277 - Superoxide Dismutase Mimic MnP3 Improves Cognitive and Motor Function in a Mouse Model of Alternating Hemiplegia of Childhood

Publication Number: 4273.277

Jai R. Narayan, Duke University, Chapel Hill, NC, United States; Tigran Margaryan, Barrow Neurological Institute, Phoenix, AZ, United States; William Knight, Barrow Neurological Institute, Phoenix, AZ, United States; Jad Kourany, Duke University School of Medicine, Cary, NC, United States; Mohamad Mikati, Duke University, Durham, NC, United States; Artak Tovmasyan, Barrow Neurological Institute, Phoenix, AZ, United States; Arsen Hunanyan, Duke University School of Medicine, Chapel Hill, NC, United States

Background: Alternating Hemiplegia of Childhood (AHC) is a rare and severe neurodevelopmental disorder primarily caused by de novo mutations in ATP1A3, which encodes the α3 subunit of Na⁺/K⁺-ATPase. Prior studies have identified elevated levels of reactive oxygen species (ROS) in brain regions of ATP1A3-mutant mice, suggesting oxidative stress may contribute to AHC. MnP3, a novel brain-penetrant superoxide dismutase (SOD) mimic, has shown potent antioxidant activity and neuroprotective potential in central nervous system disease models with favorable safety profiles. It is hypothesized that reducing oxidative stress with MnP3 will improve behavioral outcomes in an AHC mouse model.

Objective: To evaluate the efficacy of MnP3 in mitigating behavioral impairments in Mashl⁺/⁻ mice modeling AHC.

Design/Methods: ATP1A3-mutant mice were randomized into two groups to receive daily subcutaneous injections of MnP3 (10 mg/kg) or vehicle (sterile dH₂O) from postnatal day 22 (P22) through P64. Each group included 14 mice (MnP3: 7F/7M; vehicle: 8F/6M). Behavioral tests included mesh hanging, rotarod, beam walking, and T-maze spontaneous alternation. Survival, toxicity, and weight progression were monitored throughout the study. Following behavioral testing, mice were sacrificed, and blood and brain tissue were collected for assessment of ROS levels to determine whether MnP3 treatment reduced oxidative stress in vivo. Statistical analyses included Student’s/Welch’s t-tests, Mann-Whitney U tests, Kaplan-Meier survival curves, and repeated-measures ANOVA.

Results: MnP3-treated mice showed significant improvements in mesh hanging (MnP3: 66.64±22.75 s vs. vehicle: 46.44±17.76 s, p=0.0434) and T-maze alternation (MnP3: 51.75±9.79% vs. vehicle: 38.46±15.39%, p=0.0305), indicating enhanced endurance and working memory. Differences in rotarod performance (MnP3: 138.82±52.38 s vs. vehicle: 113.56±46.82 s, p=0.276), beam duration (MnP3: 11.73±2.05 s vs. vehicle: 12.33±2.29 s, p=0.541), and hindlimb slips (MnP3: 0.73±0.75 vs. vehicle: 1.78±1.23, p=0.061) were not statistically significant. No differences in survival or body weight were observed. Studies are in progress to evaluate the impact of MnP3 on oxidative stress in mice brain.

Conclusion(s): MnP3 significantly improved select motor and cognitive functions in an AHC mouse model without inducing toxicity. These findings support further investigation into ROS-targeting strategies for AHC and the broader therapeutic potential of SOD mimics in redox-related neurological disorders.