Abstract WP347: Brain-Penetrant Superoxide Dismutase Mimic MnP-05 Improves Neurological Outcomes After Experimental Subarachnoid Hemorrhage

Introduction: Early brain injury (EBI) and delayed cerebral ischemia (DCI) resulting from subarachnoid hemorrhage (SAH) significantly impact patient neurological outcomes. Oxidative stress plays a crucial role in both EBI and DCI following SAH. Although preclinical studies have demonstrated the beneficial effects of drugs targeting oxidative stress, translating these findings into clinical practice has been challenging, particularly due to issues with blood–brain barrier (BBB) penetration. MnP-05 is a novel manganese porphyrin-based superoxide dismutase mimic that exhibits superior anti-free radical properties and penetrates the BBB more effectively than earlier generation free radical scavengers. This study aimed to evaluate the effect of MnP-05 treatment on neurological outcomes in mice following SAH. Methods: Twelve-week-old male C57BL/6J mice underwent experimental SAH by endovascular perforation of the right internal carotid artery. A total of 51 mice were randomly assigned to receive either MnP-05 treatment or a vehicle (phosphate-buffered saline), starting 60 minutes after SAH. The treatment regimen included a 1 mg/kg intravenous bolus followed by continuous intraperitoneal administration at a rate of 5 mg/kg per day for 72 hours. A composite neurological score and rotarod test were assessed daily over a period of 7 days. Additionally, the Barnes maze test was conducted for five consecutive days starting on day 8. Results: No treatment-related adverse effects were noted in the MnP-05 group. Over the 7-day period, the mice treated with MnP-05 showed significantly better neurological outcomes compared to the vehicle group (two-way ANOVA; Treatment main effect, P < 0.01; Fig. A). Bonferroni-adjusted comparisons revealed a significant difference between the groups on Day 2 (P < 0.01; Fig. A). Furthermore, on Day 7, mice treated with MnP-05 treatment outperformed the vehicle group on the rotarod test (P < 0.01; Fig. B). In the Barnes maze test, mice receiving MnP-05 treatment demonstrated faster learning, with improved performance observed on Day 9 (P = 0.01; Fig. C). Conclusion: MnP-05 treatment improved functional outcomes over 7 days following SAH without any detectable side effects, potentially by reducing oxidative stress. In the future, it will be necessary to clarify the mechanism by which MnP-05 improves the neurological outcome of SAH.