Abstract Body: Introduction: Oxidative stress plays an important role in both early brain injury and delayed cerebral ischemia after subarachnoid hemorrhage (SAH). Despite the beneficial effects demonstrated in preclinical studies with drugs targeting oxidative stress, their clinical translation has been hindered. There were critical issues in previous preclinical studies underpinning clinical translation, including inadequate demonstration of blood-brain barrier (BBB) penetration and insufficient assessment of drug concentration and biological activity in brain tissue. MnP-05 is a novel manganese porphyrin-based superoxide-dismutase mimic, which penetrates the BBB far better than previous compounds and exhibits superior anti-free radical properties compared to previous free radical scavenger. In this study, we evaluated the effect of MnP-05 on short-term outcomes of SAH in mice.
Methods: We used 12-week-old male C57BL/6J mice. We induced SAH by an endovascular perforation of the right internal carotid artery. Mice (n = 31) were started on treatment with either MnP-05 or PBS 60 minutes after the induction of SAH. We set the dosing regimen as 1 mg/kg intravenous bolus followed by 5 mg/kg/day continuous intraperitoneal injection for 72 hours. We compared a composite neurological score, and rotarod performance (%baseline), between the two treatment groups for 7 days. We also compared the mRNA expression of oxidative stress and apoptosis markers in perihematomal brain tissue between the groups.
Results: There were no specific side effects found in MnP-05 treatment group. There were no differences in blood pressure or body weight between the two groups. Seven-day neurological outcomes were better in MnP-05 group as evidenced by the significantly better composite neurological scores (22.9 vs. 19.4, P<0.05, Fig. A). Mice treated with MnP-05 showed better rotarod performance compared to vehicle group on day 7 (227% vs. 120%, P<0.01, Fig. B). MnP-05 significantly reduced the mRNA expression of oxidative stress markers (HO-1 and NRF) and apoptosis markers (Caspase-3 and BAX) compared to vehicle group (P<0.05, respectively, Fig C).
Conclusion: MnP-05 improved short-term outcomes of SAH without specific side effects by reducing oxidative stress and neuronal apoptosis at the target site. In further studies, we will test how MnP-05 affects long-term outcomes of SAH. Our results serve as a basis for future clinical trials using MnP-05 to improve the neurological outcomes of SAH.