RESULTS:

Neurosteroids pregnenolone-sulfate (PREGS) and dehydroepiandrosterone (DHEA) have been shown to enhance neurogenesis in the hippocampal dentate gyrus (DG) of adult rodents. In Alzheimer’s disease (AD) brain the levels of these neurosteroids are known to be altered compared to age-matched non-demented controls. The aim of this study was to examine the effects of PREGS and DHEA on the hippocampal neurogenesis in 8-month-old male APPswe/PS1dE9 transgenic (APP/PS1) mice that show amyloid plaques and impaired spatial cognitive performance. In the DG of APP/PS1 mice the proliferation of progenitor cells was increased while the neurite growth and survival of newborn neuronal cells were markedly impaired. Treatment with PREGS or DHEA rescued perfectly the hypoplastic neurite of newborn neurons in APP/PS1 mice while neither of them affected the over-proliferation of progenitor cells. Notably the administration of PREGS but not DHEA to APP/PS1 mice could protect the survival and maturation of newborn neuronal cells which was accompanied by the improvement of spatial cognitive performance. The results indicate that treatment of AD like brains of APP/PS1 mice with PREGS might protect the hippocampal neurogenesis leading to the improved spatial cognitive performance.

A high proportion (∼40%) of breast cancers are hormone dependent. The female hormones estradiol and androstenediol are believed to play a key role in the initiation and promotion of this disease. In the fight against hormone dependent breast cancers extensive research has been undertaken to produce compounds which are potent inhibitors against the cytochrome P-450 enzyme aromatase (AR) which converts the C19 androgens to the C18 estrogens. However the administration of AR inhibitors alone has failed to produce the expected decrease in plasma levels of estrone. The major impetus to the development of steroid sulfatase inhibitors has therefore been the realisation that in order to improve therapeutic response for women with hormone-dependent breast cancer not only must the AR enzyme be inhibited but also the synthesis of estrogens via alternative routes. The steroid sulfatase enzyme regulates the formation of estrone (which can subsequently be converted to the potent estrogen estradiol) from estrone sulfate a steroid conjugate present in high concentrations in tissue and blood in women with breast cancer. The sulfatase enzyme system also controls the formation of dehydroepiandrosterone (DHEA) from the DHEA-sulfate. This is important since DHEA can be converted to 5-androstene-3β17β-diol which possesses estrogenic properties capable of stimulating the growth of breast cancer cells in vitro and in vivo. Considerable progress has been made in recent years in the development of a number of potent steroid / estrone sulfatase inhibitors as such both steroidal and non-steroidal compounds have been considered and a number of highly potent inhibitors have been produced and evaluated against what is now considered a crucial enzyme in the fight against hormone dependent breast cancer. The review therefore considers the work that has been undertaken todate as well as possible future development with respect to ‘dual inhibitors’ of both estrone sulfatase and AR.