Article Impact Level: HIGH Data Quality: STRONG Summary of Cardiovascular Research, cvaf118. https://doi.org/10.1093/cvr/cvaf118 Dr. Jordan J. Lee et al.
Points
- Current stroke treatments like mechanical thrombectomy are hampered by ischemia-reperfusion injury, which causes further brain damage when blood flow is restored after a clot is removed.
- This secondary damage is driven by the rapid oxidation of a chemical called succinate, which accumulates in the brain during the stroke and produces harmful free radicals.
- Researchers tested a drug, acidified disodium malonate (aDSM), which is designed to block succinate oxidation and can cross the blood-brain barrier when delivered locally.
- In a mouse model simulating the procedure, administering aDSM during reperfusion reduced the volume of dead brain tissue by approximately 60% and improved neurological function.
- This neuroprotective strategy shows promise as an adjunct therapy to improve outcomes for stroke patients and may have applications for other conditions involving reperfusion injury.
Summary
Mechanical thrombectomy (MT) has improved outcomes for ischemic stroke, yet substantial disability persists due to ischemia-reperfusion injury (IRI). This injury is initiated within minutes of reperfusion when the rapid oxidation of succinate, which accumulates in ischemic tissue, drives mitochondrial free radical production. This study aimed to determine if local administration of a succinate oxidation inhibitor during reperfusion could serve as an effective adjunct therapy to MT, thereby mitigating IRI and improving neurological outcomes for patients.
To investigate this, researchers utilized a transient middle cerebral artery occlusion (tMCAO) mouse model to simulate MT in a clinical setting. During reperfusion, a 160 mg/kg dose of acidified disodium malonate (aDSM) at pH 6 was administered via local intra-arterial delivery. This approach was designed to facilitate the compound’s passage across the blood-brain barrier, thereby blocking succinate oxidation at the critical moment of reperfusion. The primary endpoints were brain infarct volume and neurological function.
The results demonstrated that adjunctive aDSM therapy significantly reduced brain infarct volume by approximately 60%, as measured by magnetic resonance imaging (MRI) 24 hours post-reperfusion. This reduction in tissue damage was accompanied by a corresponding improvement in neurological function in the mouse model. These preclinical findings suggest that local aDSM administration is a promising adjunct therapy to MT, with the potential to substantially decrease brain damage and enhance functional recovery for stroke patients.
Link to the article: https://academic.oup.com/cardiovascres/advance-article/doi/10.1093/cvr/cvaf118/8176849
References Lee, J. J., Prag, H. A., Chary, K., Abe, J., Uno, S., Sorby-Adams, A., Yu, C. S., Sauchanka, O., Mottahedin, A., Kaggie, J. D., Gallagher, F. A., Murphy, M. P., & Krieg, T. (2025). Local arterial administration of acidified malonate as an adjunct therapy to mechanical thrombectomy in ischemic stroke. Cardiovascular Research, cvaf118. https://doi.org/10.1093/cvr/cvaf118
