Mitigation of ROS insults by Streptomyces secondary metabolites in primary cortical neurons
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Marta Leirós1, Eva Alonso, Jon A Sanchez
1Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela , Lugo 27003, Spain.
Abstract:
Oxidative stress is a common point in neurodegenerative diseases, widely connected with mitochondrial dysfunction. In this study, we screened seven natural products from Streptomyces sources against hydrogen peroxide insult in primary cortical neurons, an oxidative stress in vitro model. We showed the ability of these compounds to inhibit neuronal cytotoxicity and to reduce ROS release after 12 h treatment. Among the tested compounds, the quinone anhydroexfoliamycin and the red pyrrole-type pigment undecylprodigiosin stand out. These two compounds displayed the most complete protection against oxidative stress with mitochondrial function improvement, ROS production inhibition, and increase of antioxidant enzyme levels, glutathione and catalase. Further investigations confirmed that anhydroexfoliamycin acts over the Nrf2-ARE pathway, as a Nrf2 nuclear translocation inductor, and is able to strongly inhibit the effect of the mitochondrial uncoupler FCCP over cytosolic Ca(2+), pointing to mitochondria as a cellular target for this molecule. In addition, both compounds were able to reduce caspase-3 activity induced by the apoptotic enhancer staurosporine, but undecylprodigiosin failed to inhibit FCCP effects and it did not act over the Nrf2 pathway as was the case for anhydroexfoliamycin. These results show that Streptomyces metabolites could be useful for the development of new drugs for prevention of neurodegenerative disorders such as Parkinson's and Alzheimer's diseases and cerebral ischemia.
Insights
Natural products from Streptomyces, anhydroexfoliamycin and undecylprodigiosin, protect neurons from oxidative stress. These compounds show potential for developing new drugs for neurodegenerative diseases like Parkinson's and Alzheimer's.
Area of Science:
- Neuroscience
- Pharmacology
- Microbiology
Background:
- Oxidative stress and mitochondrial dysfunction are key factors in neurodegenerative diseases.
- Natural products offer potential therapeutic avenues for neurological disorders.
Purpose of the Study:
- To screen Streptomyces-derived natural products for neuroprotective effects against oxidative stress.
- To identify compounds that can mitigate neuronal damage and improve mitochondrial function.
Main Methods:
- Screening of seven natural products from Streptomyces against hydrogen peroxide-induced oxidative stress in primary cortical neurons.
- Assessment of neuronal cytotoxicity, reactive oxygen species (ROS) production, mitochondrial function, and antioxidant enzyme levels.
- Investigation of molecular mechanisms, including Nrf2 pathway activation and caspase-3 activity.
Main Results:
- Anhydroexfoliamycin and undecylprodigiosin demonstrated significant neuroprotection by inhibiting cytotoxicity and reducing ROS.
- Both compounds improved mitochondrial function and increased antioxidant levels (glutathione, catalase).
- Anhydroexfoliamycin activated the Nrf2-ARE pathway and modulated cytosolic Ca(2+) levels, indicating mitochondrial targeting.
Conclusions:
- Streptomyces metabolites, particularly anhydroexfoliamycin and undecylprodigiosin, possess potent antioxidant and neuroprotective properties.
- These compounds show promise for the development of novel therapeutic agents for neurodegenerative diseases and cerebral ischemia.
- Anhydroexfoliamycin's mechanism involves Nrf2 pathway activation, highlighting its potential as a targeted neuroprotective drug.
