Saracatinib Mitigates OP nerve agent-induced Long-term Neurotoxicity

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Chemical warfare nerve agents (NA) are increasingly used to attack civilians worldwide. The past sarin attacks in Tokyo, VX usage in homicide attack in Malaysia, the recent sarin attacks in Syria on civilians, and the most recent Novichok ("newcomer") attack in England reiterate the real threat of chemical warfare NA to civilian population. NA in the hands of terrorists pose threat to human health globally and currently we lack effective treatment for survivors. Preventing acute death due to NA exposure had taken top priority until recently. The reports on the life-long health consequences of sarin attacks survivors are beginning to emerge, which compels the discovery of new drugs or new therapeutic approaches to mitigate the long-term effects of acute NA exposure. Sarin exposed subjects, though hospitalized and treated with conventional therapy, in the long- term they developed seizures and cognitive, motor, and psychological impairment. Like organophosphates (OP), NA are cholinesterase inhibitors and potent seizurogenic. In animal models, acute NA or OP exposure causes prolonged seizures and other cholinergic symptoms. The current medical countermeasure drugs (atropine, oxime, and diazepam) do not prevent the long-term neurotoxicity and comorbidity, which are largely due to persistent neuroinflammation and neurodegeneration. Our overarching hypothesis is that a combination of a novel neuroprotectant, saracatinib (SAR, also known as AZD0305), and countermeasure drugs can prevent NA-induced long-term neurotoxicity and restore brain function. We propose to investigate the long-term neuroprotective effects of a novel Fyn/Src family tyrosine kinase inhibitor, SAR in diisopropyl flurophosphate (DFP) and a NA soman rat models. SAR is in clinical trials for Alzheimer's disease and for several types of cancer patients. Recently we demonstrated the role of Fyn/Src kinase in neuroinflammation, neurodegeneration, and seizures onset in the rat and mouse models, and showed that SAR treatment dampened neuroinflammation, protected neurons and prevented/modified epileptogenesis. Our current experiments also revealed a similar mechanism of epileptogenesis, neurodegeneration, and behavioral dysfunction in the rat DFP model. Since the SAR post-treatment prevented and/or significantly modified epileptogenesis, we predict that SAR can mitigate DFP- and soman-induced long-term neurotoxicity. In specific aim 1 and 2, we will investigate the neuroprotective effect and rescue of cognitive dysfunction by SAR in the rat DFP and soman models. We will also perform a battery of behavioral tests and conduct key proinflammatory cytokines (multiplex assay) and nitro-oxidative stress assays. In some animals we will implant a wireless telemetry device to monitor brain electrical activity to confirm the impact of SAR on neuroprotection, anti-epileptogenicity, and behavioral rescue. Our proposal addresses the mission of the CounterACT program ["to foster and support research and development of new and improved therapeutics to mitigate the health effects of chemical threats"], and may yield a novel therapy for NA-induced long-term neurotoxicity.