β-Estradiol CAS NO.50-28-2

β-Estradiol results in a proprotein convertase subtilisin/kexin type 9-dependent increase in low-density lipoprotein receptor levels in human hepatic HuH7 cells.[Pubmed: 25913303]

FEBS J. 2015 Jul;282(14):2682-96.

The lower risk of coronary artery disease in premenopausal women than in men and postmenopausal women implicates sex steroids in cardioprotective processes. beta-Estradiol upregulates liver low-density lipoprotein receptor (LDLR), which, in turn, decreases circulating levels of low-density lipoprotein, which is a risk factor for coronary artery disease. Conversely, LDLR protein is negatively regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9).
METHODS AND RESULTS:
Herein, we investigated PCSK9 regulation by beta-Estradiol and its impact on LDLR in human hepatocarcinoma HuH7 cells grown in the presence or absence of β-estradiol. Immunoblot analysis showed upregulation of LDLR at 3 μm beta-Estradiol (140%), and the upregulation reached 220% at 10 μm beta-Estradiol; only at the latter dose was an increase in LDLR mRNA detected by qPCR, suggesting post-translational regulation of LDLR. No changes in PCSK9 mRNA or secreted protein levels were detected by qPCR or ELISA, respectively. beta-Estradiol-conditioned medium devoid of PCSK9 failed to upregulate LDLR. Similarly, PCSK9 knockdown cells showed no upregulation of LDLR by beta-Estradiol. Together, these results indicate a requirement for PCSK9 in the beta-Estradiol-induced upregulation of LDLR. A radiolabeling assay showed a significant, dose-dependent decrease in the ratio of secreted phosphoPCSK9 to total secreted PCSK9 with increasing beta-Estradiol levels, suggesting a change in the functional state of PCSK9 in the presence of beta-Estradiol.
CONCLUSIONS:
Our results indicate that the protein upregulation of LDLR at subtranscriptionally effective doses of beta-Estradiol, and its supratranscriptional upregulation at 10 μm beta-Estradiol, occur through an extracellular PCSK9-dependent mechanism.

Gonadal status-dependent effects of in vivo β-estradiol administration to female rats on in vitro epileptiform activity induced by low [Mg2+]? in combined hippocampus-entorhinal cortex slices.[Pubmed: 24113171]

Epilepsy Res. 2013 Dec;107(3):297-301.

There are controversial data regarding estrogen effects on neuronal excitability.
METHODS AND RESULTS:
We investigated whether beta-Estradiol (EB) administration to ovariectomized (OVX) or gonadally intact female rats alters epileptiform activity within the dentate gyrus network induced in vitro by removing [Mg2+]o in combined hippocampus-entorhinal cortex slices. In vivo beta-Estradiol administration significantly influenced the epileptiform activity in gonadal status-dependent manner. The onset of epileptiform discharges was modestly delayed in slices from OVX rats replaced with physiologically relevant doses of beta-Estradiol but the number of discharges was not affected. In contrast, beta-Estradiol administration to gonadally intact rats had robust effects such that: beta-Estradiol delayed the onset of discharges but significantly increased their number within the dentate gyrus network.
CONCLUSIONS:
Our data suggest that beta-Estradiol in physiologically relevant concentrations does not seem to negatively affect hippocampal neuronal excitability, nevertheless supraphysiological beta-Estradiol levels may enhance seizure severity.

Beta-estradiol protects hippocampal CA1 neurons against transient forebrain ischemia in gerbil.[Pubmed: 9527626]

Neurosci Res. 1997 Dec;29(4):345-54.

beta-Estradiol has been considered to be a neurotrophic agent, but its in vivo effect on gerbils with transient forebrain ischemia has not yet been demonstrated.
METHODS AND RESULTS:
In the first set of the present experiments, we infused beta-Estradiol at a dose of 0.05 or 0.25 microg/day for 7 days into the lateral ventricles of normothermic gerbils starting 2 h before 3-min forebrain ischemia. beta-Estradiol infusion at a dose of 0.25 microg/day prevented significantly the ischemia-induced reduction of response latency time as revealed by a step-down passive avoidance task. Subsequent light and electron microscopic examinations showed that pyramidal neurons in the hippocampal CA1 region as well as synapses within the strata moleculare, radiatum and oriens of the region were significantly more numerous in gerbils infused with beta-Estradiol than in those receiving saline infusion. beta-Estradiol at a dose of 1.25 microg/day was ineffective and occasionally increased the mortality of experimental animals. Since the total brain content of exogenous beta-Estradiol at 12 h after forebrain ischemia was estimated to be less than 145 ng, the second set of experiments focused on the neurotrophic action of beta-Estradiol at concentrations around 100 ng/ml in vitro. beta-Estradiol at concentrations of 1-100 ng/ml facilitated the survival and process extension of cultured hippocampal neurons, but it did not exhibit any significant radical-scavenging effects at the concentration range. On the other hand, 100 microg/ml of beta-Estradiol, even though failing to support hippocampal neurons in vitro, effectively scavenged free radicals in subsequent in vitro studies, as demonstrated elsewhere.
CONCLUSIONS:
These findings suggest that beta-Estradiol at a dose of 0.25 microg/day prevents ischemia-induced learning disability and neuronal loss at early stages after transient forebrain ischemia, possibly via a receptor-mediated pathway without attenuating free radical neurotoxicity.