Abstract WP357: A novel manganese porphyrin-based SOD mimic improves short-term outcomes after transient middle cerebral artery occlusion in mice

Introduction: Oxidative stress induced by ischemic stroke and subsequent ischemia-reperfusion injury contributes to secondary brain damage. MnP-05 is a novel manganese porphyrin-based superoxide dismutase (SOD) mimic with superior blood–brain barrier (BBB) permeability and multitarget antioxidant properties compared to conventional agents. We previously demonstrated its safety and ischemic-site-specific pharmacokinetics/pharmacodynamics in mice. This study evaluated whether MnP-05 improves short-term outcomes after transient middle cerebral artery occlusion (tMCAO) in mice. Methods: Male C57BL/6J mice (12–14 weeks) underwent 60 min tMCAO. Ten minutes after reperfusion, mice received either MnP-05 (1 mg/kg, intravenous) or vehicle (phosphate-buffered saline). MnP-05 was continuously delivered at 5 mg/kg/day for 72 hours after tMCAO using an osmotic pump implanted intraperitoneally. At 72 h after tMCAO, Evans Blue (2%, 6 mg/kg, intravenous) was administered, and BBB permeability was quantified 24 h later. We compared the survival curve between the two groups. Neurological function was assessed daily for 3 days using the Garcia score. mRNA expression of major oxidant enzymes (catalase and glutathione peroxidase) and apoptosis markers (Caspase-3 and Bcl-2-associated X protein) was measured in peri-infarct brain tissue at 72 h. Results: MnP-05-treated mice showed higher survival rates and improved neurological scores (P < 0.05, respectively, Fig. A). MnP-05 significantly attenuated BBB disruption compared with the vehicle group (43.49 µg/g vs. 63.92 µg/g, P < 0.05, Fig. B). Oxidative stress-related and apoptosis-related gene expression was significantly reduced in the MnP-05 group (P < 0.05, respectively, Fig. C). Conclusions: MnP-05 suppresses oxidative stress and apoptosis, mitigates BBB breakdown, and improves short-term functional and survival outcomes after experimental ischemic stroke in mice. These findings support further development of MnP-05 as a neuroprotective strategy targeting ischemic reperfusion injury after stroke.