TY - JOUR
T1 - The role of presenilin-1 in the excitotoxicity of ethanol withdrawal
AU - Jung, Marianna E.
AU - Metzger, Daniel B.
AU - Das, Hriday K.
N1 - Funding Information:
This work was supported by the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant AA015982] and an Institute for Aging and Alzheimer's Disease Research grant to M.E.J. and H.K.D. dx.doi.org/10.1124/jpet.116.233361.
Publisher Copyright:
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2016/9
Y1 - 2016/9
N2 - Presenilin-1 (PS1) is a core component of g-secretase that is involved in neurodegeneration. We have previously shown that PS1 interacts with a mitogen- Activated protein kinase [(MAPK) jun-NH2- Terminal-kinase], and another MAPK (p38) is activated by ethanol withdrawal (EW), abrupt termination from chronic ethanol exposure. EW is excitotoxic in nature, induces glutamate upregulation, and provokes neuronal damage. Here, we explored a potential mechanistic pathway involving glutamate, p38 (p38a isozyme), and PS1 that may mediate EW-induced excitotoxic stress. We used the prefrontal cortex of male rats withdrawn from a chronic ethanol diet. Additionally, we used ethanol-withdrawn HT22 cells (mouse hippocampal) treated with the inhibitor of glutamate receptors [dizocilpine (MK-801)], p38α (SB203580; 4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1Himidazol- 5-yl]pyridine), or g-secretase [N-[N- (3,5-difluorophenacetyl)- l- Alanyl]-S-phenylglycine t-butyl ester (DAPT)] during EW. Separately, ethanol-free HT22 cells were exposed to glutamate with or without SB203580 or DAPT. Protein levels, mRNA levels, and cell viability were assessed using immunoblotting, qualitative polymerase chain reaction, and calcein assay, respectively. The prefrontal cortex of ethanolwithdrawn rats or HT22 cells showed an increase in PS1 and p38a, which was attenuated by MK-801 and SB203580, but mimicked by glutamate treatment to ethanol-free HT22 cells. DAPT attenuated the toxic effect of EW or glutamate on HT22 cells. These results suggest that PS1 expression is triggered by glutamate through p38a, contributing to the excitotoxic stimulus of EW.
AB - Presenilin-1 (PS1) is a core component of g-secretase that is involved in neurodegeneration. We have previously shown that PS1 interacts with a mitogen- Activated protein kinase [(MAPK) jun-NH2- Terminal-kinase], and another MAPK (p38) is activated by ethanol withdrawal (EW), abrupt termination from chronic ethanol exposure. EW is excitotoxic in nature, induces glutamate upregulation, and provokes neuronal damage. Here, we explored a potential mechanistic pathway involving glutamate, p38 (p38a isozyme), and PS1 that may mediate EW-induced excitotoxic stress. We used the prefrontal cortex of male rats withdrawn from a chronic ethanol diet. Additionally, we used ethanol-withdrawn HT22 cells (mouse hippocampal) treated with the inhibitor of glutamate receptors [dizocilpine (MK-801)], p38α (SB203580; 4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1Himidazol- 5-yl]pyridine), or g-secretase [N-[N- (3,5-difluorophenacetyl)- l- Alanyl]-S-phenylglycine t-butyl ester (DAPT)] during EW. Separately, ethanol-free HT22 cells were exposed to glutamate with or without SB203580 or DAPT. Protein levels, mRNA levels, and cell viability were assessed using immunoblotting, qualitative polymerase chain reaction, and calcein assay, respectively. The prefrontal cortex of ethanolwithdrawn rats or HT22 cells showed an increase in PS1 and p38a, which was attenuated by MK-801 and SB203580, but mimicked by glutamate treatment to ethanol-free HT22 cells. DAPT attenuated the toxic effect of EW or glutamate on HT22 cells. These results suggest that PS1 expression is triggered by glutamate through p38a, contributing to the excitotoxic stimulus of EW.
UR - http://www.scopus.com/inward/record.url?scp=84983746105&partnerID=8YFLogxK
U2 - 10.1124/jpet.116.233361
DO - 10.1124/jpet.116.233361
M3 - Article
C2 - 27278235
AN - SCOPUS:84983746105
SN - 0022-3565
VL - 358
SP - 516
EP - 526
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -