Targeting Pro-Oxidant Iron with Deferoxamine as a Treatment for Ischemic Stroke: Safety and Optimal Dose Selection in a Randomized Clinical Trial

Abstract

A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40–60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40–60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50–58% of the 40–60 mg/Kg/day DFO-treated patients.

Mechanism of Ferroptosis and Its Relationships with Other Types of Programmed Cell Death: Insights for Potential Therapeutic Benefits in Traumatic Brain Injury

“…It was discovered by analyzing the human glioma genome that ferroptosis-related gene signature can be applied to low-grade glioma border localization and detection and predict glioma cell death and glioma patient progression [ 133 – 136 ]. DFO is effective in treating ischemic stroke in a randomized clinical trial [ 137 ]. These findings suggest that ferroptosis is a potential target for treatment for TBI.…”

The underlying pathological mechanism of ferroptosis in the development of cardiovascular disease

“…Conversely, administration of deferoxamine which chelates redox-active iron to inhibit ferroptosis has been shown to improve blood oxidative stress markers as an adjunctive therapy for patients with ST-segment elevation MI ( 142 ). Intravenous infusion of deferoxamine mesylate at the initiation of thrombolysis was also effective in ischemic stroke patients, with no apparent adverse effects ( 143 ). Therefore, pharmacological treatment to maintain iron homeostasis and inhibit ferroptosis may serve as a new therapeutic strategy for CVDs.…”

Crosstalk Between the Oxidative Stress and Glia Cells After Stroke: From Mechanism to Therapies

“…Deferoxamine is an inducer of HIF-1 and its mediated antioxidant effect may be related to the inhibition of the Fenton reaction by chelating Fe 2+ (180). Clinical trials conducted by Mònica et al confirmed the effectiveness and safety of desferrioxamine in the treatment of ischemic stroke (181).Neuroglobin protein (ngb1) is a member of the bead protein family and its initiation process is regulated by transcription factors, such as HIF-1 and VEGF (182). Animal experiments have demonstrated that sub-nanomolar concentrations of Ngb1 prevent ROS accumulation, reduced antioxidant enzymes, and reduced expression of apoptotic proteins in astrocytes after exposure to H 2 O 2 (183).…”