A pilot study of a novel brain penetrant Mn(III) porphyrin-based SOD mimic on middle cerebral artery occlusion in 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 and data collection was aggregated. 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, effcacy studies of MnP-05 were assessed following a 60-minute tMCAO. Intravenous administration of 1 mg/kg of MnP-05 occurred 10 minutes after recanalization, followed by intraperitoneal implantation of an osmotic pump delivering 5 mg/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 by Garcia score and neurological deficit score (NDS) and compared at 72 hours between the control and MnP-05 groups in the effcacy study. Results: The safety study revealed that doses of 10mg/kg or less were considered safe, not causing hypotension (Fig.1). In the PK study, MnP-05 demonstrated preferential distribution to ischemic lesions compared to contralateral side (p = 0.03, Fig.2). In the effcacy study, MnP-05 group demonstrated improved neurological symptoms at 72 hours in Garcia score (p = 0.02), NDS (p = 0.006), and probability of survival (p = 0.03)(Fig.3). Conclusions: We established the safety dose of MnP-05 in tMCAO mice. It penetrates in ischemic lesions through BBB. Our findings suggest that MnP-05 is a promising therapeutic agent for AIS. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.