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Soman‐induced status epilepticus, epileptogenesis, and neuropathology in carboxylesterase knockout mice treated with midazolam
Author(s) -
MarreroRosado Brenda,
Araujo Furtado Marcio,
Schultz Caroline R.,
Stone Michael,
Kundrick Erica,
Walker Katie,
O’Brien Sean,
Du Fu,
Lumley Lucille A.
Publication year - 2018
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.14582
Subject(s) - status epilepticus , epileptogenesis , neuropathology , soman , neuroinflammation , pharmacology , anticonvulsant , epilepsy , convulsion , medicine , anesthesia , neuroscience , psychology , chemistry , acetylcholinesterase , inflammation , biochemistry , disease , enzyme
Summary Objective Exposure to chemical warfare nerve agents ( CWNA s), such as soman ( GD ), can induce status epilepticus ( SE ) that becomes refractory to benzodiazepines when treatment is delayed, leading to increased risk of epileptogenesis, severe neuropathology, and long‐term behavioral and cognitive deficits. Rodent models, widely used to evaluate novel medical countermeasures ( MCM s) against CWNA exposure, normally express plasma carboxylesterase, an enzyme involved in the metabolism of certain organophosphorus compounds. To better predict the efficacy of novel MCM s against CWNA exposure in human casualties, it is crucial to use appropriate animal models that mirror the human condition. We present a comprehensive characterization of the seizurogenic, epileptogenic, and neuropathologic effects of GD exposure with delayed anticonvulsant treatment in the plasma carboxylesterase knockout ( ES 1−/−) mouse. Methods Electroencephalography (EEG) electrode‐implanted ES 1−/− and wild‐type (C57 BL /6) mice were exposed to various seizure‐inducing doses of GD , treated with atropine sulfate and the oxime HI ‐6 at 1 minute after exposure, and administered midazolam at 15‐30 minutes following the onset of seizure activity. The latency of acute seizure onset and spontaneous recurrent seizures (SRS) was assessed, as were changes in EEG power spectra. At 2 weeks after GD exposure, neurodegeneration and neuroinflammation were assessed. Results GD ‐exposed ES 1−/− mice displayed a dose‐dependent response in seizure severity. Only ES 1−/− mice exposed to the highest tested dose of GD developed SE , subchronic alterations in EEG power spectra, and SRS . Degree of neuronal cell loss and neuroinflammation were dose‐dependent; no significant neuropathology was observed in C57 BL /6 mice or ES 1−/− mice exposed to lower GD doses. Significance The US Food and Drug Administration ( FDA) animal rule requires the use of relevant animal models for the advancement of MCMs against CWNA s. We present evidence that argues for the use of the ES 1−/− mouse model to screen anticonvulsant, antiepileptic, and/or neuroprotective drugs against GD ‐induced toxicity, as well as to identify mechanisms of GD ‐induced epileptogenesis.