3 Search Results

Abstract Despite new antiseizure medications, the development of cholinergic‐induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia . 2005;46:142 demonstrated that the initiation and maintenance of cholinergic‐induced RSE are associated with trafficking and inactivation of gamma‐aminobutyric acid A receptors (GABA _A R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N‐methyl‐ d ‐aspartate receptors (NMDAR) and alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation ( Neurobiol Dis . 2013;54:225; Epilepsia . 2013;54:78). Thus, Dr.more » Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic‐induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic‐induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic‐induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine‐induced seizure in rats, organophosphorus nerve agent (OPNA)‐induced seizure in rats, and OPNA‐induced seizure in two mouse models: (1) carboxylesterase knockout (Es1 ^−/− ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock‐in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic‐induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic‐induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.« less

Introduction Chemical warfare nerve agents (CWNAs) inhibit acetylcholinesterase (AChE), which leads to status epilepticus (SE), spontaneous recurrent seizures (SRS) and severe neuropathology when treatment is delayed. In addition to binding to AChE, some organophosphorus (OP) CWNAs such as soman (GD) also inhibit carboxylesterase (CaE), which acts as a bioscavenger and can thus reduce the severity of the toxicity of OP agent exposure. Unlike humans, rodents have plasma CaE activity. The CaE knockout (ES1−/−) mouse specifically lacks plasma CaE and might better model human GD exposure compared to wildtype rodents. Delayed treatment of CWNA‐induced SE with midazolam leads to benzodiazepine‐refractory SE.more » We evaluated combination therapy of midazolam and the NMDA antagonist ketamine in male and female mice for efficacy against soman‐induced lethality, SE and epileptogenesis. Methods Mice implanted with telemetry transmitters for electroencephalography (EEG) seizure identification were exposed to 82 μg/kg GD (~4LD ₅₀ ) and treated with an admix (ip) of atropine sulfate (4 mg/kg) and HI‐6 (50 mg/kg) 1 min after exposure, and with midazolam (3 mg/kg; ip) alone or in combination with ketamine (30 mg/kg, ip) at 40 min after seizure onset. Mice were continuously recorded to evaluate initial seizure duration and SRS and then euthanized 2 weeks after exposure for neuropathology assessment. Results Delayed treatment with midazolam resulted in poor survival, was unable to rapidly terminate behavioral or EEG seizure activity and did not prevent the development of SRS or neuronal loss following GD exposure. Combination therapy of midazolam and ketamine resulted in improved outcome, including an increase in survival from 30% to 78% in female and from 57% to 77% in males compared to midazolam monotherapy. In addition, the incidence of epileptogenesis was lower in mice treated with ketamine and midazolam dual therapy compared to midazolam monotherapy. Conclusions This study demonstrates that delayed treatment of SE with midazolam is not fully protective against the GD‐induced epileptogenesis and neuropathology, exemplifying the need for adjunct treatment to midazolam to prevent or reduce effects of GD‐induced SE. Ketamine combination with midazolam improves outcome. Support or Funding Information Research was supported by the CounterACT Program, NIH OD, and the NINDS (Grant 1R21NS103820‐01 to LA Lumley‐Lange) and by DTRA‐JSTO. Erica Kundrick, Katie Walker, and Sean O'Brien were supported in part by an appointment to the Research Participation Program for the U.S. Army Medical Research and Materiel Command administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and U.S. Army Medical Research and Materiel Command. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .« less