title: Cross-talk between phosphatidic acid and ceramide during ethanol-induced apoptosis in astrocytes.
abstract: BACKGROUND
  Ethanol inhibits proliferation in astrocytes, an effect that was recently linked to the suppression of phosphatidic acid (PA) formation by phospholipase D (PLD). The present study investigates ethanol's effect on the induction of apoptosis in astrocytes and the formation of ceramide, an apoptotic signal. Evidence is presented that the formation of PA and ceramide may be reciprocally linked during ethanol exposure.
  
  
  RESULTS
  In cultured rat cortical astrocytes, ethanol (0.3-1 %, v/v) induced nuclear fragmentation and DNA laddering indicative of apoptosis. Concomitantly, in cells prelabeled with [3H]-serine, ethanol caused a dose-dependent, biphasic increase of the [3H]-ceramide/[3H]-sphingomyelin ratio after 1 and 18 hours of incubation. As primary alcohols such as ethanol and 1-butanol were shown to inhibit the phospholipase D (PLD)-mediated formation of PA, a mitogenic lipid messenger, we tested their effects on ceramide formation. In astrocytes prelabeled with [3H]-serine, ethanol and 1-butanol, in contrast to t-butanol, significantly increased the formation of [3H]-ceramide. Moreover, exogenous PA, added to transiently permeabilized astrocytes, suppressed ethanol-induced [3H]-ceramide formation. Vice versa, addition of C2-ceramide to astrocytes inhibited PLD activity induced by serum or phorbol ester.
  
  
  CONCLUSIONS
  We propose that the formation of ceramide in ethanol-exposed astrocytes is secondary to the disruption of phospholipase D signaling. Ethanol reduces the PA:ceramide ratio in fetal astrocytes, a mechanism which likely participates in ethanol-induced glial apoptosis during brain development.
authors.affiliation: Department of Pharmacology, School of Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany. beate.schatter@gmx.de
authors.forename: Beate
authors.initials: B
authors.lastname: Schatter
authors.forename: Shenchu
authors.initials: S
authors.lastname: Jin
authors.forename: Konrad
authors.initials: K
authors.lastname: Löffelholz
authors.forename: Jochen
authors.initials: J
authors.lastname: Klein
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D000431:Ethanol / Q000494:pharmacology*; D006868:Hydrolysis; D010712:Phosphatidic Acids / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D051381:Rats; D013109:Sphingomyelins / Q000378:metabolism
chemical_list: D002518:Ceramides; D010712:Phosphatidic Acids; D013109:Sphingomyelins; D000431:Ethanol; D010739:Phospholipase D