Abstract
It is widely accepted that glutamate-mediated neuronal hyperexcitation plays a causative role in eliciting seizures. Among glutamate receptors, the roles of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors in physiological and pathological conditions represent major clinical research targets. It is well known that agonists of NMDA or AMPA receptors can elicit seizures in animal or human subjects, while antagonists have been shown to inhibit seizures in animal models, suggesting a potential role for NMDA and AMPA receptor antagonists in anti-seizure drug development. Several such drugs have been evaluated in clinical studies; however, the majority, mainly NMDA-receptor antagonists, failed to demonstrate adequate efficacy and safety for therapeutic use, and only an AMPA-receptor antagonist, perampanel, has been approved for the treatment of some forms of epilepsy. These results suggest that a misunderstanding of the role of each glutamate receptor in the ictogenic process may underlie the failure of these drugs to demonstrate clinical efficacy and safety. Accumulating knowledge of both NMDA and AMPA receptors, including pathological gene mutations, roles in autoimmune epilepsy, and evidence from drug-discovery research and pharmacological studies, may provide valuable information enabling the roles of both receptors in ictogenesis to be reconsidered. This review aimed to integrate information from several studies in order to further elucidate the specific roles of NMDA and AMPA receptors in epilepsy.
Highlights
The central nervous system utilizes various substances as neurotransmitters
An increase in glutamate levels in the extracellular fluid during the ictal phase is well documented [9,10,11], and glutamate receptor agonists such as domoate are known to elicit seizures in humans and animals [12,13,14], while N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainate have been reported to elicit seizures in rodent models [15,16]
Potschka et al demonstrated that the glutamate receptor antagonist, LU 73,068 (4,5-dihydro-1-methyl-4-oxo-7-trifluoromethyl-imidazo [1,2a]quinoxaline-2-carbonic acid), which binds with high affinity to both AMPA receptors and the glycine site of NMDA receptors, dose-dependently increased the after-discharge threshold (ADT) for focal seizures, and completely blocked seizures when rats were stimulated with a current 20% greater than the prespecified control ADT [58]
Summary
The central nervous system utilizes various substances as neurotransmitters. Among them, glutamate and gamma aminobutyric acid (GABA) are the major neurotransmitters for excitatory and inhibitory function, respectively. An increase in glutamate levels in the extracellular fluid during the ictal phase (i.e., during a seizure) is well documented [9,10,11], and glutamate receptor agonists such as domoate are known to elicit seizures in humans and animals [12,13,14], while N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainate have been reported to elicit seizures in rodent models [15,16] These reports indicate that glutamate receptors, ionotropic glutamate receptors, have a significant role in ictogenesis (i.e., the generation of a seizure). Agonists of both NMDA and AMPA receptors have been shown to elicit seizures in animal models, but clinical study results differ between the two receptor types This inconsistency might be due to a limited understanding of each receptor’s function in epilepsy, and this review aims to clarify the role of these two major glutamate receptor types in epilepsy from various points of view
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