MnTM‐4‐PyP Modulates Endogenous Antioxidant Responses and Protects Primary Cortical Neurons against Oxidative Stress

Summary Aims Oxidative stress is a direct cause of injury in various neural diseases. Manganese porphyrins (MnPs), a large category of superoxide dismutase (SOD) mimics, shown universally to have effects in numerous neural disease models in vivo. Given their complex intracellular redox activities, detailed mechanisms underlying the biomedical efficacies are not fully elucidated. This study sought to investigate the regulation of endogenous antioxidant systems by a MnP (MnTM‐4‐PyP) and its role in the protection against neural oxidative stress. Methods Primary cortical neurons were treated with MnTM‐4‐PyP prior to hydrogen peroxide–induced oxidative stress. Results MnTM‐4‐PyP increased cell viability, reduced intracellular level of reactive oxygen species, inhibited mitochondrial apoptotic pathway, and ameliorated endoplasmic reticulum function. The protein levels and activities of endogenous SODs were elevated, but not those of catalase. SOD2 transcription was promoted in a transcription factor–specific manner. Additionally, we found FOXO3A and Sirt3 levels also increased. These effects were not observed with MnTM‐4‐PyP alone. Conclusion Induction of various levels of endogenous antioxidant responses by MnTM‐4‐PyP has indispensable functions in its protection for cortical neurons against hydrogen peroxide‐induced oxidative stress.