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Neuroinflammatory Responses in a Mouse Model of Tetramethylenedisulfotetramine‐Induced Status Epilepticus
Author(s) -
Calsbeek Jonas,
Gonzalez Eduardo,
Boosalis Casey,
Zolkowska Dorota,
Rogawski Michael,
Lein Pamela
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb645
Subject(s) - status epilepticus , pharmacology , benzodiazepine , diazepam , medicine , midazolam , epilepsy , pentylenetetrazol , anesthesia , anticonvulsant , receptor , sedation , psychiatry
Tetramethylenedisulfotetramine (TETS) is a GABA A receptor antagonist that is considered a chemical threat agent due to its ease of synthesis and its potent bioactivity in humans. Acute exposure to TETS can trigger seizures that evolve into status epilepticus (SE), and death. The current medical countermeasure for treating acute intoxication with seizurogenic chemicals like TETS includes the administration of benzodiazepines such as diazepam or midazolam. When administered 40 min post‐exposure in a mouse model of TETS‐induced SE, these positive allosteric modulators of the GABA A receptor are effective in stopping seizures and reducing mortality from ~90% to ~25%. The goal of this project was to determine the efficacy of this intervention in mitigating the neuroinflammatory response following TETS‐induced SE, with the objective of determining a feasible window of time for therapeutic intervention. In the current study, adult male NIH Swiss mice were pretreated with riluzole (10 mg/kg, i.p.) 10 min prior to receiving a lethal dose of TETS (0.2 mg/kg, i.p.). Control animals received vehicle in place of TETS and benzodiazepine. Animals were continuously monitored by EEG and/or scored for seizure behavior to confirm that TETS exposure elicited electrographic and/or behavioral seizures. At 10 or 40 min after the first myoclonic body twitch, animals were administered either diazepam (1.8 mg/kg, i.p.) or midazolam (1.8 mg/kg, i.m.) to terminate the persistent seizures. At 72h post‐intoxication, animals were perfused with fixative and brains were removed for FluoroJade C (FJC) labeling to assess neurodegeneration, and for GFAP and IBA1 immunohistochemistry to quantify neuroinflammation. Relative to vehicle control, GFAP immunoreactivity was significantly increased in the piriform cortex of all TETS‐exposed groups regardless of time of benzodiazepine administration. Midazolam was not superior to diazepam in protecting against neurodegeneration or neuroinflammation. These findings do not support the hypothesis that earlier treatment with either benzodiazepine is more effective in mitigating TETS‐induced neuropathology. Support or Funding Information Supported by the NINDS CounterACT Program (grant # U54 NS079202). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .