The selective beta1-adrenoceptor antagonist nebivolol is a potential oestrogen receptor agonist with neuroprotective abilities.
OBJECTIVE
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.


METHODS
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.


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
We showed that nebivolol acts as ER agonist in neuronal cell lines, and suggest oestrogen-like neuroprotective effects mediated by nebivolol.
Manthey
D
D
Department of Pathobiochemistry, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
Gamerdinger
M
M
Behl
C
C
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000235:genetics; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics; D004983:Ethanolamines / Q000494:pharmacology*; D006801:Humans; D049409:Luciferases, Firefly / Q000235:genetics; D051379:Mice; D000068577:Nebivolol; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011485:Protein Binding; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D014162:Transfection
D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D016564:Amyloid beta-Protein Precursor; D001578:Benzopyrans; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004983:Ethanolamines; D018696:Neuroprotective Agents; D018342:Receptors, Adrenergic, beta-1; D000068577:Nebivolol; D049409:Luciferases, Firefly