Testing brain penetrant iron chelators and investigating putative clearance pathway in ICH
Testing brain penetrant iron chelators and investigating putative clearance pathway in ICH
批准号:
10201369
负责人:
Sylvain DORE
金额:
$38.13万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-08-01 至 2023-07-31
关键词:
AcidsAddressAdultAffinityAftercareAlbuminsAnatomyAnimalsAttenuatedAutologousBilirubinBindingBloodBlood gasBrainBrain EdemaBrain hemorrhageC57BL/6 MouseCD3 AntigensCD36 geneCarboxylic AcidsCell DeathCellsCerebral hemisphere hemorrhageChelating AgentsChemistryClinical TrialsCremophorCytolysisDataDeferoxamineDoseEnzyme-Linked Immunosorbent AssayEnzymesErythrocytesEthylenediaminesFemaleFutureGlial Fibrillary Acidic ProteinGliosisGlucoseGoalsH ferritinHalf-LifeHematocrit procedureHematomaHemoglobinHemoglobin concentration resultHemorrhageHomeostasisHumanHydroxyl RadicalIn Situ Nick-End LabelingIndividualInflammationInflammatoryInjectionsInjuryInternationalIronIron Chelating AgentsKnock-outKnowledgeLeadLiteratureLiverMeasuresMedicalMitochondriaModelingMonitorMotorMusNeuroanatomyNeuronsOperative Surgical ProceduresOrganOutcomeOxidative StressPathogenesisPathologyPathway interactionsPhagocytesPharmaceutical PreparationsPhasePhysiologicalPlasmaPre-Clinical ModelProcessProdrugsReaction TimeRegimenRoleSafetySecondary toSerumSerum iron level resultStressStrokeTestingTherapeuticThiazolesTimeToxic effectTraumatic Brain InjuryWhite Blood Cell Count procedureanalogbasebrain cellclinical investigationcompare effectivenessdesigneffective therapyefficacy testingexperimental studyfluoro jadeforced swim testheme oxygenase-1improvedinnovationlipophilicitymalemortalitynephrotoxicityneurobehavioralnoveloutcome forecastphase III trialpreventprimary outcomeprolyl-prolinereceptorresponsesecondary outcomestroma free hemoglobinsymposiumtherapeutic targettool
中文摘要
脑出血(ICH)是一种由脑出血引起的严重疾病。值得注意的是
英文摘要
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 are confident that we can accomplish the
proposed aims to inform our stroke partners, allowing them to design a rigorous clinical trial.
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DOI:
10.3390/ijms22126408
发表时间:
2021-06-15
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[Ashouri R, Fangman M, Burris A, Ezenwa MO, Wilkie DJ, Doré S]
通讯作者:
Doré S
Nutritional Supplementation of Naturally Occurring Vitamin D to Improve Hemorrhagic Stroke Outcomes.
DOI:
10.3389/fneur.2021.670245
发表时间:
2021
期刊:
Frontiers in neurology
影响因子:
3.4
作者:
[Ashouri R, Fangman M, Brielmaier J, Fields ZA, Campo N, Doré S]
通讯作者:
Doré S
DOI:
10.1007/s12975-021-00978-2
发表时间:
2022-08
期刊:
TRANSLATIONAL STROKE RESEARCH
影响因子:
6.9
作者:
[Gaastra, Ben, Alexander, Sheila, Bakker, Mark K., Bhagat, Hemant, Bijlenga, Philippe, Blackburn, Spiros, Collins, Malie K., Dore, Sylvain, Griessenauer, Christoph, Hendrix, Philipp, Hong, Eun Pyo, Hostettler, Isabel C., Houlden, Henry, IIhara, Koji, Jeon, Jin Pyeong, Kim, Bong Jun, Kumar, Munish, Morel, Sandrine, Nyquist, Paul, Ren, Dianxu, Ruigrok, Ynte M., Werring, David, Galea, Ian, Bulters, Diederik, Tapper, Will]
通讯作者:
Tapper, Will
DOI:
10.3390/brainsci12060742
发表时间:
2022-06-05
期刊:
Brain sciences
影响因子:
3.3
作者:
[]
通讯作者:
DOI:
10.3390/ijms22189977
发表时间:
2021-09-15
期刊:
International journal of molecular sciences
影响因子:
5.6
作者:
[Lua J, Ekanayake K, Fangman M, Doré S]
通讯作者:
Doré S
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