title: Neuroprotection of ischemic postconditioning by downregulating the postsynaptic signaling mediated by kainate receptors.
abstract: OBJECTIVE
  Ischemic postconditioning, a brief episode of ischemia after a prolonged ischemic insult, has been found to reduce the delayed neuronal loss after stroke. However, the mechanisms underlying such endogenous neuroprotective strategy remain obscure. In this study, we try to explore the excitatory postsynaptic signal events associated with neuroprotective effect of ischemic postconditioning.
  
  
  METHODS
  Global cerebral ischemia was induced for 15 minutes by the 4-vessel occlusion method in male Sprague-Dawley rats. Ischemic postconditioning was conducted 10 minutes later by a single reocclusion for 3 minutes.
  
  
  RESULTS
  A severe global cerebral ischemia after 5 days of reperfusion destroyed almost all hippocampal CA1 pyramidal neurons. A brief ischemic postconditioning robustly reduced the neuronal loss after ischemia. Preadministration of phosphoinositide 3-kinase inhibitor LY294002 blocked the neuroprotection of postconditioning, whereas mitogen-activated protein kinase kinase 1 inhibitor PD98059 had no effect. Ischemic postconditioning significantly increased the Akt phosphorylation (Ser473). In addition, postconditioning not only perturbed the binding of postsynaptic density protein-95 with glutamatergic kainate receptor subunit 2 and mixed lineage kinase 3 but also suppressed the downstream activation of mixed lineage kinase 3, mitogen-activated protein kinase kinase 7, and c-Jun N-terminal kinase 3. LY294002, but not PD98059, abolished the postconditioning-induced decreases in the assembly of glutamatergic kainate receptor subunit 2-postsynaptic density protein-95-mixed lineage kinase 3 complex and in the mixed lineage kinase 3-c-Jun N-terminal kinase 3 signaling. Akt inhibitor IV, a specific Akt inhibitor, showed the same effects as LY294002.
  
  
  CONCLUSIONS
  Ischemic postconditioning protects neurons against stroke by attenuating the postsynaptic glutamatergic kainate receptor subunit 2-postsynaptic density protein-95-mixed lineage kinase 3-c-Jun N-terminal kinase 3 signal cascade via phosphoinositide 3-kinase-Akt pathway.
authors.affiliation: Department of Pharmacology, Nanjing General Hospital of Nanjing Military Command, Jiangsu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Qin
authors.initials: Q
authors.lastname: Xu
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Ran
authors.initials: R
authors.lastname: Wang
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Hou
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D002545:Brain Ischemia / Q000209:etiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D057775:Ischemic Postconditioning / Q000379:methods*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018696:Neuroprotective Agents; D018092:Kainic Acid Receptors
keywords: cerebral ischemia; ischemic postconditioning; kainate receptors; mixed lineage kinase 3; neuroprotection; postsynaptic density protein-95