The Limitations of Diazepam as a Treatment for Nerve Agent–Induced Seizures and Neuropathology in Rats: Comparison with UBP302

Abstract

Exposure to nerve agents induces prolonged status epilepticus (SE), causing brain damage or death. Diazepam (DZP) is the current US Food and Drug Administration-approved drug for the cessation of nerve agent-induced SE. Here, we compared the efficacy of DZP with that of UBP302 [(S)-3-(2-carboxybenzyl) willardiine; an antagonist of the kainate receptors that contain the GluK1 subunit] against seizures, neuropathology, and behavioral deficits induced by soman in rats. DZP, administered 1 hour or 2 hours postexposure, terminated the SE, but seizures returned; thus, the total duration of SE within 24 hours after soman exposure was similar to (DZP at 1 hour) or longer than (DZP at 2 hours) that in the soman-exposed rats that did not receive the anticonvulsant. Compared with DZP, UBP302 stopped SE with a slower time course, but dramatically reduced the total duration of SE within 24 hours. Neuropathology and behavior were assessed in the groups that received anticonvulsant treatment 1 hour after exposure. UBP302, but not DZP, reduced neuronal degeneration in a number of brain regions, as well as neuronal loss in the basolateral amygdala and the CA1 hippocampal area, and prevented interneuronal loss in the basolateral amygdala. Anxiety-like behavior was assessed in the open field and by the acoustic startle response 30 days after soman exposure. The results showed that anxiety-like behavior was increased in the DZP-treated group and in the group that did not receive anticonvulsant treatment, but not in the UBP302-treated group. The results argue against the use of DZP for the treatment of nerve agent-induced seizures and brain damage and suggest that targeting GluK1-containing receptors is a more effective approach.

Antiseizure Activity of Midazolam in Mice Lackingδ-Subunit Extrasynaptic GABAAReceptors

“…Midazolam also has some of the significant limitations found in other benzodiazepines. Chiefly, it must be administered within 10-20 minutes, after which there is little or no protection against seizures, and progressive neurologic damage occurs (Goodkin et al, 2009;Apland et al, 2014). This timeline is often not practical in many cases because it can take a minimum of 30-60 minutes to get medical intervention.…”

The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala

“…Seizures were monitored behaviorally in a blind fashion by two expert observers. Seizure severity was scored for 1 hour, using a modified version of the Racine (1972) scale as we described previously (Figueiredo et al, 2011) (Abdullah and Rafiqul Islam, 2012;Rossetti et al, 2012;Apland et al, 2014;Deshpande et al, 2014).…”

A rat model of nerve agent exposure applicable to the pediatric population: The anticonvulsant efficacies of atropine and GluK1 antagonists

“…), and, in the brain, induces seizures and status epilepticus (SE). Without timely pharmacological intervention, death will ensue, or if death is prevented but the SE is not controlled, brain damage will result, with long-term neurological and behavioral consequences (Apland et al, 2010, 2014; Coubard et al, 2008; Figueiredo et al, 2011a, 2011b; Filliat et al, 2007; Prager et al, 2014a, 2014b; Yanagisawa et al, 2006). The nerve agent sarin that was released during a terrorist attack in Syria, in August 2013, resulted in the death of over 1,400 civilians, 426 of which were children (Dolgin, 2013).…”

“…In addition, diazepam has been approved for the cessation of nerve agent-induced SE. Improvements to this regimen are likely to be made in the future, as more effective anticonvulsants are being discovered (Apland et al, 2013; Capacio et al, 2004; Figueiredo et al, 2011a; Figueiredo et al, 2011b; Gilat et al, 2005), and, as recent studies suggest, diazepam does not protect against brain damage and behavioral deficits associated with nerve agent exposure (Apland et al, 2014; Myhrer et al, 2005), while other anticonvulsant compounds have high neuroprotective efficacy (Apland et al, 2014). Due to the nature of this research, nerve agent studies can be carried out only in animal models.…”

“…In the P21 rats, we determined the LD 50 of the nerve agent soman, measured AChE activity after soman exposure in brain regions that play an important role in seizure generation, and determined the effects of atropine administration on ongoing, behaviorally-monitored SE. In addition, because we have shown previously in young-adult rats that antagonists of kainate receptors containing the GluK1 subunit (GluK1Rs; formerly known as GluR5Rs, see Collingridge et al, 2009; Jane et al, 2009) are very effective anticonvulsants and neuroprotectants against soman exposure (Apland et al, 2013; Apland et al, 2014; Figueiredo et al, 2011b), we also examined the efficacy of these compounds in the immature, P21 rats.…”