skip to main content
Show Results with:

Neurosteroid metabolites of testosterone and progesterone differentially inhibit ERK phosphorylation induced by amyloid β in SH-SY5Y cells and primary cortical neurons

Mendell, Ari L. et al.

Brain research. Volume 1686: (2018, May 1st); pp 83-93 -- Elsevier Science

Online access

  • Title:
    Neurosteroid metabolites of testosterone and progesterone differentially inhibit ERK phosphorylation induced by amyloid β in SH-SY5Y cells and primary cortical neurons
  • Author: Mendell, Ari L.;
    Chung, Beryl Y.T.;
    Creighton, Carolyn E.;
    Kalisch, Bettina E.;
    Bailey, Craig D.C.;
    MacLusky, Neil J.
  • Found In: Brain research. Volume 1686: (2018, May 1st); pp 83-93
  • Journal Title: Brain research
  • Subjects: Brain--Periodicals; Brain--Research--Periodicals; Allopregnanolone--Androstanediol--Neuroprotection--ERK kinase--GABA--Amyloid--Neurosteroids; Dewey: 573.86
  • Rights: Licensed
  • Publication Details: Elsevier Science
  • Abstract: Highlights Androstanediol and allopregnanolone inhibit ERK phosphorylation induced by neurotoxins. Effects are observed in SH-SY5Y neuroblastoma cells and primary cortical neurons. Both GABAAR-dependent and -independent mechanisms appear to be involved. Local neurosteroid synthesis may contribute to neuroprotection by the parent hormonal steroids. Abstract Gonadal steroid hormones exert neurotrophic and neuroprotective effects on the brain. Recent work suggests potential neuroprotective roles for the 3α-hydroxy, 5α-reduced metabolites of these hormones. Two such metabolites are 5α-androstane-3α, 17β-diol (3α-diol) and 5α-pregnan-3α-ol-20-one (allopregnanolone; Allo), which may contribute to the overall protection conferred by their precursors (testosterone and progesterone, respectively) through mechanisms including potentiation of gamma-aminobutyric acid (GABA)Areceptor (GABAAR) activity. We have previously demonstrated that physiological concentrations of 3α-diol inhibit prolonged phosphorylation of extracellular signal-regulated kinase (ERK) and the associated neurotoxicity resulting from amyloid β peptide 1–42 (Aβ42) exposure in vitro . In the present study, we sought to characterize the GABAAR-dependency of 3α-diol's effects, compared to those of Allo, in SH-SY5Y human female neuroblastoma cells and primary cortical neurons isolated from postnatal day 0–1 mice. Both 3α-diol and Allo prevented Aβ42-mediated ERK phosphorylation in SH-SY5Y cells, with substantially different concentration requirements (10 nM for 3α-diol, 100 nM for Allo). Pharmacological inhibition of GABAAR with picrotoxin did not prevent this effect, indicating that neurosteroid-mediated ERK inhibition in SH-SY5Y cells may be GABAAR-independent. While 10 nM and 100 nM concentrations of both neurosteroids inhibited ERK phosphorylation induced by Aβ42 in primary cortical neurons, which have high expression levels of GABAARs, only the effects of Allo were significantly inhibited by picrotoxin. These results suggest that neurosteroid metabolites of testosterone and progesterone may contribute to neuroprotection by suppressing ERK phosphorylation through both GABAAR-dependent and -independent mechanisms.
  • Identifier: System Number: ETOCvdc_100063805684.0x000001; Journal ISSN: 0006-8993; 10.1016/j.brainres.2018.02.023
  • Publication Date: 2018
  • Physical Description: Electronic
  • Shelfmark(s): 2268.200000
  • UIN: ETOCvdc_100063805684.0x000001

Searching Remote Databases, Please Wait