# Testing brain penetrant iron chelators and investigating putative clearance pathway in ICH

> **NIH NIH R56** · UNIVERSITY OF FLORIDA · 2020 · $381,250

## Abstract

Intracerebral hemorrhage (ICH) is a serious medical condition caused by bleeding in the brain. It should be noted
that at the last AHA/ASA International Stroke Conference in Feb. 2019, findings were presented from a Phase
III trial showing that deferoxamine (DFO) was futile against ICH. One potential explanation is that DFO does not
cross the BBB, and it has significant toxicity issues. Thus, the main focus now is to determine the efficacy and
therapeutic window of a novel, safe, and effective therapy against ICH by testing unique brain penetrant iron
chelators. To achieve this goal, and based on the literature and our preliminary data, we will test potent and
selective iron chelators such as HBED, and their efficacy will be compared to other iron chelators such as the
DADMDFT analog and DFO.
 After intracranial bleeding, red blood cells lyse and release large amounts of hemoglobin (Hb). These have to
be actively phagocytosed, after which the heme (which cannot be recycled) gets degraded to generate iron
intracellularly. Under normal physiological conditions, iron homeostasis should be maintained; however, when
there are too many (heme) substrates, there is also too much iron, a process called iron dyshomeostasis. Our
overall hypothesis is that a lipophilic brain penetrant iron chelator would be effective against ICH. Notably, HBED
also has a much better safety profile compared to DFO, which was noted after a thorough Phase I safety trial.
We observed that HBED was most potent after a traumatic brain injury model. Also, we found that DADMDFT
provides benefits by improving functional and anatomical outcomes in the stroma-free Hb injection model.
Besides binding iron, HBED binds ferrous (toxic) iron and converts it into ferric (nontoxic) iron in cells and
mitochondria, preventing prooxidant and proinflammatory cascades.
 Aim 1 is to investigate the efficacy of HBED over DADMDFT and DFO in improving neurobehavioral and
anatomical outcomes after ICH. We will determine and compare the optimal dose-response and therapeutic
window of HBED, DADMDFT, and DFO in adult male mice and in parallel in females. Aims 2, 3, and 4 are to
investigate the importance of the known phagocytic receptors CD36 and CD163 for RBCs and Hb, respectively,
using the autologous blood ICH preclinical model. We will use the single and double knockouts (versus matched
C57BL/6 littermates) that we have already generated. The goal is to understand mechanistically the respective
role of these phagocytic receptors because they should participate in the clearance of RBCs and hemoglobin
and test the added benefits of the optimal iron chelator, helping to limit the oxidative/inflammatory stress
cascades. Toxicity will be monitored, along with brain and serum iron levels over time, after treatment with the
iron chelator.
 This project is timely, and we believe we have assembled a unique team with the tools, animals, models, and
expertise necessary to rigorously perform these experiments. We...

## Key facts

- **NIH application ID:** 10201369
- **Project number:** 1R56NS116076-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Sylvain DORE
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 1
- **Project period:** 2020-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201369

## Citation

> US National Institutes of Health, RePORTER application 10201369, Testing brain penetrant iron chelators and investigating putative clearance pathway in ICH (1R56NS116076-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10201369. Licensed CC0.

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