Development of Cobinamide as a Potential Antidote for Paraquat Poisoning
Paraquat is a commonly used herbicide that is highly toxic when ingested and has been increasingly used in suicide cases. No effective treatment for paraquat poisoning exists. There are two mechanisms of paraquat toxicity: the production of reactive oxygen species like superoxide and the inhibition of mitochondrial respiration. Cobinamide, the vitamin B12 precursor, has been shown to be an effective scavenger of reactive oxygen species (ROS). Due to cobinamide’s ability to scavenge ROS, we hypothesized that cobinamide could be used as a potential treatment for paraquat poisoning. We tested the hypothesis by assessing cobinamide’s effectiveness in reversing paraquat-induced toxicity in vitro and in vivo. Experiments with mammalian cells and Drosophila melanogaster showed that cobinamide partially rescued these model organisms from paraquat toxicity. Further experiments were performed to determine the mechanism of this rescue. The production of ATP was assessed in COS7 cells showing a dose-dependent decrease in ATP levels in response to paraquat, but surprisingly, was not restored upon addition of cobinamide. Mechanistically, this is maybe due to the lack of binding between cobinamide and paraquat. Results suggest that the mechanism of antagonism occurs mainly through ROS scavenging. Overall, these findings suggest the potential use of cobinamide as an antidote for paraquat poisoning in the clinical setting.