Project 3: Normalization of Neuronal Excitability

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Project Summary – Project 3 Both clinical and preclinical data clearly demonstrate that survivors of OP-induced status epilepticus (SE) can develop persistent neuropathology, spontaneous recurring seizures (SRS) and cognitive dysfunction. Current standard-of-care (SOC) for acute OP intoxication includes the muscarinic receptor antagonist, atropine, combined with an oxime, such as pralidoxime chloride (2-PAM) to reactivate acetylcholinesterase and finally a benzodiazepine to increase inhibitory tone. However, it is now clear that the potential for SOC to prevent SE or to counteract the downstream consequences of the OP-induced cholinergic storm rapidly diminishes with time. Specifically, immediate treatment with atropine and 2-PAM can increase viability, but does not prevent a transition into SE. Once in SE, the potential for benzodiazepines to interrupt seizures and protect against ongoing cell death quickly declines. It is also clear that as the interval between acute intoxication and treatment increases, the severity of the corresponding chronic neurological deficits increases as well. It is likely that following a mass casualty event, treatment of civilians exposed to chemical threat agents is going to fall outside of the optimal therapeutic window, increasing the likelihood that they will develop persistent SRS and cognitive disorders. Therefore, there is a clear need to identify biological markers to identify those individuals with the highest risk of developing long-term morbidity and also to move beyond the management of acute OP intoxication in the field, and to investigate therapeutic strategies for managing chronic neurological sequelae, including SRS and cognitive dysfunction. In Project 3, we will first evaluate the natural history of acute DFP intoxication. This will include a rigorous assessment of neural oscillations recorded from depth and cortical electrodes over the course of four months following injury, the quantification of SRS and also evaluation of both a standard battery of cognitive outcomes (Y-maze, novel object recognition and contextual fear conditioning) and also translationally relevant touchscreen behaviors (that evaluate memory, executive function, and attention). We will then evaluate four therapeutic candidates for their potential to modulate excitability, restore oscillations, reduce seizures and improve cognition. These candidates include: (i) FDA-approved lacosamide, which enhances the slow inactivation of voltage-gated sodium channels (Nav); (ii) FDA-approved riluzole, which blocks Nav, but also enhances the activity of small-conductance calcium-activated potassium channels (KCa) and also glutamine transport; (iii) SKA-19, a mixed Nav blocker and KCa activator; and (iv) NS13001, a relatively selective KCa activator. Finally, we will determine the potential of combinatorial therapy including one of the above therapeutic candidates with theta frequency deep brain stimulation to further manage the chronic neurological outcomes associated with acute OP intoxication. Ultimately, Project 3 will uncover molecular mechanisms of toxicity and potentially identify novel therapeutic targets to prevent (with acute delivery of identified therapies) or treat (with chronic delivery) the devastating long-term neurological sequelae, including SRS and cognitive dysfunction.