Identification of Treatments for Chemical Threat Agent Seizures

摘要-项目二

Summary – Project 2 There is a need for improved treatments to terminate status epilepticus (SE) and increase survival following exposure to seizure-inducing chemical threat agents. There are two major classes of convulsant chemical threat agents: organophosphate (OP) anticholinesterases, including soman and diisopropylfluorophosphate (DFP), and GABAA receptor antagonists, including tetramethylenedisulfotetramine (TETS) and picrotoxin. The current standard of care treatment for chemical threat agent seizures is the benzodiazepine diazepam, but the benzodiazepine midazolam will likely be used in the future. These agents fail to terminate chemical threat agent induced SE in many situations, particularly when they are administered at delayed times after exposure, and they are not effective at preventing seizure-induced brain damage. In the initial project period, a mouse model of TETS-induced SE was developed. In addition, a rat model of DFP-induced SE was adapted to the laboratory. Diazepam and midazolam at doses equivalent to recommended human doses were partially active in the TETS SE model. However, allopregnanolone, a positive modulator of GABAA receptors, had superior activity in terminating TETS-induced behavioral and electrographic SE, particularly when administered at a delayed time. At effective doses, allopregnanolone did not cause marked sedation, motor impairment or adverse effects on blood pressure or respiration. Unlike other similar agents, allopregnanolone is uniquely suited for intramuscular administration via autoinjector. DFP-induced SE was not terminated by benzodiazepines or allopregnanolone. However, the combination of perampanel, a potent AMPA receptor antagonist, and allopregnanolone administered intramuscularly was highly effective in terminating DFP- induced behavioral and electrographic SE. It is hypothesized that a combination of allopregnanolone and perampanel would represent an effective and safe “universal” treatment for chemical threat agent seizures. In the proposed research, studies will be conducted that are required for the lead compound allopreganolone to enter advanced development, including studies in conjunction with standard therapy as well as non-human primate pharmacokinetic and efficacy testing. Proof-of-concept data will be obtained for perampanel and the combination of perampanel and allopregnanolone. Testing will also be conducted of additional antiseizure agents identified in Project 1 to determine if they are superior to the candidate treatments. Efficacy and safety testing will be conducted in both male and female animals to assess sex differences; and safety tests will be conducted in young and aged animals. Project 3 will identify candidate anti-inflammatory treatments to mitigate the long-term consequences of chemical treat agent seizures. Project 2 will assess whether these treatments interact with the antiseizure treatments. The results from this project will permit the lead compound allopregnanolone to enter advanced development and an assessment of whether perampanel or another candidate antiseizure agent should become development leads.