Abstract W MP48: Post-stroke Administration of Exogenous Inter-alpha Inhibitor Proteins is Neuroprotective.
Background and Purpose: Current stroke therapies approved for human use are limited by time constraints and carry significant hemorrhagic risk. Down regulation of pro-inflammatory cytokines, modulation of peripheral leukocyte infiltration and reduced microglial activation benefit the ischemic brain. A novel immunomodulator protein family extracted from human plasma (Inter-alpha Inhibitor Proteins - IAIP) has been developed that has desirable anti-inflammatory properties in addition to an advantageous long half-life (8-12 hours).
Methods: C57BL/6 mice were subjected to transient focal ischemia by middle cerebral artery occlusion (MCAO) for 90 minutes. One cohort was given IAIP (30mg/kg) immediately at reperfusion (90 minutes after stroke). A second “delayed treatment” cohort was given IAIP 6 hours after stroke onset. Both cohorts were given a second dose 24 hours post-stroke. Motor and sensory deficits were assessed using the neurological deficit score (NDS). Infarct was assessed at either 48 hours or 7 day time points. Infarct data presented as mean ±SEM, NDS data are presented as median±IQR.
Results: At 48 hours mice given IAIP at reperfusion had significantly smaller cortical (59.26%±1.80% versus 31.58%±8.53%, n=8, p<.05) and hemisphere (46.05%±1.55% vs. 22.53%±6.55%, n=8, p<.05) infarct volumes. Delayed IAIP treated mice also had significantly smaller cortical (52.44%±1.73% vs. 22.99%±4.59%, n=6, p<.05) and hemispheric infarcts (43.86%±2.11% vs. 19.45%±3.59%, n=6, p<.05) at 48 hours. Analysis at 7 days showed significantly smaller cortical (23.30%±2.53% vs. 3.46%±0.46%, n=6, p<.05) and total hemisphere (22.33%±2.87% vs 5.90%±0.86%, n=6, p<.05) infarcts in mice treated with IAIP 6 hrs after stroke suggesting durability of neuroprotective effects. Significant improvement in NDS (1±1, n=19 versus 2±1, n=18) was also seen in mice treated with IAIP vs. controls. Similar beneficial effects of IAIP were seen in aged mice.
Conclusions: Delayed administration of IAIP at 6 and 24 hours post-stroke results in significantly smaller infarcts and improved functional outcomes, indicating IAIP could potentially be translated into an important novel treatment strategy for adults with brain ischemia.
Author Disclosures: V.R. Venna: None. N. Mancini: None. V. Scranton: None. A. Patrizz: None. Y. Lim: Other; Significant; Patent for Humanized IAIP. 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.
- © 2014 by American Heart Association, Inc.