Sequential DFO + Sulforaphane Prevents Iron-Ferroptosis Cascade in Rat Cardiac-Arrest Model

In_Vivo Score: 0.768 Price: $0.50 post-cardiac-arrest neurodegeneration Sprague-Dawley rat asphyxial cardiac arrest (6-min anoxia + CPR), n=12/group x 4 groups Status: proposed

What This Experiment Tests

In_Vivo experiment designed to assess clinical efficacy targeting GPX4 in Sprague-Dawley rat asphyxial cardiac arrest (6-min anoxia + CPR), n=12/group x 4 groups. Primary outcome: 4-CBA-trapped hydroxyl radical flux <=30% of vehicle; 72-h NDS >=8 (max 12)

Description

Test whether IV deferoxamine (DFO) administered at ROSC followed by oral sulforaphane (SFN) for 72 h prevents the iron-ferroptosis-cerebral edema cascade and improves 72-h neurological outcomes in a rat cardiac-arrest/CPR model.

TARGET GENE

GPX4 (Score: 0.565)

MODEL SYSTEM

Sprague-Dawley rat asphyxial cardiac arrest (6-min anoxia + CPR), n=12/group x 4 groups

ESTIMATED COST

$48,000

TIMELINE

12 months

PATHWAY

Labile iron pool -> lipid peroxidation/ferroptosis -> GPX4 depletion -> cerebral edema

SOURCE

task:a989715e-c687-4558-91ca-74fce1474bd2

PRIMARY OUTCOME

4-CBA-trapped hydroxyl radical flux <=30% of vehicle; 72-h NDS >=8 (max 12)

Scoring Dimensions

Protocol

Asphyxial CA: 6-min KCl arrest + CPR in adult SD rats. 2. Groups: sham, CA-vehicle, CA-DFO (100 mg/kg IV at ROSC), CA-DFO+SFN (DFO at ROSC + 25 mg/kg SFN oral q12h x 3 days). 3. Biomarkers at 6h and 24h post-ROSC: plasma 4-HNE (lipid peroxidation), CSF ferritin/LIP (calcein-AM chelator assay), hippocampal GPX4 protein (WB), ferroptosis ACSL4/SLC7A11. 4. Imaging: MRI T2 brain edema at 24 h. 5. Neurological deficit score (NDS, 0-12) at 24, 48, 72 h. 6. Primary: 72-h NDS; secondary: 4-HNE, MRI edema volume, GPX4 expression.

Expected Outcomes

DFO+SFN will blunt the iron surge (CSF ferritin <=50% of vehicle), maintain GPX4 activity, reduce MRI edema volume >=35%, and achieve 72-h NDS >=8.

Success Criteria

Primary: NDS >=8 at 72 h (vs <=4 in CA-vehicle; Mann-Whitney p<0.05). Secondary: GPX4 protein >=70% of sham levels; 4-HNE <=30% of CA-vehicle.

Related Hypotheses (4)

Sequential Iron Chelation (Deferoxamine) and GPX4 Restoration (Sulforaphane) Prevents the Self-Ampli0.838

GPX4 reserve failure gates selective ALS motor-neuron ferroptosis0.745

Ferroptosis Inhibition for α-Synuclein Neuroprotection0.705

GPX4 Selenopeptide Mimetics as Neuroprotective Ferroptosis Blockade0.680

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