Abstract WP264: The Growth Factor Progranulin Suppresses Inflammatory Reactions and Attenuates Neuronal Injury Induced by Cerebral Ischemia-Reperfusion in Mice.
Objective—The growth factor progranulin (PGRN) is a widely expressed protein with various biological functions, and it is known to have an anti-inflammatory effect. The aim of this study was to investigate the possible ameliorative effects of PGRN against cerebral ischemia-reperfusion (I/R) injury.
Methods—In vivo ischemic stroke was induced in 4-week-old male ddY mice by 2 h of middle cerebral artery occlusion (MCAO) followed by 22 h of reperfusion. The following 4 experimental protocols were devised: (1) to determine the expression level of PGRN in the I/R brain (n = 4 per group); (2) to establish the dose-response effects of intracerebroventricularly administered recombinant PGRN (r-PGRN; 0.1 to 1.0 ng) on cerebral I/R injury (n = 6 to 8 per group); (3) to establish the therapeutic time window of r-PGRN treatment (n = 8 to 9 per group); and (4) to investigate the effects of r-PGRN treatment on the expression of inflammatory cytokines in the I/R brain (n = 5 per group).
Results—We found that the expression level of PGRN was significantly reduced in the I/R brain (P < 0.01, vs. Sham; t test). The administration of 1.0 ng of r-PGRN at 2 h after MCAO resulted in a reduction in the infarct volume and brain swelling at 24 h after MCAO (P < 0.01, vs. Vehicle, in each; Dunnett test), and this led to an improvement in neurological scores (P < 0.05; Wilcoxon signed-rank test). Delayed administration of r-PGRN at 6 h after MCAO did not reduce the infarct volume, but significantly reduced brain swelling (P < 0.05; t test). We also confirmed that r-PGRN administration significantly reduced the phosphorylation of NF-κB and expression of MMP-9 in the I/R brain (P < 0.05, vs. Vehicle, in each; t test).
Conclusion—r-PGRN treatment exerts ameliorative effects on experimental ischemic stroke, and these effects are due to the prevention of harmful inflammatory reactions following cerebral I/R. This study suggests the feasibility of r-PGRN administration as a novel therapeutic strategy for treatment in the acute phase of ischemic stroke.
- © 2012 by American Heart Association, Inc.