibition of steroid sulphatase by estrone-3-O-sulphamate led to a shift of the minimum effective concentration of PS against AMPA cytotoxicity from 30 to 10 microm. The protective action of PS was not affected by inhibition of protein synthesis or by blockade of glucocorticoid receptors, GABAA receptors or sigma-receptors. In dissociated cortical neurons, PS attenuated AMPA-induced inward currents whereas pregnenolone and PHS exhibited no significant effect. Thus, with strict structural specificity, PS but not pregnenolone or PHS attenuates AMPA cytotoxicity, probably by inhibiting activities of AMPA receptor-associated channels.

Eur J Neurosci. 2005 May;21(9):2329-35