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



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.



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.



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.
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA, 02140, USA.
Robert H
RH
LeBlanc
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA, 02140, USA.
Ruiya
R
Chen
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA, 02140, USA.
Magdy H
MH
Selim
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA, 02140, USA. khanafy@bidmc.harvard.edu.|Division of Neurointensive Care Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, Boston, MA, 02140, USA. khanafy@bidmc.harvard.edu.
Khalid A
KA
Hanafy
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D003676:Deferoxamine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000517:prevention & control*
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D018696:Neuroprotective Agents; D051547:Heme Oxygenase-1; D003676:Deferoxamine
Deferoxamine; Heme oxygenase; Immunology; Intracerebroventricular; Microglia; Subarachnoid hemorrhage; Vasospasm-independent