Suppression of survival kinases and activation of JNK mediate ethanol-induced cell death in the developing rat brain.
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.
Han
Jae Yoon
JY
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.
Jeong
Joo Yeon
JY
Lee
Yeon Kung
YK
Roh
Gu Seob
GS
Kim
Hyun Joon
HJ
Kang
Sang Soo
SS
Cho
Gyeong Jae
GJ
Choi
Wan Sung
WS
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
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