کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8839845 | 1613759 | 2018 | 43 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Neurosteroid metabolites of testosterone and progesterone differentially inhibit ERK phosphorylation induced by amyloid β in SH-SY5Y cells and primary cortical neurons
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب (عمومی)
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چکیده انگلیسی
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)A receptor (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 (10â¯nM for 3α-diol, 100â¯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 10â¯nM and 100â¯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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Brain Research - Volume 1686, 1 May 2018, Pages 83-93
Journal: Brain Research - Volume 1686, 1 May 2018, Pages 83-93
نویسندگان
Ari L. Mendell, Beryl Y.T. Chung, Carolyn E. Creighton, Bettina E. Kalisch, Craig D.C. Bailey, Neil J. MacLusky,