Abstract Details

Title Intravenous Dimethyl Fumarate Promotes Hemoglobin Clearance in a Preclinical Hemorrhagic Stroke Model

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) P1 - Poster Session 1 (12:00 PM-1:00 PM)

Poster/Presentation
Number 4-017

Objective To examine the ability of dimethyl fumarate (DMF) to reduce brain hemoglobin content (BHC) in a preclinical rat model of intracerebral hemorrhage (ICH).

Background

DMF is hypothesized to aid in detoxification of blood present in brain after hemorrhagic event through anti-oxidative properties resulting from its activation of nuclear factor erythroid-2-related factor 2 (Nrf2).

Design/Methods ICH was induced by unilateral stereotaxic injection of collagenase into the striatum of male, Sprague Dawley rats (n=12-14 per group). Rats were dosed intravenously with vehicle, 15mg/kg or 100mg/kg DMF, beginning at 1 hour after ICH induction and continuing once daily until sacrifice on day 3 post-injury. The amount of hemoglobin present in the ipsilateral striatum was measured using a colorimetric assay. Brain exposure of MMF and DMF conjugates was determined by LC-MS/MS. Nrf2-dependent gene activation was used to measure target engagement.

Results There is a 98% probability of BHC reduction in the ICH model with 100mg/kg DMF dose based on the data we observed and the removal of an outlier. No impact on BHC was seen following the 15mg/kg DMF dose. Ten-fold higher brain exposure was seen with 100mg/kg dose versus 15mg/kg dose. While a dose-proportional increase in Nrf2-dependent gene response was seen with increasing DMF concentration in non-ICH rats, repeated high dose administration in the context of ICH elicited reduced Nrf2-dependent gene expression compared to vehicle.

Conclusions

We found an estimated 19% BHC decrease in response to treatment with a high dose of DMF compared to vehicle in the rat ICH model, but no impact on BHC when using a lower dose. Gene regulation at high dose demonstrates pathway modulation, but unexpected directionality may indicate the need for protein-based biomarkers. Additional work is needed to understand the impact of BHC reduction on functional outcome in this model and further, to understand translatability in relation to human disease.

Authors/Disclosures
PRESENTER	No disclosure on file
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Ashley Nelson, DO (University of Rochester Medical Center/Strong Memorial Hospital)	Dr. Nelson has nothing to disclose.
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Jacob S. Elkins, MD	No disclosure on file