NBQX, a highly selective competitive antagonist of AMPA and KA ionotropic glutamate receptors, increases seizures and mortality following picornavirus infection

Abstract

Seizures occur due to an imbalance between excitation and inhibition, with the balance tipping towards excitation, and glutamate is the predominant excitatory neurotransmitter in the central nervous system of mammals. Since upregulation of expression and/or function of glutamate receptors can contribute to seizures we determined the effects of three antagonists, NBQX, GYKI-52466 and MK 801, of the various ionotropic glutamate receptors, AMPA, NMDA and KA, on acute seizure development in the Theiler’s murine encephalomyelitis virus (TMEV)-induced seizure model. We found that only NBQX had an effect on acute seizure development, resulting in a significantly higher number of mice experiencing seizures, an increase in the number of seizures per mouse, a greater cumulative seizure score per mouse and a significantly higher mortality rate among the mice. Although NBQX has previously been shown to be a potent anticonvulsant in animal seizure models, seizures induced by electrical stimulation, drug administration or as a result of genetic predisposition may differ greatly in terms of mechanism of seizure development from our virus-induced seizure model, which could explain the opposite, proconvulsant effect of NBQX observed in the TMEV-induced seizure model.

Acute treatment with minocycline, but not valproic acid, improves long‐term behavioral outcomes in the Theiler's virus model of temporal lobe epilepsy

“…30,31 Our present results further highlight the need to carefully and rigorously evaluate dosedependent effects of investigational and repurposed compounds in etiologically relevant models of a disease by multiple independent groups. 32 However, these present results for disease worsening with twice-daily MIN, coupled with prior observations with either carbamazepine 11 or the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3dione (NBQX), 33 would suggest that the TMEV model may identify not only treatments that can improve acute outcomes, but also those that could be disease worsening.…”

“…Our present results further highlight the need to carefully and rigorously evaluate dose‐dependent effects of investigational and repurposed compounds in etiologically relevant models of a disease by multiple independent groups . However, these present results for disease worsening with twice‐daily MIN, coupled with prior observations with either carbamazepine or the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate (KA)‐ receptor antagonist 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo[f]quinoxaline‐2,3‐dione (NBQX), would suggest that the TMEV model may identify not only treatments that can improve acute outcomes, but also those that could be disease worsening. That the beneficial effects of acute once‐daily MIN treatment on chronic outcomes were not associated with acute improvements during the viral infection period clearly suggest that MIN conferred a disease‐, rather than insult‐modifying effect, a finding in direct contrast with that of VPA.…”

Neuroinflammation in epileptogenesis: Insights and translational perspectives from new models of epilepsy

“…Furthermore, we have also demonstrated a disease‐worsening effect with CBZ, as measured by clinical odds ratio analysis, as well as other outcome metrics. This disease‐worsening effect has also been detected with the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/kainate (KA)–receptor antagonist 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo[f]quinoxaline‐2,3‐dione (NBQX) . From this perspective, the TMEV model can serve as an important platform for identifying agents that are acutely anticonvulsant and/or disease modifying, and agents that may be disease worsening.…”

“…This diseaseworsening effect has also been detected with the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/ kainate (KA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 62 From this perspective, the TMEV model can serve as an important platform for identifying agents that are acutely anticonvulsant and/or disease modifying, and agents that may be disease worsening. In this regard, the TMEV model is further validated as a valuable tool in the early screening of novel treatments for infection-induced epilepsy.…”

Transcriptional modulation of calcium‐permeable AMPA receptor subunits in glioblastoma by MEK–ERK1/2 inhibitors and their role in invasion

“…NBQX and CNQX are the most commonly used and well-established AMPAR inhibitors. NBQX is potent, highly selective, and competitive AMPAR antagonist (Libbey et al, 2016). Whereas, CNQX is a nonselective AMPA blocker (Ishida et al, 2017).…”