School of Life Science and Biotechnology, China Pharmaceutical University, 24 Tongjia Street, Nanjing, 210009, People's Republic of China.
Neuroscience. 2010 Jun 2;167(4):1125-37. doi: 10.1016/j.neuroscience.2010.02.018. Epub 2010 Feb 26.
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 (CdCl(2)) can demolish the neuroprotective effects of ethanol. The results suggest that during ischemia-reperfusion, ethanol may activate presynaptic Gluk1-KA and facilitate Ca(2+)-dependent GABA release. The released GABA activates postsynaptic GABA(A) 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.
我们的最新研究表明，乙醇可通过激活离子型谷氨酸受体 kainate 家族 (Gluk1)-kainate (KA) 受体和γ-氨基丁酸 (GABA) 受体来减轻脑缺血/再灌注引起的脑损伤。然而，乙醇的神经保护作用的可能机制仍不清楚。在这项研究中，我们报告乙醇通过增强 GABA 释放，然后降低 c-Jun N 末端激酶 3 (JNK3) 激活，显示出对缺血性脑损伤的神经保护作用。电生理记录表明，乙醇增强来自突触前神经元的 GABA 释放，并且释放的 GABA 随后抑制 KA 受体介导的全细胞电流。此外，我们的数据表明，乙醇可以抑制由脑缺血引起的 Gluk2-PSD-95-MLK3（突触后密度蛋白-95、PSD-95 和混合谱系激酶 3、MLK3）模块的增加组装和 MLK3-MKK4/7-JNK（丝裂原活化蛋白激酶激酶 4/7、MKK4/7）级联的激活。GABA(A)受体拮抗剂 Bicuculline 和 VGCC（电压门控钙通道 [VGCC] 的广谱阻滞剂）Chromic（CdCl(2)）的预处理可以破坏乙醇的神经保护作用。结果表明，在缺血再灌注期间，乙醇可能激活突触前 Gluk1-KA 并促进 Ca(2+)-依赖性 GABA 释放。释放的 GABA 激活突触后 GABA(A)受体，其抑制缺血性去极化并减少由突触后 Gluk2-KA 受体的激活引起的信号转导模块 Gluk2-PSD-95-MLK3 的缔合。乙醇抑制 JNK3 凋亡途径（MLK3/MKK4/7/JNK3/c-Jun/Fas-L）对缺血性脑损伤具有神经保护作用的可能性增加。
