Efficacy of the GluK1/AMPA Receptor Antagonist LY293558 against Seizures and Neuropathology in a Soman-Exposure Model without Pretreatment and its Pharmacokinetics after Intramuscular Administration

Abstract

Control of brain seizures after exposure to nerve agents is imperative for the prevention of brain damage and death. Animal models of nerve agent exposure make use of pretreatments, or medication administered within 1 minute after exposure, in order to prevent rapid death from peripheral toxic effects and respiratory failure, which then allows the testing of anticonvulsant compounds. However, in a real-case scenario of an unexpected attack with nerve agents, pretreatment would not be possible, and medical assistance may not be available immediately. To determine if control of seizures and survival are still possible without pretreatment or immediate pharmacologic intervention, we studied the anticonvulsant efficacy of the GluK1 (GluR5)/ a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl) ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) in rats that did not receive any treatment until 20 minutes after exposure to the nerve agent soman. We injected LY293558 intramuscularly, as this would be the most likely route of administration to humans. LY293558 (15 mg/kg), injected along with atropine and the oxime HI-6 at 20 minutes after soman exposure, stopped seizures and increased survival rate from 64% to 100%. LY293558 also prevented neuronal loss in the amygdala and hippocampus, and reduced neurodegeneration in a number of brain regions studied 7 days after soman exposure. Analysis of the LY293558 pharmacokinetics after intramuscular administration showed that this compound readily crosses the blood-brain barrier. There was good correspondence between the time course of seizure suppression by LY293558 and the brain levels of the compound.

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

“…Therefore, suppressing glutamatergic hyperactivity can be a more effective way to control seizures, particularly if immediate treatment is not possible and the anticonvulsant is administered with a delay after seizure onset. Indeed, we previously showed that the GluK1/AMPA receptor antagonist LY293558, administered 1 hour after soman exposure, stops seizures and fully protects against neuronal damage (Figueiredo et al, 2011;Apland et al, 2013).…”

“…LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid], which is an antagonist of both the AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors and the kainate receptor subtype that contains the GluK1 subunit (GluK1R; formerly known as GluR5 kainate receptors or GLU K5 receptors; see Collingridge et al, 2009 andJane et al, 2009) was very efficacious in stopping seizures induced by the nerve agent soman and protecting against neuronal damage (Figueiredo et al, 2011;Apland et al, 2013). In this study, we used a rat model of nerve agent exposure in which the anticonvulsant treatment was delayed to at least 1 hour, and compared the efficacy of DZP with that of another GluK1R antagonist UBP302 [(S)-3-(2-carboxybenzyl)willardiine], which selectively antagonizes the GluK1Rs (More et al, 2004), against soman-induced seizures, as well as acute and long-term neuropathology.…”

The discovery and development of perampanel for the treatment of epilepsy

“…This receptor is known to have a substantial role in glutamate-mediated excitatory neurotransmission and synaptic plasticity [7][8][9], as well as in various types of neurodegenerative conditions [10]. The AMPA glutamate receptor has also been specifically linked to epilepsy in the human hippocampus [11,12], and animal studies have indicated that it has a key role in seizure-induced neuronal injury [13,14], epileptogenesis [15] and seizure activity and expression [16][17][18]. Furthermore, prototype competitive and noncompetitive AMPA receptor antagonists have demonstrated anticonvulsant activity in a variety of animal models [17,[19][20][21].…”

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

“…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.…”