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Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine.
- Source :
- Journal of Neuroinflammation; 9/13/2016, Vol. 13, p1-15, 15p
- Publication Year :
- 2016
-
Abstract
- <bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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 Hmox1 (fl/fl) control and Nes (Cre) :Hmox1 (fl/fl) mice, but not LyzM (Cre) :Hmox1 (fl/fl) mice.<bold>Conclusions: </bold>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. [ABSTRACT FROM AUTHOR]
- Subjects :
- HEME oxygenase
SUBARACHNOID hemorrhage
DEFEROXAMINE
CEREBRAL vasospasm
ANIONS
ERYTHROCYTES
THERAPEUTICS
ANIMAL experimentation
BIOLOGICAL models
CALCIUM-binding proteins
CELL culture
CELLS
COGNITION disorders
DOSE-effect relationship in pharmacology
LEARNING
MICE
MICROFILAMENT proteins
OXIDOREDUCTASES
RESEARCH funding
NEUROPROTECTIVE agents
INTRAVENTRICULAR injections
DISEASE complications
PREVENTION
Subjects
Details
- Language :
- English
- ISSN :
- 17422094
- Volume :
- 13
- Database :
- Complementary Index
- Journal :
- Journal of Neuroinflammation
- Publication Type :
- Academic Journal
- Accession number :
- 118143779
- Full Text :
- https://doi.org/10.1186/s12974-016-0709-1