title: Paradoxical exacerbation of neuronal injury in reperfused stroke despite improved blood flow and reduced inflammation in early growth response-1 gene-deleted mice.
abstract: OBJECTIVE
  Early growth response gene-1 (Egr-1) coordinates the rapid upregulation of diverse inflammatory and coagulation-related genes following ischemia/reperfusion. Genetic deletion of Egr-1 results in attenuated post-ischemic injury in diverse tissue systems. In the present study, we utilized a murine model of transient middle cerebral artery occlusion to probe the functional effects of Egr-1 deletion following cerebral ischemia/reperfusion.
  
  
  METHODS
  The time course of Egr-1 expression was established by Northern/Western blot analysis, and immunocytochemistry localized Egr-1 to specific cell populations. Flow cytometry was then employed to characterize the ischemic cellular infiltrate of both wild-type (+/+) and Egr-1-null (-/-) mice. Next, the functional effect of Egr-1 deletion was investigated in Egr-1-deficient mice and their wild-type littermates subjected to middle cerebral artery occlusion. Infarct volumes, neurological scores, and reperfusion cerebral blood flow were compared between cohorts.
  
  
  RESULTS
  Rapid upregulation of Egr-1 was observed in the ischemic hemisphere, and localized primarily to neurons and mononuclear cells. Egr-1 deletion led to a suppression of infiltrating neutrophils and activated microglia/macrophages (P<0.001). Additionally, although Egr-1 deletion enhanced post-ischemic cerebral blood flow, Egr-1-deficient mice suffered larger infarcts (P=0.01) and demonstrated a trend towards worse neurological scores (P=0.06) than wild-type controls.
  
  
  CONCLUSIONS
  Despite a reduction in the proportion of infiltrating inflammatory cells/activated microglia and improvement in post-ischemic reperfusion, Egr-1-deficient animals suffer larger infarcts in our model. Therefore, cerebral Egr-1 expression may function to protect neurons despite its adverse modulatory consequences for inflammation and thrombosis.
authors.affiliation: Department of Neurological Surgery, Columbia University, New York 10032, USA. afd12@columbia.edu
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Ducruet
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Sosunov
authors.forename: Scott H
authors.initials: SH
authors.lastname: Visovatti
authors.forename: Danica
authors.initials: D
authors.lastname: Petrovic-Djergovic
authors.forename: William J
authors.initials: WJ
authors.lastname: Mack
authors.forename: E Sander
authors.initials: ES
authors.lastname: Connolly
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis* / Q000235:genetics*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000503:physiopathology*; D002546:Ischemic Attack, Transient / Q000235:genetics / Q000503:physiopathology; D008262:Macrophage Activation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000502:physiology; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D015854:Up-Regulation
chemical_list: D051766:Early Growth Response Protein 1