The Roles of Glutamate Receptors and Their Antagonists in Status Epilepticus, Refractory Status Epilepticus, and Super-Refractory Status Epilepticus

Abstract

Status epilepticus (SE) is a neurological emergency with a high mortality rate. When compared to chronic epilepsy, it is distinguished by the durability of seizures and frequent resistance to benzodiazepine (BZD). The Receptor Trafficking Hypothesis, which suggests that the downregulation of γ-Aminobutyric acid type A (GABAA) receptors, and upregulation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors play major roles in the establishment of SE is the most widely accepted hypothesis underlying BZD resistance. NMDA and AMPA are ionotropic glutamate receptor families that have important excitatory roles in the central nervous system (CNS). They are both essential in maintaining the normal function of the brain and are involved in a variety of neuropsychiatric diseases, including epilepsy. Based on animal and human studies, antagonists of NMDA and AMPA receptors have a significant impact in ending SE; albeit most of them are not yet approved to be in clinically therapeutic guidelines, due to their psychomimetic adverse effects. Although there is still a dearth of randomized, prospective research, NMDA antagonists such as ketamine, magnesium sulfate, and the AMPA antagonist, perampanel, are regarded to be reasonable optional adjuvant therapies in controlling SE, refractory SE (RSE) or super-refractory SE (SRSE), though there are still a lack of randomized, prospective studies. This review seeks to summarize and update knowledge on the SE development hypothesis, as well as clinical trials using NMDA and AMPA antagonists in animal and human studies of SE investigations.

Efficacy of Perampanel in Refractory and Super-Refractory Status Epilepticus with Suspected Inflammatory Etiology: A Case Series

“…It is established that AMPA receptors play a relevant role during and after SE. In the CNS, Glu serves as the primary excitatory neurotransmitter, and N-methyl-D-aspartate (NMDA) and AMPA receptors are widely distributed [ 28 ]. It is known that the current paradigm of the SE entails the downregulation of GABA A receptors and the upregulation of NMDA and AMPA receptors.…”

“…It is known that the current paradigm of the SE entails the downregulation of GABA A receptors and the upregulation of NMDA and AMPA receptors. Notably, these two glutamatergic receptors play a crucial role in regulating ion permeability, particularly Ca 2+ , and may contribute to the initiation and maintenance of seizures and SE [ 28 ]. As indicated by preclinical data [ 29 ], the AMPA receptor antagonists present a potential therapeutic effect for patients with SE, especially in the early phase.…”

Socrates: A Novel N-Ethyl-N-nitrosourea-Induced Mouse Mutant with Audiogenic Epilepsy

“…The main role in the process of neuronal network excitation is assigned to glutamate, which transmits excitation from one neuron to another. An increase in the glutamate concentration in the extracellular space has been shown during epileptic seizures [46,47], and glutamate receptor agonists can enhance seizures in humans and animals [48,49]. Glutamate receptor antagonists are able to suppress seizures.…”