Saracatinib and 1400W Counteract Nerve Agents-Induced Long-Term Neurotoxicity - 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.
