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An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
The selective beta1-adrenoceptor antagonist nebivolol is a potential oestrogen receptor agonist with neuroprotective
D Manthey1, M Gamerdinger, C Behl
1Department of Pathobiochemistry, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Background And Purpose:
Nebivolol, a selective beta(1)-adrenoceptor antagonist mediating rapid vasodilating effects, is used clinically to treat hypertension. Recently, it was reported that nebivolol also acts as an oestrogen receptor (ER) agonist. To investigate the neuroprotective potential of oestrogens, we assessed the oestrogenic effects of nebivolol in several in vitro neuronal models.
Experimental Approach:
Human neuroepithelioma SK-N-MC cells stably transfected with human ER alpha and beta, and mouse N2A neuroblastoma cells expressing human APP695(SWE)[N2Aswe, stably transfected with the Swedish mutation form of the Alzheimer-associated amyloid precursor protein (APPswe, K670M/N671L)] were incubated with different concentrations of nebivolol and 17beta-oestradiol (E2) for 24-48 h. ER activation was detected in a specific reporter assay, and ER-dependent gene expression was measured by quantitative real-time PCR (qRT PCR). Furthermore, cell survival rates were determined, and oxidative stress was induced by hydrogen peroxide and paraquat. Amyloid beta protein precursor (APP) processing was investigated, and the cleavage fragments sAPPalpha and Abeta were quantified via alpha-, beta- and gamma-secretase activity assays. Alterations of secretase expression levels were determined by qRT PCR.
Key Results:
Nebivolol induces oestrogen-dependent gene transcription, and protects neuronal cells against oxidative stress even at low and physiological concentrations (10(-8) M). Moreover, nebivolol modulates processing of APP in mouse neuronal N2Aswe cells by increasing alpha-secretase activity, ultimately leading to enhanced release of soluble non-amyloidogenic sAPPalpha.
Conclusions And Implications:
We showed that nebivolol acts as ER agonist in neuronal cell lines, and suggest oestrogen-like neuroprotective effects mediated by nebivolol.
Insights
Nebivolol demonstrates estrogen receptor agonist activity, offering neuroprotection against oxidative stress and modulating amyloid precursor protein processing in neuronal cells.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Nebivolol is a beta-blocker used for hypertension.
- Nebivolol exhibits estrogen receptor (ER) agonist properties.
- Estrogens are known to possess neuroprotective potential.
Purpose of the Study:
- To investigate the estrogenic effects of nebivolol in neuronal models.
- To assess the neuroprotective potential of nebivolol via ER agonism.
- To explore nebivolol's impact on amyloid precursor protein (APP) processing.
Main Methods:
- Utilized human neuroepithelioma and mouse neuroblastoma cell lines.
- Measured ER activation using reporter assays and gene expression via qRT PCR.
- Assessed cell survival, oxidative stress response, and APP processing pathways.
Main Results:
- Nebivolol induced ER-dependent gene transcription at physiological concentrations.
- Nebivolol protected neuronal cells against oxidative stress.
- Nebivolol increased alpha-secretase activity, enhancing sAPPalpha release.
Conclusions:
- Nebivolol acts as an ER agonist in neuronal cell lines.
- Nebivolol exhibits estrogen-like neuroprotective effects.
- Nebivolol may offer therapeutic benefits for neurodegenerative conditions.
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