Abstract W P90: Insulin-like Growth Factor-1-mediated Reduction of Stroke-induced Brain Infarction is Preceded by Improvement of Blood Brain Barrier Integrity and Inflammatory Cytokines
Background and Purpose: Although insulin-like growth factor (IGF)-1 treatment has been shown to reduce stroke-induced infarct volume, the mechanisms underlying its neuroprotective actions are not fully understood. The present study tested the hypothesis that IGF-1 may regulate the neuroinflammatory cascade initiated by ischemic stroke, specifically, by promoting the integrity of the blood brain barrier.
Methods: Middle-aged (10-12 month old) female rats were implanted with a cannula directed toward the lateral ventricle. One week later, animals were anesthetized using isoflurane and the middle-cerebral artery was occluded using an intraluminal suture maintained in place for 90 mins. IGF-1 or vehicle was delivered icv, via a mini-pump, following reperfusion. All animals were terminated at 4h or 24h post MCAo. Blood brain barrier permeability was determined using Evan’s blue extravasation and infarct volumes were determined from TTC-stained brain sections. Inflammatory cytokines were analyzed from brain lysates by ELISA.
Results: IGF-1 treatment to middle-aged females resulted in a 39% reduction in infarct volume when measured 24h post MCAo, confirming the neuroprotective action of this peptide hormone. In order to assess the effects of IGF-1 on early stroke induced effects, we next determined blood brain permeability 4h post stroke as well as the expression of cytokines in the ischemic hemisphere. IGF-1 treatment resulted in a significant reduction of blood brain barrier permeability at 4h post-stroke compared to vehicle treated animals. Moreover, multiplex cytokine analysis showed that IGF-1 significantly reduced inflammatory markers such as IL-6, IFN-gamma, TNF-alpha, eotaxin, GM-CSF. Brain infarct volume at 4h was similar in both IGF-1 and vehicle groups, indicating that the effects of IGF-1 on inflammatory markers precede its effects on infarct volume. IGF-1 also suppressed IL-6, MIP-2, GRO-KC, MCP-1, EGF and MIP-1-alpha expression at 24h post stroke, indicating a persistent anti-inflammatory effect for this growth factor.
Conclusions: The above findings support the hypothesis that IGF-1 has unique anti-inflammatory action in the aging female brain, and suggest that brain endothelial cells may be a primary target of IGF-1.
Author Disclosures: S. Bake: None. F. Sohrabji: None.
- © 2014 by American Heart Association, Inc.