Organophosphorus (OPs) neurotoxic agents, found in certains pesticides and chemical weapons, contaminate several million people worldwide each year. Due to their lipophilic nature, OPs can cross the blood-brain barrier (BBB) and exert an irreversible inhibitory action on synaptic and globular acetylcholinesterase (AChE). This inhibition leads to the accumulation of acetylcholine in the central and peripheral nervous systems, causing toxic effects (muscarinic and nicotinic responses leading to acute respiratory distress, cardiovascular disturbances, and long-term neurological disorders). Among existing medical countermeasures, oximes can be administered as antidotes because they are capable of reactivating AChE. However, their effect remains limited to the peripheral systems since oximes cannot cross the BBB and therefore do not reach the brain to exert their therapeutic action.
Transcranial focused ultrasound (FUS), combined with intravenously injected microbubbles, can be applied to temporarily disrupt the BBB and allow drug delivery to the central nervous system. In this work, researchers assessed the efficacy of FUS for the administration of two known oximes (2-PAM, HI-6) into the brain after sublethal and supralethal exposure to the VX agent in a mouse model. The HI-6 + FUS treatment restored more than 30% of AChE activity in the hippocampus, and treated animals showed improved survival rates at 24 hours. This treatment also led to a significant reduction in the expression levels of two pro-inflammatory cytokines, IL-6 and MIP-1α, in the hippocampus. By contrast, the 2-PAM + FUS treatment proved ineffective.
These findings indicate that the use of FUS is highly promising for improving medical management in cases of OPs exposure, as it enables antidotes, here, the oxime HI-6, to treat central symptoms and reduce brain damage. This approach is therefore particularly promising for effective treatment of OP exposure in a hospital setting as a second-line intervention following immediate emergency treatment.
Contact : Anthony Novell (anthony.novell@universite-paris-saclay.fr)
The nerve agent VX is an organophosphorus compound more lethal than sarin. Its absorption routes -inhalation and skin contact- and its clinical symptoms (nausea, convulsions, paralysis of respiratory muscles) are the same as for sarin.