title: Neuroprotection of ethanol against ischemia/reperfusion-induced brain injury through decreasing c-Jun N-terminal kinase 3 (JNK3) activation by enhancing GABA release.
abstract: 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.
authors.affiliation: School of Life Science and Biotechnology, China Pharmaceutical University, 24 Tongjia Street, Nanjing, 210009, People's Republic of China.
authors.forename: S-H
authors.initials: SH
authors.lastname: Qi
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: L-Y
authors.initials: LY
authors.lastname: Hao
authors.forename: Q-H
authors.initials: QH
authors.lastname: Guan
authors.forename: Y-H
authors.initials: YH
authors.lastname: Gu
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Yan
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.forename: G-Y
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001640:Bicuculline / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019256:Cadmium Chloride / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004789:Enzyme Activation; D000431:Ethanol / Q000494:pharmacology* / Q000627:therapeutic use; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D058787:GABA-A Receptor Antagonists; D018696:Neuroprotective Agents; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D048057:Mitogen-Activated Protein Kinase 10; D019256:Cadmium Chloride; D001640:Bicuculline