Fumarate decreases edema volume and improves functional outcome after experimental stroke

Area of Science:

• Neuroscience
• Pharmacology
• Immunology

Background:

• Ischemic stroke leads to brain damage exacerbated by oxidative stress and inflammation.
• Dimethyl fumarate (DMF) and its metabolite monomethyl fumarate (MMF) possess antioxidant and anti-inflammatory properties.
• Investigating MMF's therapeutic potential post-ischemic stroke is crucial.

Purpose of the Study:

• To evaluate the efficacy of monomethyl fumarate (MMF) in mitigating brain damage and improving functional recovery after ischemic stroke.
• To explore the underlying molecular mechanisms, including changes in oxidative stress markers, inflammatory cytokines, and neuroprotective proteins.

Main Methods:

• Adult male C57BL/6 mice underwent permanent middle cerebral artery occlusion (pMCAO).
• A single intravenous dose of MMF (20 mg/kg) was administered 30 minutes post-pMCAO.
• Evaluations included functional recovery, infarct volume, edema, protein/mRNA expression (Keap1, Nrf2, Hsp72, Hcar2, iNOS), and cytokine profiling (IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, TNF) at 6, 24, and 48 hours.

Main Results:

• MMF administration increased Nrf2 protein levels and Hsp72 expression within 6 hours post-stroke.
• Significant functional recovery was observed at 24 and 48 hours, accompanied by reduced brain edema.
• MMF modulated cytokine profiles, increasing IL-10 and decreasing IL-12p70 in brain and plasma.

Conclusions:

• A single MMF dose enhances sensory-motor function and reduces edema after ischemic stroke.
• MMF increases neuroprotective Hsp72 levels and influences key inflammatory mediators.
• These findings suggest MMF as a promising therapeutic agent for ischemic stroke.