Authors :
Taiza Figueiredo, PhD – Uniformed Services University of the Health Sciences
Vassiliki Aroniadou-Anderjaska, PhD – Uniformed Services University of the Health Sciences
Volodymyr Pidoplichko, PhD – Uniformed Services University of the Health Sciences
Presenting Author: Marcio De Araujo Furtado, PhD – Uniformed Services University of the Health Sciences
Katia Rossetti, BS – Uniformed Services University of the Health Sciences
Lucille Lumley, PhD – US Army Medical Research Institute of Chemical Defense
Maria Braga, PhD – Uniformed Services University of the Health Sciences
Rationale:
Nerve agents are lethal chemical weapons and highly potent chemoconvulsants. For the treatment of nerve agent-induced status epilepticus (SE), the FDA has approved the use of benzodiazepines—initially diazepam and recently midazolam (MDZ); however, benzodiazepines are not neuroprotective, particularly if not administered promptly. Here, we compared the antiseizure and antiepileptogenic efficacy of MDZ with that of LY293558 (an AMPA/GluK1 receptor antagonist) administered with caramiphen (CRM; an antagonist of muscarinic and NMDA receptors).Methods:
MDZ was administered 30 or 50 min after the onset of SE induced by exposure of adult male and female rats to the nerve agent soman. LY293558+CRM was administered 30 min after the onset of SE induced by exposure of adult male and female rats to the nerve agent soman; neuropathology assessments, and incidence of SRS and SUDEP were evaluated 1-, 3- and 6-months post-exposure. Results:
Latency to suppression of the initial SE was comparable after MDZ or LY293558+CRM treatment. However, seizures reoccurred, and MDZ-treated rats had longer SE, followed by significant neurodegeneration, neuronal and interneuronal loss in the CA1 hippocampal area and the basolateral amygdala, hippocampal and amygdalar atrophy, reduced spontaneous IPSCs in the basolateral amygdala, increased anxiety, and spontaneous recurrent seizures (SRS). MDZ-treated males had longer SE than MDZ-treated females and lower 24-h and long-term survival, with SUDEP-like deaths. MDZ-treated females displayed delayed hippocampal neurodegeneration and atrophy, as well as delayed SRS. Males and females treated with LY293558+CRM presented minimal neurodegeneration and only delayed appearance of brain damage, without significant sex differences. Conclusions:
The results suggest that MDZ treatment may carry higher risks for males. Replacing benzodiazepines with antiglutamatergic first-line treatments to prevent long-term brain damage and associated morbidities is overdue; LY293558+CRM has produced the most promising results reported so far.
Funding:
This work was supported by the CounterACT Program, National Institutes of Health, Office of the Director and the National Institute of Neurologic Disorders and Stroke [Grant Number U01 NS123252-01A1], and by an interagency agreement [AOD24006-001 00000] between National Institutes of Health Office of the Director and the U.S. Army Medical Research Institute of Chemical Defense under the oversight of the Chemical Countermeasures Research Program within the Office of Biodefense Research at the National Institutes of Health National Institute of Allergy and Infectious Diseases.