Neurocognitive and neurobiological effects of low dose organophosphate exposure.

Abstract

Organophosphates (OPs) have been used as nerve agents in the Persian Gulf Wars and terrorist attacks in Japan and the United Kingdom. While high doses of OPs may be lethal, lower dose OP exposures can lead to neurotoxic consequences for the central nervous system (CNS), which manifest as cognitive dysfunction including anxiety, depression, and learning and memory deficits. Therefore, OP toxicity poses a threat for warfighters, first responders, clean-up workers and civilians. Because the CNS effects of low dose OP exposures may be persistent, it is crucial to find countermeasures to mitigate any long-term neurological damage. This study evaluated the effect of a very low dose OP, metrifonate (MFT, 80 ​mg/kg, i.p.) and the efficacy of an orally available, small molecule adenosine kinase (ADK) inhibitor, ABT-702 (1.6 ​mg/kg, i.p., six daily doses), to ameliorate OP-induced long-term neurotoxicity. One-month post-exposure, MFT selectively impaired medial pre-frontal cortex (mPFC)-dependent executive function gauged by the puzzle box task, that was alleviated by ABT-702 treatment. MFT showed subtle effects on motor function at early (48h to one-week) post-exposure intervals without impacting spatial recognition memory or the hippocampal milieu. Dual immunofluorescence staining and volumetric quantification indicated reduced microglial activation and hypertrophic astrocytes post-ABT-702 treatment in MFT-exposed mice. ABT-702 also restored post-synaptic density protein, PSD-95, in the MFT-exposed mPFC. These data indicate that ABT-702 treatment protects mPFC-dependent function post-MFT exposure. The subtle impact of low dose MFT exposure on CNS function should be further evaluated at other time points and doses.