PMID- 29477545
OWN - NLM
STAT- MEDLINE
DCOM- 20190419
LR  - 20190419
IS  - 1872-6240 (Electronic)
IS  - 0006-8993 (Linking)
VI  - 1686
DP  - 2018 May 1
TI  - Neurosteroid metabolites of testosterone and progesterone differentially inhibit 
      ERK phosphorylation induced by amyloid beta in SH-SY5Y cells and primary cortical 
      neurons.
PG  - 83-93
LID - S0006-8993(18)30087-8 [pii]
LID - 10.1016/j.brainres.2018.02.023 [doi]
AB  - Gonadal steroid hormones exert neurotrophic and neuroprotective effects on the 
      brain. Recent work suggests potential neuroprotective roles for the 3alpha-hydroxy, 
      5alpha-reduced metabolites of these hormones. Two such metabolites are 
      5alpha-androstane-3alpha,17beta-diol (3alpha-diol) and 5alpha-pregnan-3alpha-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 (GABA(A)R) activity. We have previously demonstrated that physiological 
      concentrations of 3alpha-diol inhibit prolonged phosphorylation of extracellular 
      signal-regulated kinase (ERK) and the associated neurotoxicity resulting from 
      amyloid beta peptide 1-42 (Abeta42) exposure in vitro. In the present study, we sought 
      to characterize the GABA(A)R-dependency of 3alpha-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 3alpha-diol and Allo prevented 
      Abeta42-mediated ERK phosphorylation in SH-SY5Y cells, with substantially different 
      concentration requirements (10 nM for 3alpha-diol, 100 nM for Allo). Pharmacological 
      inhibition of GABA(A)R with picrotoxin did not prevent this effect, indicating 
      that neurosteroid-mediated ERK inhibition in SH-SY5Y cells may be 
      GABA(A)R-independent. While 10 nM and 100 nM concentrations of both neurosteroids 
      inhibited ERK phosphorylation induced by Abeta42 in primary cortical neurons, which 
      have high expression levels of GABA(A)Rs, 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 GABA(A)R-dependent and -independent 
      mechanisms.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Mendell, Ari L
AU  - Mendell AL
AD  - Department of Biomedical Sciences, Ontario Veterinary College, University of 
      Guelph, 50 Stone Road East, Guelph, ON N1G 2W1 Canada.
FAU - Chung, Beryl Y T
AU  - Chung BYT
AD  - Department of Biomedical Sciences, Ontario Veterinary College, University of 
      Guelph, 50 Stone Road East, Guelph, ON N1G 2W1 Canada.
FAU - Creighton, Carolyn E
AU  - Creighton CE
AD  - Department of Biomedical Sciences, Ontario Veterinary College, University of 
      Guelph, 50 Stone Road East, Guelph, ON N1G 2W1 Canada.
FAU - Kalisch, Bettina E
AU  - Kalisch BE
AD  - Department of Biomedical Sciences, Ontario Veterinary College, University of 
      Guelph, 50 Stone Road East, Guelph, ON N1G 2W1 Canada.
FAU - Bailey, Craig D C
AU  - Bailey CDC
AD  - Department of Biomedical Sciences, Ontario Veterinary College, University of 
      Guelph, 50 Stone Road East, Guelph, ON N1G 2W1 Canada.
FAU - MacLusky, Neil J
AU  - MacLusky NJ
AD  - Department of Biomedical Sciences, Ontario Veterinary College, University of 
      Guelph, 50 Stone Road East, Guelph, ON N1G 2W1 Canada. Electronic address: 
      nmaclusk@uoguelph.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180222
PL  - Netherlands
TA  - Brain Res
JT  - Brain research
JID - 0045503
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Androgens)
RN  - 0 (Neurotransmitter Agents)
RN  - 0 (Receptors, GABA)
RN  - 0 (Receptors, GABA-A)
RN  - 3XMK78S47O (Testosterone)
RN  - 4G7DS2Q64Y (Progesterone)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Amyloid beta-Peptides/*metabolism
MH  - Androgens/pharmacology
MH  - Cell Line
MH  - Extracellular Signal-Regulated MAP Kinases/metabolism
MH  - Female
MH  - Humans
MH  - Neurons/drug effects/*metabolism
MH  - Neurotransmitter Agents/metabolism/*pharmacology
MH  - Phosphorylation/drug effects
MH  - Progesterone/metabolism
MH  - Receptors, GABA/metabolism
MH  - Receptors, GABA-A/metabolism
MH  - Testosterone/*metabolism/pharmacology
OTO - NOTNLM
OT  - Allopregnanolone
OT  - Amyloid
OT  - Androstanediol
OT  - ERK kinase
OT  - GABA
OT  - Neuroprotection
OT  - Neurosteroids
EDAT- 2018/02/27 06:00
MHDA- 2019/04/20 06:00
CRDT- 2018/02/26 06:00
PHST- 2017/09/11 00:00 [received]
PHST- 2017/12/12 00:00 [revised]
PHST- 2018/02/16 00:00 [accepted]
PHST- 2018/02/27 06:00 [pubmed]
PHST- 2019/04/20 06:00 [medline]
PHST- 2018/02/26 06:00 [entrez]
AID - S0006-8993(18)30087-8 [pii]
AID - 10.1016/j.brainres.2018.02.023 [doi]
PST - ppublish
SO  - Brain Res. 2018 May 1;1686:83-93. doi: 10.1016/j.brainres.2018.02.023. Epub 2018 
      Feb 22.