A new chemical entity protects human brain-like endothelial cells (BLECs) from organophosphate-induced blood-brain barrier damage.

Organophosphorus compounds are highly toxic chemicals widely used as pesticides (e.g. paraoxon) and as chemical warfare nerve agents. Blood-brain barrier (BBB) leakage has been shown in rodents exposed to paraoxon, which is an organophosphate oxon.

In this study, we have elucidated the cellular effects and pathways affected by exposure to paraoxon. Furthermore, we have investigated a new chemical entity A (NCEA) and the iron chelator DFO to countermeasure paraoxon-induced BBB damage. We have found that in human brain-like endothelial cells (BLECs), these compounds not only significantly rescue cell cytotoxicity, apoptosis and mitochondrial ROS formation but more importantly, significantly inhibit barrier functionality damage.

Paraoxon rapidly initiates both a sharp increase in cellular ROS formation and more specifically, lipid peroxidation. Subsequently, 10 – 12 hours post treatment, paraoxon induces mitochondrial ROS accumulation and depolarization of its membrane, resulting in apoptosis and cell death.

Both NCEA and DFO significantly rescue BLECs from mitochondrial ROS formation, apoptosis and cell death as a result of paraoxon exposure. More importantly, they significantly inhibit paraoxon-induced permeability increase and Trans Endothelial Electrical Resistance decrease in a human in-vitro BBB model. These compounds reverse the paraoxon-induced Ve-Cadherin degradation through the HIF2α pathway.

Our findings elucidate the biological effects of paraoxon exposure to BLECs. Additionally, we have discovered a novel compound and DFO that counteract paraoxon damage to endothelium functionality. These compounds show promise as therapeutic agents against the effects of acute or chronic exposure to paraoxon and similar organophosphates.