title: Suppression of survival kinases and activation of JNK mediate ethanol-induced cell death in the developing rat brain.
abstract: Administration of ethanol to immature rat pups during the period in which synaptogenesis occurs triggers extensive apoptotic cell death in the brain. This ethanol-induced cell death is known to be mediated by Bax activation, which is caused by mitochondrial dysfunction. However, little data is available regarding the regulation of survival signaling pathways and their downstream events that lead to Bax activation. Thus, in the present study, we aimed to investigate the effect of ethanol on survival signaling pathways and their downstream events that lead to cell death in the rat brain during the brain developmental period. Ethanol (3 g/kg, 20% in saline) was administered subcutaneously to post-natal 7-day-old rat pups twice at 2-h intervals and the pups were sacrificed at 4 h following the first ethanol injection. Ethanol treatment suppressed the activation of survival kinases, particularly Akt, Erk1/2 and PKAalpha, whereas it increased the activation of JNK. Moreover, dissociation of dephosphorylated Bad from 14-3-3 and the interaction of activated JNK with Bcl-2 were elevated by ethanol treatment. The present study demonstrated that ethanol treatment during the brain developmental period induced mitochondrial dysfunction, which led to cell death by the suppression of survival kinases, Bad release from 14-3-3 and inactivation of Bcl-2 by activated JNK.
authors.affiliation: Department of Anatomy and Neurobiology, Health Science Institute, College of Medicine, Medical Research Center for Neural Dysfunction, Gyeongsang National University, 92 Chilam-dong, Jinju, Gyeongnam 660-751, South Korea.
authors.forename: Jae Yoon
authors.initials: JY
authors.lastname: Han
authors.forename: Joo Yeon
authors.initials: JY
authors.lastname: Jeong
authors.forename: Yeon Kung
authors.initials: YK
authors.lastname: Lee
authors.forename: Gu Seob
authors.initials: GS
authors.lastname: Roh
authors.forename: Hyun Joon
authors.initials: HJ
authors.lastname: Kim
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Kang
authors.forename: Gyeong Jae
authors.initials: GJ
authors.lastname: Cho
authors.forename: Wan Sung
authors.initials: WS
authors.lastname: Choi
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D002470:Cell Survival; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; C494821:Bad protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D000431:Ethanol; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048670:MAP Kinase Kinase 4