Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.

Area of Science:

• Biochemistry
• Neuroscience
• Pathology

Background:

• Ischemia-reperfusion (IR) injury is a significant complication of acute ischemic stroke treatments.
• Succinate accumulates during ischemia and its oxidation upon reperfusion drives IR injury via mitochondrial complex I.
• Targeting succinate metabolism to mitigate IR injury is an unexplored therapeutic avenue.

Purpose of the Study:

• To investigate the role of succinate metabolism in ischemia-reperfusion injury in the context of ischemic stroke.
• To explore the potential of targeting succinate oxidation as a therapeutic strategy to reduce brain injury.

Main Methods:

• Quantitative and untargeted high-resolution metabolomics to analyze succinate levels in ischemic brain tissue.
• Mass spectrometry imaging (MSI) in a mouse model of ischemic stroke and mechanical thrombectomy.
• In vivo administration of the succinate dehydrogenase (SDH) inhibitor malonate upon reperfusion.

Main Results:

• Succinate was shown to accumulate in the ischemic brain in a time-dependent manner in both human and mouse models.
• MSI confirmed succinate accumulation was localized to the ischemic region and rapidly oxidized upon reperfusion.
• Systemic infusion of malonate dose-dependently reduced acute brain injury following reperfusion.

Conclusions:

• Succinate accumulation and subsequent oxidation are key contributors to ischemia-reperfusion injury in ischemic stroke.
• Targeting succinate oxidation with SDH inhibitors like malonate upon reperfusion is a promising therapeutic strategy.
• This approach could serve as a valuable adjunct therapy to mechanical thrombectomy for acute ischemic stroke.