S100B-mediated protection against the pro-apoptotic effects of ethanol on fetal rhombencephalic neurons.
Previously, this laboratory demonstrated that ethanol treatment significantly reduces the number of developing serotonin (5-HT) and other fetal rhombencephalic neurons in rats by augmenting apoptosis. Using a 5-HT(1A) agonist we were able to attenuate the ethanol-associated reduction and apoptosis of 5-HT and rhombencephalic neurons. The downstream pro-survival effects of 5-HT(1A) stimulation were associated with the activation of phosphatidylinositol 3'kinase (PI-3K) and its subsequent up-regulation of specific NF-kappaB-dependent pro-survival genes. Using an in vitro model, we investigated the hypothesis that S100B, a protein which is released from astrocytes following 5-HT(1A) agonist stimulation, can reduce apoptosis in ethanol-treated rat fetal rhombencephalic neurons. We also evaluated whether the anti-apoptotic effects of S100B on fetal rhombencephalic neurons were linked to the activation of the PI-3K-->pAkt pro-survival pathway and the expression of two NF-kappaB-dependent pro-survival genes: XIAP and Bcl-2. Moreover, we determined whether S100B's pro-survival effects were associated with mitogen activated protein kinase kinase (MAPKK)-->p42/p44 MAPK. The results of these investigations demonstrated that S100B treatment prevented ethanol-associated apoptosis of fetal rhombencephalic neurons. In addition, it appears that these neuroprotective effects are linked to activation of the PI-3K pathways, because the PI-3K inhibitor LY294002 blocks the neuroprotective effects of S100B. Moreover, S100B increases the formation of pAkt and the up-regulation of two downstream NF-kappaB-dependent pro-survival genes: XIAP and Bcl-2. Although the MAPKK inhibitor PD98059 reduced the number of surviving neurons in S100B-treated cultures, S100B did not activate MAPKK.
Druse
Mary J
MJ
Department of Cell Biology, Neurobiology, and Anatomy, Division of Molecular and Cellular Biochemistry, Loyola University, Stritch School of Medicine, 2160 S. First Avenue, Maywood, IL 60153, USA. mmanteu@lumc.edu
Gillespie
Roberta A
RA
Tajuddin
Nuzhath F
NF
Rich
Megan
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D012249:Rhombencephalon / Q000166:cytology*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
D002492:Central Nervous System Depressants; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009414:Nerve Growth Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579158:S100b protein, rat; D051636:X-Linked Inhibitor of Apoptosis Protein; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000431:Ethanol; D019869:Phosphatidylinositol 3-Kinases