ReviewThe NMDA receptor complex as a therapeutic target in epilepsy: a review
Highlights
► NMDAR function and expression are altered in epilepsy. ► NMDAR antagonists have antiepileptic effects in clinical and preclinical studies. ► NMDARs are involved in the mechanisms of action of some conventional anticonvulsant drugs.
Introduction
Epilepsy is one of the most common neurologic disorders encountered in clinical practice, affecting approximately 2 to 4 million people in the United States or 1 in 50 children and 1 in 100 adults [1]. Over the last two decades, a new generation of antiepileptic drugs (AEDs) has emerged for the pharmacological management of seizures. Concurrent with that development, the concept of optimum therapy for seizures has evolved to include complete control of seizures, absence of bothersome side effects, and an emphasis on maximizing quality of life [2]. However, the prospect of freedom from seizures and adverse effects remains elusive for a considerable number of patients with epilepsy despite concerted attempts by their physicians to utilize available pharmacotherapies to their full advantage. Approximately 25 to 30% of patients continue to suffer from seizures despite state-of-the-art treatment [3]. Epileptic syndromes that are in most cases resistant to therapy with conventional AEDs comprise, for example, Lennox–Gastaut syndrome, West syndrome, early myoclonic encephalopathy, myoclonic astatic seizures and severe myoclonic epilepsy in infancy [4]. The presence of bothersome side effects diminishes quality of life for many patients as well, suggesting the need for better tolerated AEDs.
It is well established that alterations in central inhibitory (e.g. γ-aminobutyric acid or GABA) and excitatory (e.g. glutamate) neurotransmission play a pivotal role in the etiology of epilepsy. It has been accepted that overstimulation of glutamatergic transmission and thereby activation of glutamate receptors may be of significant relevance for its clinical manifestations [5]. Among glutamate receptors, N-methyl-D-aspartate receptors (NMDARs) have been the focus of much basic and clinical research over the past two decades, producing an overwhelming body of evidence that blocking or suppressing NMDARs is effective in the prevention of and, in some cases, reversal of pathology in various models of neurological diseases, including epilepsy. The repertoire of NMDAR-targeted drugs in neurology is expected to grow in the near future. In this review we provide a brief overview of the rationale for the development of such drugs and then focus on NMDAR-targeted drugs currently used in the clinical setting and trials for the treatment of epilepsy as well as those evaluated in preclinical studies.
Section snippets
The NMDAR complex
Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) and acts on ionotropic and metabotropic glutamate receptors located at the presynaptic terminal and in the postsynaptic membrane at synapses in the brain and spinal cord. NMDARs are tetrameric structures of seven subunits including at least one copy of an obligatory subunit, NR1, and varying expression of a family of NR2 (NR2A-D) or NR3 (NR3A-B) subunits, with multiple binding sites including for glutamate,
NMDAR alteration in patients with epilepsy
Considering the fact that NMDAR activity plays a major role in neuronal excitation in the CNS, some investigators have evaluated the possible alterations of NMDARs in epilepsy, using a variety of methods such as assessment of subunit gene expression, immunoblotting, and binding affinities. Glutamatergic impulses from the entorhinal cortex constitute the major excitatory input to the hippocampus and a shift in glutamate-mediated excitability may be involved in the pathogenesis of epileptic
Overview of animal models of epilepsy
As summarized in Table 1, a wide variety of animal models of epilepsy and status epilepticus have been used to study potential anticonvulsants, including electrical stimulation models, chemoconvulsant-induced models (e.g. kainic acid (KA), pilocarpine, picrotoxin or bicuculline); physical models (e.g. hyperthermia, or photic or auditory stimulation), genetic models (e.g. mutant, transgenic or knockout) and spontaneous seizure models (e.g. post-kindling or post-chemoconvulsant). The maximal
Felbamate
Felbamate (Felbatol®) is a propanediol dicarbamate derivative (Fig. 2) which was synthesized in 1955 and submitted to the antiepileptic drug development program within the epilepsy branch of the National Institute of Neurological Disorders and Stroke in 1982 [45]. The mechanisms of action of felbamate have not been completely elucidated yet, though several have been suggested:
- (a)
Inhibition of voltage-sensitive Na+ or Ca2+ channels [46], [47].
- (b)
Potentiation of GABA-induced chloride currents [48],
Effects of conventional AEDs on NMDARs
Convergent evidence that NMDARs could be a valid target for developing novel targets for epilepsy also comes from reports indicating that a variety of AEDs of different classes (including carbamazepine, ethosuximide, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate and valproic acid) affect functioning and expression of NMDARs in different brain regions that are involved in several seizure types (Table 5). These results again support the hypothesis that combinations
A role for NMDARs in the bidirectional relationship between epilepsy and depression
Psychiatric comorbidities in epilepsy have been considered to reflect a “consequence or complication” [360]. Depression (along with anxiety) is one of the most frequent psychiatric comorbidities in epilepsy [361]. The prevalence of mood disorders in patients with epilepsy is 20–50%; the higher prevalence rates have been typically identified in patients with poorly controlled seizures [362]. Several studies have shown that lifetime risks of major depression in patients with chronic and
Adverse effects of NMDAR antagonists in clinical settings
Because glutamate is a major excitatory transmitter in the CNS, generalized inhibition of a glutamate receptor subtype such as the NMDAR causes adverse effects that could limit the potential for clinical applications. Therefore, while using NMDAR antagonists could be a potential therapeutic approach for controlling seizures, NMDAR antagonism is associated with an array of adverse effects. Both competitive NMDA and glycine antagonists, even although effective in preventing glutamate-mediated
Conclusion
During the last three decades, a large number of studies have indicated that the NMDAR complex is important in seizure phenomena, although more studies are clearly needed to demonstrate that pathology of NMDARs underlies epilepsy. Considering animal seizure models, NMDAR antagonists may be effective anticonvulsants. However, there is no compelling evidence to date that they are useful in the chronic treatment of human epilepsy. Some antagonists such as ketamine and magnesium sulfate should be
References (522)
Seizure disorders
Med Clin North Am
(2009)Currently available antiepileptic drugs
Neurotherapeutics
(2007)- et al.
Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations
Epilepsy Res
(1988) - et al.
Increased NMDA responses and dendritic degeneration in human epileptic hippocampal neurons in slices
Neurosci Lett
(1991) - et al.
NMDA receptor activation during epileptiform responses in the dentate gyrus of epileptic patients
Brain Res
(1991) - et al.
Upregulated expression of postsynaptic density-93 and N-methyl-D-aspartate receptors subunits 2B mRNA in temporal lobe tissue of epilepsy
Biochem Biophys Res Commun
(2007) - et al.
Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis
Lancet Neurol
(2011) - et al.
Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis
J Neuroimmunol
(2011) - et al.
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Lancet Neurol
(2008) Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs
Seizure
(2011)