Enhancing oxime efficacy into brain using ultrasound to counteract nerve agent exposure

Abstract

Organophosphates (OP) found in pesticides and chemical weapons irreversibly inhibit acetylcholinesterases (AChE) and cause toxic accumulation of acetylcholine throughout the organism. Due to their lipophilicity, OP easily cross the blood-brain barrier (BBB) and affect the central nervous system (CNS), resulting in epileptic seizures and long-term cognitive impairment. The antidote includes oximes which reactivate inhibited AChE. Unfortunately, oximes have limited BBB penetration and therefore fail to prevent neurological damage. Improving the penetration of oximes through the CNS and their therapeutic effect on the brain, is a major challenge. Recent studies have demonstrated the efficacy of transcranial focused ultrasound (FUS), in combination to intravenously injected microbubbles, to transiently disrupt the BBB for drug delivery. We assessed the efficacy of FUS to deliver two known oximes (2-PAM, HI-6) into the brain and reactivate AChE following an exposure to VX in a mouse model. After both sub-lethal and supra-lethal exposure, HI-6 + FUS treatment reactivated nearly 30 % more AChE in the hippocampus than HI-6 alone. In contrast, 2-PAM+FUS was not effective. Furthermore, animals treated with HI-6 + FUS following an exposure to a supra-lethal dose of VX exhibited enhanced short-term recovery and an increased 24 hours survival rate. Finally, up to 7 days after exposure to a supra-lethal dose of VX, HI-6 + FUS showed a significant reduction of pro-inflammatory cytokines IL-6 and MIP-1α expression levels in the hippocampus. Thus, the use of FUS is very promising for improving the medical care of OP exposure because it enables antidotes to treat central symptoms and it may reduce brain damage.

Keywords: Acetylcholinesterase; Blood-brain barrier opening; Focused ultrasound; Nerve agent; Oximes.