Abstract
BackgroundEstrogens have neuroprotective properties. The aim of the study was to assess the impact of an isopropanolic extract of Cimicifuga racemosa (iCR), 17ß-estradiol (E2), testosterone (T) and Tibolone’s 3α-OH metabolite (Org4094) on local estrogen formation in hippocampus tissue from non-human primates ex vivo in vitro and human neuroblastoma cells (SH-SY5Y) in vitro.MethodsSH-SY5Y cells were incubated in RPMI 1640 medium containing 5 % steroid-depleted fetal calf serum for 3 days, and subsequently incubated in absence or presence of iCR at 10 μg/ml (n = 5) and 1 μg/ml (n = 5), E2 at 10−8 M (n = 5), and 10−6 M (n = 5), or T at 10−8 M (n = 5), and 10−6 M (n = 5), respectively, at 37 °C for either 24 h or directly in cell extracts. Hippocampus tissue from healthy female cynomolgus macaques (n = 14) was homogenized and treated with iCR, E2 and Org4049 accordingly. STS activity was evaluated by incubating homogenized brain cells and tissue with [3H]-estrone sulfate and separating the products estrone (E1) and E2 by thin layer chromatography. STS activity was expressed as total estrogen formation (E1 + E2) fmol/mg of protein/min. Statistical comparisons were made using unpaired T-Test for comparing two sets of data and ANOVA to compare many groups at once. A p value < 0.05 was considered to be significant different.ResultsBasal total estrogen formation was significantly higher in proliferative SH-SY5Y cells (1350.06 ± 109 E1 + E2 fmol/mg of protein/min) compared to hippocampus tissue (37.83 ± 3.9 E1 + E2 fmol/mg of protein/min; p < 0.01). ICR exerted a bidirectional action with an immediate strong inhibitory effect being followed by a stimulation of STS activity (85 % increase). E2 had a bidirectional dose-dependent long-term effect on STS activity (−23 % reduction and 18 % increase). T and Org4094 had an immediate strong inhibitory effect on STS activity that further maintained with 24 h T treatment (30 % decrease).ConclusionsLocal estrogen formation within brain cells and tissue may be modulated by black cohosh, 17ß-estradiol, testosterone, and Tibolone’s 3α-OH metabolite, respectively. The clinical implication of this finding has to be elucidated.
Highlights
Under the hypothesis that an increase of local estrogen formation has a positive impact on memory, the aim of our study was to investigate the effect of black cohosh on STS enzyme activity in hippocampus tissue ex vitro in vivo and neurons in vitro, respectively, in comparison to E2, T, and an estrogenic metabolite of tibolone
To our knowledge, we are the first to report on the impact of black cohosh, 17ß-estradiol (E2), testosterone (T) and Tibolone’s 3α-OH metabolite (Org4049) on brain STS activity in proliferative human neuroblastoma cells in vitro and benign hippocampus tissue from nonhuman primates ex vivo in vitro
We found that 1) both, SH-SY5Y cells and hippocampus tissue, possessed the enzymes necessary to produce E2 from E1S, 2) total estrogen formation (E1 + E2) was significantly higher in proliferative SH-SY5Y cells compared to benign hippocampus tissue, 3) isopropanolic extract of Cimicifuga racemosa (iCR) exerted a bidirectional action that was an immediate strong
Summary
The sex steroid 17β-Estradiol (E2) displays neuroprotective and -reparative properties by, e.g. promoting neuronal survival, neuritogenesis and synaptic function, reducing local inflammation of astrocytes and microglia, and facilitating remyelination, respectively [1]. As other tissues, possesses the enzymes necessary for local formation of active hormones, neurosteroids, from inactive precursor hormones. They predominantly use (non-genomic) signaling pathways common for neuromodulators such as modulating the activity of several neurotransmitter receptors. Increased dehydroepiandrosterone sulfate (DHEAS) rather than DHEA level has been found to enhance memory possibly by positively influencing brain cholinergic function [8, 9] and decreasing Υ-amino butyrate (GABAA)ergic receptor activity [10]. Unconjugated neurosteroids are thought to act on GABAA receptors as positive modulators [11]
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