Inflammation and white matter microstructural alterations after OP exposure

Project Summary Exposure to organophosphate (OP) compounds such as diisopropylfluorophosphate (DFP) results in irreversible inhibition of acetylcholinesterase (AChE), excessive accumulation of acetylcholine within synapses, and overactivation of muscarinic and nicotinic acetylcholine receptors in the peripheral and central nervous system, leading to death. Civilian populations are at risk from OP exposure. Toxic signs (hypersecretions, vomiting, diarrhea, tremors, status epilepticus [SE], respiratory distress, death) can ensue within minutes of exposure. Current medical countermeasures are effective acutely but may not prevent long-term consequences. It is known that OP compounds cause white matter damage in monkeys. In humans, white matter volume reduction is observed years after exposure as evidenced by survivors of a sarin attack in a Tokyo subway. Independently, pathologic white matter microstructural alterations, inefficient connectivity in the limbic system and default mode network (DMN) reductions have been observed in animal models of induced SE. However, the effect of OP exposure on white matter microstructure and underlying pathophysiological mechanism(s) are unknown. Our approach examines pathologic white matter microstructural alterations after DFP exposure. We will use high resolution diffuse tensor imaging (DTI) to analyze SE-induced deleterious effects. In addition to determining pathphysiological effects of DFP, we will also perform an intervention. We will test the anti-excitotoxic and anti-inflammatory efficacy of alpha-linolenic acid (LIN) to prevent the DFP-induced pathologic white matter microstructural alterations and reduction in the DMN by employing DTI and functional magnetic resonance imaging (FMRI) on a 7T MRI. Finally, we will perform target and off-target lipidomics to gain insight into the contributions of pro- and anti-inflammatory polyunsaturated fatty acid-derived oxylipins in OP-induced white matter changes. The data acquired in this study will define the pathologic white matter microstructural alterations and reduction in the DMN after DFP exposure. We will also understand mechanisms underlying DFP-induced effects. The incorporation of a pharmaco- intervention may prevent the white matter microstructural damage and DMN reduction after OP exposure. LIN derived oxyipins may tip the balance toward an anti-inflammatory state in brain to increase neuronal connectivity function and improve clinical outcome.