Involvement of ceramide in ethanol-induced apoptotic neurodegeneration in the neonatal mouse brain.
Acute administration of ethanol to 7-day-old mice is known to cause robust apoptotic neurodegeneration in the brain. Our previous studies have shown that such ethanol-induced neurodegeneration is accompanied by increases in lipids, including ceramide, triglyceride (TG), cholesterol ester (ChE), and N-acylphosphatidylethanolamine (NAPE) in the brain. In this study, the effects of ethanol on lipid profiles as well as caspase 3 activation were examined in the cortex, hippocampus, cerebellum, and inferior colliculus of the postnatal day 7 mouse brain. We found that the cortex, hippocampus, and inferior colliculus, which showed substantial caspase 3 activation by ethanol, manifested significant elevations in ceramide, TG, and NAPE. In contrast, the cerebellum, with the least caspase 3 activation, failed to show significant changes in ceramide and TG, and exhibits much smaller increases in NAPE than other brain regions. Ethanol-induced increases in ChE were observed in all brain regions tested. Inhibitors of serine palmitoyltransferase effectively blocked ethanol-induced caspase 3 activation as well as elevations in ceramide, ChE, and NAPE. Immunohistochemical studies indicated that the expression of serine palmitoyltransferase was mainly localized in neurons and was enhanced in activated caspase 3-positive neurons generated by ethanol. These results indicate that de novo ceramide synthesis has a vital role in ethanol-induced apoptotic neurodegeneration in the developing brain.
Saito
Mariko
M
Division of Neurochemisty, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York 10962, USA. marsaito@nki.rfmh.org
Chakraborty
Goutam
G
Hegde
Medha
M
Ohsie
Jason
J
Paik
Sun-Mee
SM
Vadasz
Csaba
C
Saito
Mitsuo
M
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002518:Ceramides / Q000502:physiology*; D003523:Cycloserine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D051102:Serine C-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism
D000963:Antimetabolites; D002492:Central Nervous System Depressants; D002518:Ceramides; D004791:Enzyme Inhibitors; D000431:Ethanol; D003523:Cycloserine; D051102:Serine C-Palmitoyltransferase; D053148:Caspase 3