Mitigation of ROS Insults by Streptomyces Secondary Metabolites in Primary Cortical Neurons

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.

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

“…The activation of Nrf2 is shown to inhibit the effect of the mitochondrial uncoupler carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP) on cytoplasmic Ca 2+ ions, which in turn, enhances the mitochondrial function, inhibited the production of ROS and increased the levels of antioxidant enzymes (Leirós et al 2013).…”

Streptomyces antioxidans sp. nov., a Novel Mangrove Soil Actinobacterium with Antioxidative and Neuroprotective Potentials

“…Moreover, the metabolites derived from Streptomyces are described as potent protective agents in neuronal cells against oxidative stress induced damage. In fact, a recent study by Leiros et al ( 2013 ) has identified seven bioactive compounds produced by Streptomyces sp. which protects against hydrogen peroxide (H 2 O 2 ) challenge in primary cortical neurons.…”

The neuroprotective activities of natural products through the Nrf2 upregulation

“…The results showed that two compounds, the quinone anhydroexfoliamycin and the red pyrrole‐type pigment n‐decylprodigiosin, improved mitochondrial function, increased the antioxidant enzymes, and decreased reactive oxygen species (ROS) levels and caspase‐3 apoptotic activity in primary cortical neurons. Anhydroexfoliamycin also has been reported to induce Nrf2 nuclear translocation and affect the Nrf2‐ARE pathway (Leirós et al, ).…”

“…Anhydroexfoliamycin also has been reported to induce Nrf2 nuclear translocation and affect the Nrf2-ARE pathway (Leirós et al, 2014).…”