Research efforts focus on the characterization of toxicity of organophosphorus nerve agents and other seizure-inducing chemicals, as well as on the identification of improved therapeutics against seizure and seizure-associated brain pathology. In vivo studies are performed in rodents and minipigs using outcome measures of behavior, physiology, biochemistry, and neuroanatomy to evaluate efficacy of candidate pretreatments and therapeutics against chemical-induced toxicity. Classes of anti-seizure medications being evaluated for efficacy against nerve agent exposure include, but are not limited to neurosteroids, antiglutamatergics, anticholinergics administered alone or in combination with benzodiazepines. Neurobehavioral assessments include measures of motor activity and function, cognitive performance, sensorimotor function, emotional memory, and measures of anxiety-like behavior. Telemetry is used to continuously measure electroencephalographic activity (EEG) for identification of seizure and epileptogenesis, as well to measure electrocardiographic activity and alterations in circadian rhythms (body temperature, activity). Histochemistry and stereology are used to evaluate neuropathology and neuroinflammatory responses. In addition, sex and age differences in toxic response to chemical exposure and to medical countermeasure efficacy are evaluated.

References

Lumley L, Niquet J, Marrero-Rosado B, Schultz M, Rossetti F, de Araujo Furtado M, Wasterlain C. Treatment of acetylcholinestearse inhibitor-induced seizures with polytherapy targeting GABA and glutamate receptors. Neuropharmacology 2021; 185:10844. PMID 33359073.

Lumley LA, Du F, Marrero-Rosado B, Stone M, Keith ZM, Schultz C, Whitten K, Walker K, Acon-Chen C, Wright L, Shih TM. Soman-induced toxicity, cholinesterase inhibition and neuropathology in adult male Gottingen minipigs. Toxicology Reports 2021; 8:896-907. PMID: 33996503.

Marrero-Rosado BM, De Araujo M, Kundrick ER, Walker KA, Stone MF, Schultz CR, Nguyen DA, Lumley LA. Ketamine as adjunct to midazolam treatment following soman-induced status epilepticus reduces seizure severity, epileptogenesis, and brain pathology in plasma carboxylesterase knockout mice. Epilepsy & Behavior 2020; 111:107229. PMID 32575012.

 

key words

Chemical warfare nerve agents; Behavior; Seizure; Antiseizure medications; Neuroprotection; Organophosphorus chemicals; neuroinflammation; Toxicology; Animal models; sex differences; epileptogenesis

Citizenship:  Open to U.S. citizens

Level:  Open to Postdoctoral and Senior applicants