Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine

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Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine

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Title: Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine
Author: LeBlanc, Robert H.; Chen, Ruiya; Selim, Magdy H.; Hanafy, Khalid A.

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Citation: LeBlanc, Robert H., Ruiya Chen, Magdy H. Selim, and Khalid A. Hanafy. 2016. “Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine.” Journal of Neuroinflammation 13 (1): 244. doi:10.1186/s12974-016-0709-1. http://dx.doi.org/10.1186/s12974-016-0709-1.
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Abstract: Background: Subarachnoid hemorrhage (SAH) is a devastating disease that affects over 30,000 Americans per year. Previous animal studies have explored the therapeutic effects of deferoxamine (DFX) via its iron-chelating properties after SAH, but none have assessed the necessity of microglial/macrophage heme oxygenase-1 (HO-1 or Hmox1) in DFX neuroprotection, nor has the efficacy of an intracerebroventricular (ICV) administration route been fully examined. We explored the therapeutic efficacy of systemic and ICV DFX in a SAH mouse model and its effect on microglial/macrophage HO-1. Methods: Wild-type (WT) mice were split into the following treatment groups: SAH sham + vehicle, SAH + vehicle, SAH + intraperitoneal (IP) DFX, and SAH + ICV DFX. For each experimental group, neuronal damage, cognitive outcome, vasospasm, cerebral and hematogenous myeloid cell populations, cerebral IL-6 concentration, and mitochondrial superoxide anion production were measured. HO-1 co-localization to microglia was measured using confocal images. Trans-wells with WT or HO-1−/− microglia and hippocampal neurons were treated with vehicle, red blood cells (RBCs), or RBCs with DFX; neuronal damage, TNF-α concentration, and microglial HO-1 expression were measured. HO-1 conditional knockouts were used to study myeloid, neuronal, and astrocyte HO-1 involvement in DFX-induced neuroprotection and cognitive recovery. Results: DFX treatment after SAH decreased cortical damage and improved cognitive outcome after SAH yet had no effect on vasospasm; ICV DFX was most neuroprotective. ICV DFX treatment after SAH decreased cerebral IL-6 concentration and trended towards decreased mitochondrial superoxide anion production. ICV DFX treatment after SAH effected an increase in HO-1 co-localization to microglia. DFX treatment of WT microglia with RBCs in the trans-wells showed decreased neuronal damage; this effect was abolished in HO-1−/− microglia. ICV DFX after SAH decreased neuronal damage and improved cognition in Hmox1fl/fl control and NesCre:Hmox1fl/fl mice, but not LyzMCre:Hmox1fl/fl mice. Conclusions: DFX neuroprotection is independent of vasospasm. ICV DFX treatment provides superior neuroprotection in a mouse model of SAH. Mechanisms of DFX neuroprotection after SAH may involve microglial/macrophage HO-1 expression. Monitoring patient HO-1 expression during DFX treatment for hemorrhagic stroke may help clinicians identify patients that are more likely to respond to treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12974-016-0709-1) contains supplementary material, which is available to authorized users.
Published Version: doi:10.1186/s12974-016-0709-1
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020472/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29407682
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