Abstract T MP14: The Critical Role of Macrophage Migration Inhibitory Factor on Post-Stroke Recovery
Objective: One-third of stroke survivors are affected by post-stroke depression. Evidence from epidemiological and clinical studies demonstrates that depression either before or after stroke is associated with poor recovery and high mortality. Recently it was found that loss of macrophage migration inhibitory factor (MIF) is associated with depressive behavior and impaired neurogenesis. Therefore, here we tested the hypothesis that MIF plays a role in stroke recovery and that chronic MIF inhibition contributes to post-depressive phenotypes and poor stroke outcomes.
Methods: C57BL/6 male mice (20-25g; Charles River), were subjected to a 60min right middle cerebral artery occlusion (MCAO) and randomly assigned to vehicle or MIF antagonist, ISO-1 (7mg/kg/day intraperitoneal) treatment. Infarcts quantified with TTC. Recovery was investigated using neurological deficit scores (NDS), corner test, the forced swim test (FST) and the tail suspension test (TST). MIF levels were assessed by ELISA and western-blot (n=4/grp). Further, the effects of MIF loss were tested using knockout (KO) mice. Data are expressed as mean±sem. P value < .05 was set for statistical significance.
Results: Post-stroke chronic ISO-1 treatment significantly increased immobility in TST at 14d (126±8 vs 83±6s; p<.05), delayed stroke recovery in the corner test (p<.05) and NDS (p<.05) compared to vehicle group. These detrimental effects were observed in parallel to reduced plasma MIF levels (p<.05). Stroke alone did not affect mobility in FST compared to sham (p>.05). Infarct size was similar in ISO-1 and vehicle groups (48±3.2% versus 46±2.8%; p>.05). When subjected MIF KO mice to stroke, similar pattern of delayed post-stroke recovery is observed suggesting that MIF plays a critical role in pre- or post-stroke depression and recovery.
Conclusions: MIF KO mice had a depressive phenotype at baseline, and poor recovery after stroke compared to WT. Post-stroke MIF inhibition led to the development of a post-stroke depressive phenotype and also led to poorer recovery. These effects are independent of stroke volume. These findings suggest that targeting MIF might be a novel therapeutic strategy to treat post-stroke depression and to enhance recovery in stroke survivors.
Author Disclosures: V.R. Venna: None. S.E. Benashski: None. R. Verma: None. Y. Xu: None. L. Capozzi: None. F. Liu: None. L.D. McCullough: None.
This research has received full or partial funding support from the American Heart Association, Founders - Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont.
- © 2015 by American Heart Association, Inc.