Paradoxical exacerbation of neuronal injury in reperfused stroke despite improved blood flow and reduced inflammation in early growth response-1 gene-deleted mice.

Objectives: 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.

Discussion: 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.