Dexpramipexole improves bioenergetics and outcome in experimental stroke

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Pharmacology

Background:

• Dexpramipexole, previously studied in amyotrophic lateral sclerosis (ALS), targets F1Fo ATP synthase to boost mitochondrial ATP production.
• Investigated potential therapeutic applications in experimental ischemic brain injury.

Purpose of the Study:

• To evaluate the efficacy of dexpramipexole in mitigating experimental ischemic brain injury.
• To assess its impact on neuronal bioenergetics, cellular function, and survival under ischemic conditions.

Main Methods:

• Assessed effects on neuronal cultures and hippocampal slices subjected to oxygen-glucose deprivation (OGD).
• Evaluated infarct volumes and neurological function in mice after middle cerebral artery occlusion (MCAo).
• Utilized mass spectrometry imaging to determine dexpramipexole distribution in ischemic brain tissue.

Main Results:

• Dexpramipexole increased mitochondrial ATP production, reduced energy failure, prevented calcium overload, and protected neurons and glia against OGD-induced injury.
• In hippocampal slices, it counteracted ATP depletion, mitochondrial swelling, anoxic depolarization, synaptic dysfunction, and neuronal death.
• In mice, post-ischemic treatment with dexpramipexole significantly reduced infarct size and improved neurological scores after MCAo.
• Achieved neuroprotective concentrations within the ischemic penumbra, consistent with in vitro findings.

Conclusions:

• Dexpramipexole effectively reduces ischemic brain injury by enhancing mitochondrial ATP synthase activity.
• Demonstrates significant neuroprotective effects in vitro and in vivo models of stroke.
• Its brain penetration and established safety profile in humans suggest strong translational potential for stroke therapy.