The GluK1 (GluR5) Kainate/α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Antagonist LY293558 Reduces Soman-Induced Seizures and Neuropathology

Abstract

The possibility of mass exposure to nerve agents by a terrorist attack necessitates the availability of antidotes that can be effective against nerve agent toxicity even when administered at a relatively long latency after exposure, because medical assistance may not be immediately available. Nerve agents induce status epilepticus (SE), which can cause brain damage or death. Antagonists of kainate receptors that contain the GluK1 (formerly known as GluR5) subunit (GluK1Rs) are emerging as a new potential treatment for SE and epilepsy from animal research, whereas clinical trials to treat pain have shown that the GluK1/␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist LY293558 [(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid] is safe and well tolerated. Therefore, we tested whether LY293558 is effective against soman-induced seizures and neuropathology, when administered 1 h after soman exposure, in rats. LY293558 stopped seizures induced by soman and reduced the total duration of SE, monitored by electroencephalographic recordings within a 24 h-period after exposure. In addition, LY293558 prevented neuronal loss in the basolateral amygdala (BLA) and the CA1 hippocampal area on both days 1 and 7 after soman exposure and reduced neuronal degeneration in the CA1, CA3, and hilar hippocampal regions, entorhinal cortex, amygdala, and neocortex on day 1 after exposure and in the CA1, CA3, amygdala, and neocortex on day 7 after exposure. It also prevented the delayed loss of glutamic acid decarboxylase-67 immuno-stained BLA interneurons on day 7 after exposure. LY293558 is a potential new emergency treatment for nerve agent exposure that can be expected to be effective against seizures and brain damage even with late administration.

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

“…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.…”

“…For electroencephalographic recordings (obtained 10 days after electrode implantation), rats were placed in the electroencephalography (EEG) chamber and connected to the EEG system (200 Hz sampling rate; Stellate, Montreal, QC, Canada). Video-EEG recordings were performed in the freely moving rats, as previously described (Figueiredo et al, 2011). EEG was continuously recorded for 24 hours after soman injection; during that time, the animals had free access to food and water.…”

“…Rats (aged 6 weeks) were anesthetized with isoflurane using a gas anesthesia system (Kent Scientific, Torrington, CT). Five stainless steel, cortical screw electrodes were stereotaxically implanted, as previously described (Figueiredo et al, 2011), using the following coordinates (from Paxinos and Watson, 2005): two frontal electrodes, 2.0 mm posterior from bregma and 2.5 mm lateral from the midline, and two parietal electrodes, 5.0 mm posterior from bregma and 2.5 mm lateral from the midline; and a cerebellar reference electrode was implanted 1.0 mm posterior to lambda. Each screw electrode (Plastics One Inc., Roanoke, VA) was placed in a plastic pedestal (Plastics One Inc.) and fixed to the skull with dental acrylic cement.…”

Mechanism and Clinical Importance of Respiratory Failure Induced by Anticholinesterases

“…It is generally accepted that soman and other centrallyacting AChE inhibitors via cholinoceptor hyperstimulation start a vicious circle that ends up with glutamatergic excitatory discharges that clinically manifest themselves as seizures and leave the survivors with serious brain damage (45,46). It is not clear what the relation between the onset of seizures and the occurrence of respiratory depression is in soman-poisoned animals, since most of the cited experiments have been performed under urethane anaesthesia (47).…”

Pathological and Pathophysiological Alterations in Temporal Lobe Structures After Mild Traumatic Brain Injury

“…Design-based stereology was performed to quantify the total number of neurons in Nissl-stained sections and interneurons in GAD-67-imrnunostained sections in the BLA (90). Sections were viewed with a Zeiss (Oberkochen, Germany) Axioplan 2ie fluorescent microscope with a motorized stage, interfaced with a computer running For Nissl-stained neurons in the CAI, a l-in-10 series of sections was analyzed (seven sections on average).…”