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MnTM-4-PyP modulates endogenous antioxidant responses and protects primary cortical neurons against oxidative stress
Kuo-Yuan Cheng1, Fei Guo, Jia-Qi Lu
1Department of Chemical Biology, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
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.
Insights
Manganese porphyrins (MnPs) like MnTM-4-PyP boost endogenous antioxidant systems, protecting neurons from oxidative stress. This study reveals MnPs enhance cell viability and function by upregulating superoxide dismutase (SOD) activity.
Area of Science:
- Neuroscience
- Biochemistry
- Oxidative Stress Research
Background:
- Oxidative stress is a key factor in neural disease pathogenesis.
- Manganese porphyrins (MnPs) are superoxide dismutase (SOD) mimics with demonstrated efficacy in neural disease models.
- The precise mechanisms of MnP neuroprotection, particularly their interaction with endogenous antioxidant systems, require further elucidation.
Purpose of the Study:
- To investigate how a specific MnP, MnTM-4-PyP, modulates endogenous antioxidant systems.
- To determine the role of MnTM-4-PyP in protecting cortical neurons against oxidative stress induced by hydrogen peroxide.
- To elucidate the molecular mechanisms underlying MnTM-4-PyP's neuroprotective effects.
Main Methods:
- Primary cortical neurons were utilized as an in vitro model system.
- Neurons were pre-treated with MnTM-4-PyP.
- Oxidative stress was induced using hydrogen peroxide.
Main Results:
- MnTM-4-PyP treatment enhanced neuronal viability and reduced reactive oxygen species (ROS) levels.
- Mitochondrial apoptosis was inhibited, and endoplasmic reticulum function was improved.
- Endogenous SOD protein levels and activity increased, alongside elevated SOD2 transcription, FOXO3A, and Sirt3. Catalase activity remained unchanged. These effects were dependent on MnTM-4-PyP treatment.
Conclusions:
- MnTM-4-PyP confers neuroprotection by activating endogenous antioxidant defense mechanisms.
- The induction of multiple antioxidant pathways by MnTM-4-PyP is crucial for its protective effects against oxidative stress in neurons.
- This study highlights the therapeutic potential of MnPs in combating oxidative stress-related neurological conditions.
