The Role of Presenilin-1 in the Excitotoxicity of Ethanol Withdrawal.
Presenilin-1 (PS1) is a core component of γ-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 (p38α 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 We used the prefrontal cortex of male rats withdrawn from a chronic ethanol diet. Additionally, we used ethanol-withdrawn HT22 cells (mouse hippocampal) treated with the inhibitor of glutamate receptors [dizocilpine (MK-801)], p38α (SB203580;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)-1H-imidazol-5-yl]pyridine), or γ-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 The prefrontal cortex of ethanol-withdrawn rats or HT22 cells showed an increase in PS1 and p38α, which was attenuated by MK-801 and SB203580, but mimicked by glutamate treatment to ethanol-free HT22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 p38α, contributing to the excitotoxic stimulus of EW.
Institute for Health Aging, Center for Neuroscience Discovery (M.E.J., D.B.M., H.K.D.), and Institute of Cancer Research (H.K.D.), University of North Texas Health Science Center, Fort Worth, Texas Marianna.Jung@unthsc.edu.
Marianna E
ME
Jung
Institute for Health Aging, Center for Neuroscience Discovery (M.E.J., D.B.M., H.K.D.), and Institute of Cancer Research (H.K.D.), University of North Texas Health Science Center, Fort Worth, Texas.
Daniel B
DB
Metzger
Institute for Health Aging, Center for Neuroscience Discovery (M.E.J., D.B.M., H.K.D.), and Institute of Cancer Research (H.K.D.), University of North Texas Health Science Center, Fort Worth, Texas.
Hriday K
HK
Das
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000473:pathology
D004791:Enzyme Inhibitors; D053764:Presenilin-1; D000431:Ethanol; D018698:Glutamic Acid; D048308:Mitogen-Activated Protein Kinase 14; D053829:Amyloid Precursor Protein Secretases