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

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 
investigations 
catalase. 
confirmed 
Further 
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 Ca2+, 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 
ischemia.