Ferrostatin-1 mitigates cellular damage in a ferroptosis-like environment in Caenorhabditis elegans.

Although iron (Fe) is the most biologically abundant transition metal, it is highly toxic when it accumulates as Fe2+, forming a labile Fe pool and favoring the Fenton reaction. This oxidative scenario leads to a type of caspase-independent programmed cell death, referred to as ferroptosis, where following processes take place: (i) Fe2+ overload, (ii) glutathione peroxidase 4 inactivation, (iii) lipid peroxidation, and (iv) glutathione depletion. The present study sought to evaluate the consequences of Fe2+ administration on ferroptosis induction in Caenorhabditis elegans. We demonstrated higher mortality, increased lipid peroxidation, reduced glutathione peroxidase activity, and morphological damage in dopaminergic neurons upon Fe2+ overload. Pharmacological intervention at the level of lipid peroxidation with ferrostatin-1 (250 µM) mitigated the damage and returned the biochemical parameters to basal levels, revealing the potential of this therapeutical approach. Finally, to assess the relationship between ferroptosis and dopamine in a Parkinsonian background, we evaluated the UA44 worm strain which overexpresses the alpha-synuclein protein in cherry-labeled dopaminergic neurons. We demonstrated that Fe2+ administration reduced lethality associated with similar alterations in biochemical and dopaminergic morphological parameters in wild-type animals. These experiments provide mechanistic-based evidence on the efficacy of a pharmacological approach to mitigate the physiological, biochemical, and morphological consequences of Fe2+ overload. At the same time, they encourage further research on the impact of the combined effects resulting from the genetic background and dopamine signaling in a Parkinsonian phenotype.

Enduring Ethanol-Induced Behavioral Alterations in Caenorhabditis elegans After Developmental Lead Exposure.

The roundworm Caenorhabditis elegans (C. elegans) has become a powerful tool to evaluate the deleterious effects of early-life exposure to xenobiotics, including metals. The present chapter describes a detailed protocol for developmental lead (Pb)-exposure in C. elegans. Preliminary assays as well as the final procedure are described in detail. In addition, further protocols aimed to assess ethanol exposure at later stages of life demonstrate the impact of this drug on locomotor behavior, revealing the enduring effects that Pb can imprint on this organism when exposure occurs during development.