期刊
NEUROSCIENCE
卷 167, 期 4, 页码 1125-1137出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2010.02.018
关键词
ethanol; neuroprotection; brain ischemia-reperfusion; GABA; c-Jun N-terminal kinase 3 (JNK3)
资金
- National Nature Science Foundation of China [90608015]
- Natural Science Foundation of the Jiangsu Higher Education Institutions of China [08KJB180010, 07KJA18030]
- National Youth Science Foundation of China [30700117]
Our latest study indicated that ethanol could attenuate cerebral ischemia/reperfusion-induced brain injury through activating Ionotropic glutamate receptors Kainate Family (Gluk1)-kainate (KA) receptors and gamma-aminobutyric acid (GABA) receptors. However, the possible mechanism of the neuroprotective effects of ethanol remains unclear. In this study we report that ethanol shows neuroprotective effects against ischemic brain injury through enhancing GABA release and then decreasing c-Jun N-terminal kinase 3 (JNK3) activation. Electrophysiologic recording indicated that ethanol enhances GABA release from presynaptic neurons and the released GABA subsequently inhibits the KA receptor mediated whole-cell currents. Moreover, our data show that ethanol can inhibit the increased assembly of the Gluk2-PSD-95-MLK3 (postsynaptic density protein-95, PSD-95 and mixed-lineage kinase 3, MLK3) module induced by cerebral ischemia and the activation of the MLK3-MKK4/7-JNK (mitogen-activated protein kinase kinase 4/7, MKK4/7) cascade. Pretreatment of the GABA(A) receptor antagonist bicuculline and antagonist of VGCC (a broad-spectrum blocker of the voltage-gated calcium channel [VGCC]) Chromic (CdCl2) can demolish the neuroprotective effects of ethanol. The results suggest that during ischemia-reperfusion, ethanol may activate presynaptic Gluk1-KA and facilitate Ca2+-dependent GABA release. The released GABA activates postsynaptic GABAA receptors, which suppress the ischemic depolarization and decrease the association of signaling module Gluk2-PSD-95-MLK3 induced by the activation of postsynaptic Gluk2-KA receptors. There is a raised possibility that ethanol inhibiting the JNK3 apoptotic pathway (MLK3/MKK4/7/JNK3/c-Jun/Fas-L) performs a neuroprotective function against ischemic brain injury. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.
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