Abstract WP218: Intraperitoneal Igf1 Treatment Ameliorates The Chronic Impact Of Ischemic Stroke In Reproductively Senescent Female Rats And Repairs The Gut While Icv-igf-1 Does Not

Abstract

Background: Our previous studies have shown that reproductively senescent (RS) female rats, who have lower circulating levels of the peptide hormone Insulin-like Growth Factor (IGF-1), display worse outcomes after a stroke event than young adult female rats. ICV administration of IGF-1, decreases infarct volume, improves sensory motor performance, and reduces cytokine levels in the ischemic hemisphere of RS females as compared to vehicle-treated controls. Yet, icv IGF1 administration failed to attenuate peripheral inflammation and depressive behaviors in the chronic phase of stroke. In view of the evidence that stroke induces gut dysbiosis, and that gut dysfunction is implicated in depressive and cognitive behaviors, we hypothesize that, unlike icv administration of IGF-1, which is restricted to the brain, systemic i.p. administration of IGF1 would repair the gut, attenuate peripheral cytokine levels and improve long-term behavior outcomes. Methods: Acyclic middle-aged Sprague Dawley female rats (9-11 mos) were subjected to endothelin-1 induced middle cerebral artery occlusion (MCAo) or sham operation. Animals received IGF1 via i.p. injections 4h post MCAo and 24 h post MCAo, or icv infusions, while controls received vehicle. Sensory motor tests, blood and gut samples were acquired pre and post MCAo. Animals were terminated either in the acute phase (2d) or chronic phase (30d). The latter group was also subject to tests of cognition and depressive-like behavior. Results: In contrast to icv treatment, i.p.-IGF-1 did not reduce infarct volume or acute sensory motor impairment, but significantly attenuated circulating levels of several inflammation associated cytokines. In addition, ip-IGF-1 significantly attenuated post stroke gut dysmorphology, by preserving villus:crypt ratio and the mucin barrier. Furthermore, in the chronic phase, i.p.-IGF1 attenuated cognitive decline post stroke in the NORT and Barnes Maze tasks, while icv IGF-1 did not. Conclusion: Since long term disability after stroke is correlated with elevated levels of peripheral cytokines, our data suggest that systemic IGF1 may be a better therapeutic option for long term outcomes.Supported by NS074895 to FS. YEH is supported by a generous gift from the WoodNext Foundation.