title: Neuroprotective effects of preconditioning ischaemia on ischaemic brain injury through inhibition of mixed-lineage kinase 3 via NMDA receptor-mediated Akt1 activation.
abstract: A number of works show that the mitogen-activated protein kinase (MAPK) signalling pathway responds actively in cerebral ischaemia and reperfusion. We undertook our present studies to clarify the role of mixed-lineage kinase 3 (MLK3), a MAPK kinase kinase (MAPKKK) in MAPK cascades, in global ischaemia and ischaemic tolerance. The mechanism concerning NMDA receptor-mediated Akt1 activation underlying ischaemic tolerance, was also investigated. Sprague-Dawley rats were subjected to 6 min of ischaemia and differing times of reperfusion. Our results showed MLK3 was activated in the hippocampal CA1 region with two peaks occurring at 30 min and 6 h, respectively. This activation returned to base level 3 days later. Both preconditioning with 3 min of sublethal ischaemia and NMDA pretreatment inhibited the 6-h peak of activation. However, pretreatment of ketamine before preconditioning reversed the inhibiting effect of preconditioning on MLK3 activation at 6 h of reperfusion. In the case of Akt1, however, preconditioning and NMDA pretreatment enhanced Akt1 activation at 10 min of reperfusion. Furthermore, ketamine pretreatment reversed preconditioning-induced increase of Akt1 activation. We also noted that pretreatment of LY294002 before preconditioning reversed both the inhibition of MLK3 activation at 6 h of reperfusion and the increase in Akt1 activation at 10 min of reperfusion. The above-mentioned results lead us to conclude that, in the hippocampal CA1 region, preconditioning inhibits MLK3 activation after lethal ischaemia and reperfusion and, furthermore, this effect is mediated by Akt1 activation through NMDA receptor stimulation.
authors.affiliation: Research Centre for Biochemistry and Molecular Biology, Xuzhou Medical College, Jiangsu, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Yin
authors.forename: Quan-Guang
authors.initials: QG
authors.lastname: Zhang
authors.forename: Bei
authors.initials: B
authors.lastname: Miao
authors.forename: Guang-Yi
authors.initials: GY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000098:blood supply* / Q000166:cytology / Q000187:drug effects; D002545:Brain Ischemia / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D019194:Ischemic Preconditioning / Q000379:methods*; D007649:Ketamine / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015424:Reperfusion / Q000379:methods; D013997:Time Factors; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D002867:Chromones; D004121:Dimethyl Sulfoxide; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D007649:Ketamine; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D009025:Morpholines; D016202:N-Methylaspartate; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016194:Receptors, N-Methyl-D-Aspartate; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one