Saracatinib and 1400W Counteract Nerve Agents-induced Long-term Neurotoxicity

点击翻译按钮获取中文摘要

Abstract Chemical warfare nerve agents (CWNAs) are increasingly used to attack civilians worldwide. The sarin attacks in Tokyo and Syria and VX attack in Malaysia and England prove the real threat of CWNA. CWNA exposure impacts human health globally, but we lack effective treatment for survivors. Until recently, preventing acute death due to CWNA exposure was a top priority. However, addressing the long-term effects is also crucial given that survivors of sarin attacks, though hospitalized and treated with conventional therapy, developed seizures and cognitive, motor, and psychological impairments. Like organophosphates (OP), CWNAs are cholinesterase inhibitors and potent seizurogenics. In animal models, acute CWNA or OP exposure induces status epilepticus (SE) and other cholinergic symptoms. The current medical countermeasures (MCM- atropine, oxime, and diazepam or midazolam) do not prevent long-term neurotoxicity and comorbidity, which are primarily due to persistent neuroinflammation and neurodegeneration. Our overarching hypothesis is that neuroprotectant/s, in combination with MCM, will effectively counteract NA-induced long-term neurotoxicity and restore brain function. We propose two novel neuroprotectants; saracatinib (SAR/AZD0530, a Src kinase inhibitor) and 1400W (an inducible NO synthase inhibitor). Both demonstrated significant neuroprotective and disease-modifying effects in kainate (KA) and DFP (a soman surrogate) rat models of chronic epilepsy. Both tested in humans for other indications, and no adverse effects were reported. Histology of brain sections from animal models confirmed that the test drugs significantly reduced neuroinflammation and neurodegeneration, the most common features of CWNA exposure that follows SE. We had administered both drugs (separately) and the MCM after DFP/KA/soman exposure in animals to mimic an "after field evacuation and in-hospital" scenario (FOA). As expected, MCM alone did not prevent DFP/KA-induced neurodegeneration, seizures, and neurobehavioral deficits. When neuroprotectant was administered as a follow-on therapy, we could mitigate DFP/KA/soman-induced brain pathology, which provide the proof-of-concept for the neuroprotective strategy for a CWNA exposure scenario. We will optimize both SAR and 1400W in rat DFP and soman models and validate in G. pig (soman) and rat VX models and determine the efficacy of single or combination of both drugs in mitigating neuropathology and behavioral deficits [Specific Aims (SA) 1-3]. We will conduct non-GLP PK/PD-toxicity studies and initiate drug development (SA 4) for intended use in humans (FOA). We will employ unbiased long-term video-EEG studies to quantify seizures and epileptiform spikes, and conduct MRI/PET scan, stereology to determine neuronal loss, and multiplex assay for neuroinflammatory cytokines. We will conduct a battery of behavioral tests at various time-points. This research addresses the CounterACT mission, i.e., "to foster and support research and development of new and improved therapeutics to mitigate the health effects of chemical threats." The lead compound will move forward for FDA approval.