Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine
| Autor: | Jay Spampanato, F. Edward Dudek, Steven L. Bealer, Melissa Smolik |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Isoflurophate Status epilepticus Electroencephalography Pharmacology Time-to-Treatment Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Status Epilepticus 0302 clinical medicine Memantine Prohibitins medicine Animals Drug Interactions Dexmedetomidine Neurons Cell Death Dose-Response Relationship Drug medicine.diagnostic_test business.industry Organophosphate Brain Rats Disease Models Animal Treatment Outcome 030104 developmental biology chemistry Phenobarbital Adjunctive treatment Molecular Medicine Midazolam Anticonvulsants medicine.symptom business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 375:59-68 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.120.000175 |
| Popis: | Organophosphate (OP) exposure induces status epilepticus (SE), a medical emergency with high morbidity and mortality. Current standard medical countermeasures lose efficacy with time so that treatment delays, in the range of tens of minutes, result in increasingly poor outcomes. As part of the Countermeasures Against Chemical Threats Neurotherapeutics Screening Program, we previously developed a realistic model of delayed treatment of OP-induced SE using the OP diisopropyl fluorophosphate (DFP) to screen compounds for efficacy in the termination of SE and elimination of neuronal death. Male rats were implanted for electroencephalogram (EEG) recordings 7 days prior to experimentation. Rats were then exposed to DFP, and SE was induced for 60 minutes and then treated with midazolam (MDZ) plus one of three antiseizure drugs (ASDs)-phenobarbital (PHB), memantine (MEM), or dexmedetomidine (DMT)-in conjunction with antidotes. EEG was recorded for 24 hours, and brains were stained with Fluoro-Jade B for quantification of degenerating neurons. We found that PHB + MDZ induced a prolonged suppression of SE and reduced neuronal death. MEM + MDZ treatment exacerbated SE and increased mortality; however, surviving rats had fewer degenerating neurons. DMT + MDZ significantly suppressed SE with only a minimal reduction in neuronal death. These data demonstrate that delayed treatment of OP-induced SE with other ASDs, when added to MDZ, can achieve greater seizure suppression with additional reduction in degenerating neurons throughout the brain compared with MDZ alone. The effect of a drug on the severity of seizure activity did not necessarily determine the drug's effect on neuronal death under these conditions. SIGNIFICANCE STATEMENT: This study assesses the relative effectiveness of three different delayed-treatment regimens for the control of organophosphate-induced status epilepticus and reduction of subsequent neuronal death. The data demonstrate the potential for highly effective therapies despite significant treatment delay and a potential disconnect between seizure severity and neuronal death. |
| Databáze: | OpenAIRE |
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