Antiseizure and neuroprotective effects of delayed treatment with midazolam in a rodent model of organophosphate exposure
Funding information
This work was supported by USAMRICD subcontract W81XWH-14-C-0119, W81XWH-16-C-0140, and W81XWH-18-C-0181.
Abstract
Objective
Exposure to organophosphates (OPs) and OP nerve agents (NAs) causes status epilepticus (SE) and irreversible brain damage. Rapid control of seizure activity is important to minimize neuronal injury and the resulting neurological and behavioral disorders; however, early treatment will not be possible after mass release of OPs or NAs.
Methods
We utilized a delayed-treatment model of OP exposure in adult rats by administration of diisopropyl fluorophosphate (DFP) to study the relationship between the antiseizure and neuroprotective effects of the “standard-of-care” benzodiazepine, midazolam (MDZ), when given at 30, 60, and 120 minutes after SE onset. After electroencephalography (EEG) recordings, neural damage in serial brain sections was studied with Fluoro-Jade B staining.
Results
MDZ-induced seizure suppression was equivalent in magnitude regardless of treatment delay (ie, seizure duration). When assessed globally (ie, normalized across 10 different brain regions) for each treatment delay, MDZ administration resulted in only nonsignificant reductions in neuronal death. However, when data for MDZ treatment were combined from all three delay times, a small but significant reduction in global neuronal death was detected when compared to vehicle treatment, which indicated that the substantive MDZ-induced seizure suppression led to only a small reduction in neuronal death.
Significance
In conclusion, MDZ significantly reduced DFP-induced SE intensity when treatment was delayed 30, 60, and even up to 120 minutes; however, this reduction in seizure intensity had no detectable effect on neuronal death at each individual delay time. These data show that although MDZ suppressed seizures, additional neuroprotective therapies are needed to mitigate the effects of OP exposure.
DISCLOSURE OF CONFLICT OF INTERESTS
F.E. Dudek has equity interest in and receives gifts (reduced cost for wireless equipment) and consultant fees from Epitel, Inc., a company that makes wireless recording devices. He has also received consulting fees from Neurotherapeutics Pharma, Rugen Holdings, and Neurona Therapeutics. The other authors declare no other financial interests. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
