Abstract TP290: A Pilot Study of a Novel Brain Penetrant Mn(III) Porphyrin-Based Sod Mimic on Middle Cerebral Artery Occlusion in Female and Male Mice

Abstract

Introduction: Oxidative stress exacerbates acute ischemic stroke (AIS). Manganese Porphyrin (MnP)-based superoxide dismutase (SOD) mimics have shown therapeutic benefits for AIS. However, earlier MnP versions faced limited blood-brain barrier (BBB) penetration and hypotension. A novel SOD mimic MnP-05 is designed to overcome the limitations of previous generation structural analogs. Our study aimed to assess whether MnP-05 improves transient middle cerebral artery occlusion (tMCAO) outcomes in mice. Methods: Male and female C57BL/6J mice aged 12-14 weeks were used. Initially, a safety study was conducted using uninjured mice to establish safe dosage levels independent of hypotension. Subsequently, pharmacokinetic (PK) analysis assessed BBB penetration of MnP-05. Finally, efficacy studies of MnP-05 were assessed following a 45-minute tMCAO. Intravenous administration of 0.5mg/kg of MnP-05 occurred 5 minutes before recanalization, followed by intraperitoneal implantation of an osmotic pump delivering 2.5mg/kg/day of MnP-05 for 72 hours after tMCAO. The concentration of MnP-05 was evaluated in ischemic core and contralateral normal brain by LC-MS/MS. The neurological symptoms were assessed at 72 hours. Results: The safety study revealed that doses of 10mg/kg or less were considered safe (Fig.1). In the PK study, MnP-05 demonstrated preferential distribution to ischemic lesions. In the efficacy study, MnP-05 group demonstrated improved neurological outcomes, although statistical significance was not achieved (Fig.2). Conclusions: We established the safety of MnP-05 in tMCAO mice. Our findings suggest that MnP-05 is a promising therapeutic agent for AIS.