The effect of deferoxamine on brain lipid peroxide levels and Na-K ATPase activity following experimental subarachnoid hemorrhage

2009

Stroke

115

Abstract-Iron resulting from hemoglobin degradation is linked to delayed neuronal injury after intracerebral hemorrhage. Extensive preclinical investigations indicate that the iron chelator, deferoxamine mesylate, is effective in limiting hemoglobin-and iron-mediated neurotoxicity. However, clinical studies evaluating the use of deferoxamine in intracerebral hemorrhage are shortcoming. This article reviews the potential role of deferoxamine as a promising neuroprotective agent to target the secondary effects of intracerebral hemorrhage to limit brain injury and improve outcome, and ongoing efforts to translate the preclinical findings into clinical investigations. Key Words: deferoxamine Ⅲ ICH Ⅲ edema Ⅲ neuroprotection A t present, there is no specific treatment for spontaneous intracerebral hemorrhage (ICH) beyond supportive medical care. Therapeutic attempts to target hematoma and its expansion might provide some benefit in carefully selected patients. However, this strategy alone is likely to be of limited usefulness because hematoma expansion often occurs within the first hours after onset. Furthermore, neuronal injury in ICH is not only related to hematoma expansion. Other secondary processes, including apoptosis, necrosis, autophagy, inflammation, and edema formation, have been implicated. 1,2 A potential adjunctive approach to the treatment of ICH might be to target hemoglobin-and iron-mediated neurotoxicity. Iron-Mediated NeurotoxicityHemoglobin degradation products resulting from hemolysis after ICH include the iron-containing heme. Iron plays a role in neuronal injury by catalyzing a sequence of reactions "Haber-Weiss reaction" that yield highly reactive toxic hydroxyl radicals leading to oxidative stress and cell death, activating lipid peroxidation, and exacerbating excitotoxicity. 3,4 The time course for hemoglobin hemolysis and toxicity after ICH is 2 to 3 days. 5,6 This delayed time window can have important therapeutic advantages. Deferoxamine MesylateDeferoxamine has been used in clinical practice for more than 30 years in iron-overloaded patients with acute iron intoxication or overload due to transfusion-dependent anemia. It is a hydrophilic chelator, which chelates Fe ϩϩϩ and hemosiderin forming a stable complex that prevents iron from entering into Haber-Weiss reaction. The drug is relatively well tolerated. Serious adverse effects are uncommon. Hypotension and shock occur in 2% of patients, mostly with rapid intravenous administration at high doses. The infusion rate should not exceed 15 mg/kg per hour, and the total amount administered should not exceed 6000 mg in 24 hours. PharmacokineticsDeferoxamine is rapidly absorbed. Plasma concentrations between 80 and 130 mol/L are recorded 3 minutes after intravenous injections. The drug's serum protein-binding rate is Ͻ10%. It is distributed throughout all body fluids and has a volume of distribution of 0.8 to 1.35 L/kg. The drug is mostly metabolized by oxidative deamination, yielding metabolite B. The drug, its iron chelate complex (ferrioxamin...

Section: In Vivo Studiesmentioning

confidence: 99%

Deferoxamine Mesylate

2009

Stroke

115

“…In rat models of SAH, DFX has been shown to decrease overall mortality, edema, oxidative stress, and neuronal death [ 15 , 16 ]. Additionally, DFX treatment after SAH has been shown to decrease cortical apoptotic markers [ 16 ] and reduce markers of brainstem damage in rats [ 45 ], as well as reduce lipid peroxidation markers and improve sodium-potassium ATPase activity in guinea pigs [ 46 ]. Our study looked to further elucidate the mechanisms of DFX-induced neuroprotection in a mouse model of SAH.…”

Section: Discussionmentioning

confidence: 99%

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

LeBlanc

Chen

et al. 2016

J Neuroinflammation

BackgroundSubarachnoid 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.MethodsWild-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.ResultsDFX 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.ConclusionsDFX 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 materialThe online version of this article (doi:10.1186/s12974-016-0709-1) contains supplementary material, which is available to authorized users.

“…In one study, treatment with deferoxamine attenuated death rate and hemorrhagic transformation in a rat model of transient focal ischemia [109]. Treatment with deferoxamine also attenuates the production of ROS, blocks hemoglobin-mediated potentiation of glutamate neurotoxicity, reduces brain malondialdehyde content and induces recovery of sodium-potassium pump activity, and exerts diverse protective effects after experimental ICH [29,33,[110][111][112]. Emerging evidence also supports a potential therapeutic role for deferoxamine following intraventricular and subarachnoid hemorrhages [113,114].…”

Section: Iron-modifying Agentsmentioning

confidence: 96%

Antioxidant Strategies in Neurocritical Care

Hanafy

2012

Neurotherapeutics

An increase in oxidative stress and overproduction of oxidizing reactive species plays an important role in the pathophysiology of several conditions encountered in the neurocritical care setting including: ischemic and hemorrhagic strokes, traumatic brain injury, acute respiratory distress syndrome, sepsis, and organ failure. The presence of oxidative stress in these conditions is supported by a large body of preclinical and clinical studies, and provides a rationale to support a potential therapeutic role for antioxidants. The purpose of this article is to briefly review the basic mechanisms and molecular biology of oxidative stress, summarize its role in critically ill neurological patients, and review available data regarding the potential role of antioxidant strategies in neurocritical care and future directions.