The NMDA receptor complex as a therapeutic target in epilepsy: a review

Epilepsy & Behavior 22 (2011) 617–640

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Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h

Review

The NMDA receptor complex as a therapeutic target in epilepsy: a review Mehdi Ghasemi a,⁎, Steven C. Schachter b a b

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Departments of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA

a r t i c l e

i n f o

Article history: Received 13 April 2011 Revised 1 July 2011 Accepted 18 July 2011 Available online 4 November 2011 Keywords: Epilepsy Seizure NMDA receptor NMDA receptor antagonist

a b s t r a c t A substantial amount of research has shown that N-methyl-D-aspartate receptors (NMDARs) may play a key role in the pathophysiology of several neurological diseases, including epilepsy. Animal models of epilepsy and clinical studies demonstrate that NMDAR activity and expression can be altered in association with epilepsy and particularly in some specific seizure types. NMDAR antagonists have been shown to have antiepileptic effects in both clinical and preclinical studies. There is some evidence that conventional antiepileptic drugs may also affect NMDAR function. In this review, we describe the evidence for the involvement of NMDARs in the pathophysiology of epilepsy and provide an overview of NMDAR antagonists that have been investigated in clinical trials and animal models of epilepsy. © 2011 Elsevier Inc. All rights reserved.

1. 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-ofthe-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. γaminobutyric acid or GABA) and excitatory (e.g. glutamate) neuro-

⁎ Corresponding author. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. E-mail addresses: [email protected], [email protected] (M. Ghasemi), [email protected] (S.C. Schachter). 1525-5050/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2011.07.024

transmission 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. 2. 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 (NR2AD) or NR3 (NR3A-B) subunits, with multiple binding sites including for glutamate, polyamine, Mg2+, and glycine (Fig. 1). Pharmacological regulation of the NMDAR depends on effects on unique combinations of subunit-specific binding sites. Both the NR1 and NR2 subunits contribute to the formation of the NMDAR ion channel. The glutamate-binding site is on the NR2 subunits, and the glycine-binding site is located on the NR1 subunits. The glycine (and/or D-serine) coagonist site must be

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Fig. 1. NMDAR model showing binding sites for agonists and antagonists. The extracellular portions of NR1 and NR2 subunits consist of two domains, the modulatory domain and the agonist binding domain. Glycine and D-serine are agonists for NR1 subunits, whereas glutamate and NMDA act on the NR2 subunit agonistic site. Kynurenic acid is an endogenous ligand for NR1. Zn2+ is an endogenous ligand for NR2A and NR2B modulatory domains. Low concentrations (nanomolar) of Zn2+ have affinity for the NR2A subunit, whereas higher concentrations (micromolar) have affinity for the NR2B subunit. Zn2+ at higher concentrations can also act as an NMDAR pore blocker. Ifenprodil and its derivatives bind at the modulatory domain in an NR2B-selective manner. D-AP5 is an antagonist for the agonistic site of NR2 subunit. Mg2+, MK-801, ketamine, PCP, and memantine act as noncompetitive antagonists whose binding sites are within the ion channel pore region.

occupied before glutamate can activate the ion channel. Although NMDAR channels can conduct Na + and Ca 2+, under basal conditions the channel is blocked by Mg 2+ within the channel pore. The Mg 2+ blockade is relieved by cellular depolarization, which has implications for synaptic plasticity, especially long-term potentiation (LTP). Continuous strong stimulation optimally activates NMDARs and plays an important role in LTP. With neurotoxic insults, disruption of energy metabolism diminishes the driving force for the Na + pump that maintains the resting membrane potential of cells so that neurons become depolarized, relieving the Mg 2+ block of NMDARs. Excess Ca 2+ entry then leads to neuronal excitotoxicity and even cell death. Therefore, NMDAR-mediated responses contribute to the later components in paroxysmal depolarizing shifts and provide for much of the Ca 2+ entry associated with seizure discharges. 3. 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 discharges [6]. Moreover, NMDARs may be responsible for the seizure-induced selective excitotoxic cell death of certain hippocampal neuronal populations inasmuch as NMDAR antagonists provide protection against such damage [7]. Using non-radioactive situ hybridization methods, Bayer et al. in 1995 [8] demonstrated that in situ hippocampal specimens of patients with chronic temporal lobe epilepsy showed a loss of NR1-positive cells that was closely related to the overall neuronal

loss in the resected specimen and to Ammon's horn sclerosis. They suggested that loss of NR1 expression may partly reflect pyramidal cell loss [8]. Further investigation revealed that NR2 subunit mRNA levels were increased in the hippocampus of patients with hippocampal sclerosis (HS) [9]. In the dentate gyrus, there appears to be an increase in NR2 immunoreactivity that is associated with abnormal mossy fiber sprouting in this region [10]. Human hippocampal studies suggest that mossy fiber sprouting is associated with physiologically active NMDARs. It has been consistently demonstrated that inhibition of the glutamate binding site (NR2 subunit) decreases granule cell hyperexcitability in cases showing mossy fiber sprouting in hippocampi, whereas granule cells in non-sprouted hippocampi were not affected by such treatment [11–13]. Mathern et al. [10] demonstrated that, compared with autopsy hippocampi, non-HS and HS patients showed increased NR2A and NR2B hybridization densities per dentate granule cell. Non-HS hippocampi also showed increased NR1 and NR2B mRNA levels per CA2/3 pyramidal neuron compared with autopsy cases. Patients with HS, by contrast, showed decreased NR2A hybridization densities per CA2/3 pyramidal neuron compared with non-HS and autopsy cases. They concluded that chronic temporal lobe seizures are associated with differential changes in hippocampal NR1 and NR2A–D hybridization densities that vary by subfield and physio-pathological category. Therefore, in patients with temporal lobe epilepsy, these findings support the hypothesis that NMDARS are increased in dentate granule cells and further that excitatory postsynaptic potentials should be strongly NMDA-mediated compared with non-epilepsy autopsies [14,15]. Using human focal cortical dysplasia specimens obtained during epilepsy surgery, Crino et al. [16] reported that NR2B and NR2C subunit mRNA was increased, and NR2A subunit mRNA was decreased in dysplastic compared with pyramidal and heterotopic neurons (which were microdissected from postmortem control cortex and from temporal cortex without dysplasia

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resected during temporal lobectomy). These differential mRNA expressions of NMDAR subunits in dysplastic and heterotopic neurons demonstrate cell specific gene transcription changes in focal cortical dysplasia [16]. More recent studies [17,18] reported an upregulation of NR2B subunit composition and an altered Mg2+ sensitivity in pediatric cortical dysplasia or adult temporal lobe tissues. Some studies have also suggested a role for NMDARs in the genesis of seizures arising from cortical tubers in the tuberous sclerosis complex [19]. White et al. [19] demonstrated an increase in the level of NR2B and 2D subunit mRNAs and functional NR2B-containing receptors (using a ligand-binding method) in tubers. Enhanced expression of NR2B and 2C subunit mRNAs was noted in the dysplastic neurons, whereas only the NR2D mRNA was upregulated in giant cells, indicating that dysplastic neurons and giant cells make differential contributions to epileptogenesis in tuberous sclerosis complex [19]. Considering the results of previous studies, it seems that the type of epilepsy, its anatomical involvement and the underlying diseases that could be responsible for seizure development (such as tuberous sclerosis) could contribute to the variable alterations in different subunits of NMDARs (especially NR1 and NR2 subunits) in different brain regions. Although more investigation is needed to specify the role of each NMDAR subunit in pathophysiologic aspects of epilepsy, targeting specific NMDAR subunits may provide new insights into the control of seizures. For example, because the NR1 subunit is an obligatory subunit of NMDARs, inhibition of this subunit could cause a global inhibition of NMDAR within all areas of the CNS in which NMDARs are present, leading to significant adverse effects on brain function. Accordingly, in patients with antiNMDAR encephalitis, it has been suggested that autoantibodies against NMDARs cause a reversible reduction in NMDAR function on the cell surface of neurons [20–23]. Autoantibodies in the serum or cerebrospinal fluid (CSF) of these patients were also reported to bind specifically to an epitope located in the extracellular domain of NR1 subunits [24]. These patients initially present with a non-specific flulike prodrome followed by a psychosis (bizarre behavior, disorientation, hallucinations, paranoid thoughts, memory deficits and confusion). In the following stage, neurologic symptoms (e.g. decreased

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consciousness, lethargy and autonomic instability) are prominent and a considerable number of patients develop seizures and status epilepticus. These symptoms can be improved by immediate treatment with immunomodulatory therapy [23]. 4. NMDAR alteration in preclinical studies 4.1. 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 electroshock seizure (MES) test is predictive of activity against generalized tonic-clonic seizures (Table 2). The subcutaneous (s.c.) pentylenetetrazole (PTZ or metrazol) test is thought to be predictive of activity against nonconvulsive (absence or myoclonic) seizures [25]. However, some AEDs (e.g. levetiracetam) that protect against nonconvulsive seizures in patients failed in the s.c. PTZ test (for a review see [26]). Although these two acute animal seizure tests are suitable screening tools for the identification of potential anticonvulsant agents, they are not closely related to human epilepsy, but rather represent models for induction of single epileptic seizures. Moreover, the MES test can fail to identify drugs that are clinically effective in treating partial seizures (e.g. vigabatrin, tiagabine, and levetiracetam) or for identification of drugs for pharmacoresistant epilepsies (for a review see [27]). Chronic models of epilepsy can be divided into models of acquired (symptomatic) epilepsy and models of genetic (idiopathic) epilepsy (Table 2). The first category includes models in which epilepsy or epilepsy-like conditions are induced by electrical or chemical methods in previously healthy (non-epileptic) animals, mostly rats. Models with electrical induction of epilepsy or epilepsy-like conditions include the kindling model and models in

Cobalt-homocystine Lithium-pilocarpine Recurrent stimulation Brain slices Rodent hippocampal slices Isolated cell preparations Human neurosurgical tissue Injection into area tempesta KA Kindling Tetanus toxin

Simple partial (acute)

Bilateral cortical foci General rat models Y-Hydroxy-butyrate Intraventricular opiates Systemic penicillin Thalamic stimulation

Acute electrical stimulation GABA-withdrawal Neocortical brain slices Topical convulsants Anticholinergics Bicuculline Cholinergics Penicillin Picrotoxin Strychnine Other

Simple partial (chronic)

Generalized absence Status epilepticus

Chemical convulsants Bemegride Bicuculline Cocaine Methionine sulfoximide NMDA PTZ Picrotoxin Penicillin Other Genetic Audiogenic seizures in mice Drosophila shakers Genetically prone rats GAERS Mongolian gerbil Photosensitive baboons Totterer and El mice MES test Metabolic derangements Drug withdrawal Hyperbaric oxygen Hypercarbia Hyperthermia Hypoglycemia Hypoxia Uremia

Complex partial

Generalized tonic-clonic or clonic

Table 1 Preclinical animal studies in epilepsy research.

Cortically implanted metals Aluminum hydroxide Cobalt Iron Tungsten Zinc Cryogenic injury Ganglioside antibody injections Systemic focal epileptogenesis

Abbreviations: GAERS, Genetic Absence Epilepsy Rat from Strasbourg; KA, kainite; MES, maximal electroshock; PTZ, pentylenetetrazole.

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Table 2 Overview of acute and chronic models of epilepsy that are currently used widely in epilepsy research.

Acute Models of Seizures (Screening Tools) With electrical stimulation With chemical stimulation

Chronic Models of Epilepsy Models of acquired (symptomatic) epilepsy

With electrical stimulation

With chemical stimulation Models of genetic (idiopathic) epilepsy

Spontaneous mutations in diverse animal species Induced mutations in mice

Test

Related seizure type in humans

MES test in rodents PTZ test

Tonic–clonic seizures Absence Seizures

Kindling Post-status models in which epilepsy develops after an electrically induced status epilepticus Post-status models in which epilepsy develops after a chemically induced status epilepticus (e.g. pilocarpine and KA models of epilepsy) Mutant animals with “reflex epilepsy” (e.g. audiogenic seizuresusceptible rats and DBA/2 mice, photosensitive baboons, or E1 mice) Mutant animals with “spontaneous recurrent” seizures (e.g. GAERS) Transgenic or knock-out mice

Temporal lobe epilepsy (TLE) Status epilepticus Status epilepticus Generalized tonic–clonic seizures in response to sensory stimulation Generalized tonic–clonic seizures Generalized tonic–clonic seizures

Abbreviations: GAERS, Genetic Absence Epilepsy Rat from Strasbourg; KA, kainite; MES, maximal electroshock; PTZ, pentylenetetrazole.

which recurrent spontaneous seizures develop after a self-sustained status epilepticus (SSSE), which is elicited by sustained electrical stimulation of the hippocampus, the lateral or basolateral nucleus of the amygdala, or other limbic brain regions (for a review see [28,29]). The kindling, pilocarpine, and KA models are wellestablished animal models of limbic epileptogenesis. Post-status epilepsy models, in which SSSE is induced by sustained electrical stimulation of the hippocampus or amygdala, are characterized by neuropathological changes reminiscent of mesiotemporal sclerosis (as encountered in many patients with TLE), and recurrent spontaneous seizures develop after the status. SSSE can also be induced by chemical convulsants, such as pilocarpine and KA. Genetic animal models of epilepsy can be subdivided into animals with spontaneous mutations and animals, usually mice, with induced mutations. Models with spontaneous mutations can be further subdivided into two groups: (i) Mutant animals with “reflex epilepsy”. In this group, seizures are elicited by specific sensory stimulation. Audiogenic seizure-susceptible rats and DBA/2 mice, photosensitive baboons, or the E1 mouse (in which seizures are induced by vestibular stimulation) belong to this category; and (ii) animals with “spontaneous recurrent” seizures. For example, the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) has spontaneous spike-wave discharges. Mutant animals, such as transgenic or knockout mice, are rarely used for drug studies (Table 2). 4.2. NMDAR alteration in animal models Using several animal models of epilepsy, investigators have attempted to identify possible alterations in NMDARs. There are variable results among these studies which could be due to differences in the animal models, brain regions, and NMDAR subunits that were examined (Table 3). In 1993, Pratt et al. [30] reported that in partially kindled rats (10 stimulations), while the NR1 subunit mRNA remained unaltered after a period of 2 h, the NR2A and NR2B subunit mRNAs were bilaterally reduced in dentate gyrus granule cells. They also found that in fully kindled animals (40 stimulations), there was a progressive reduction in NR1 subunit mRNA levels in the dentate gyrus, being maximal after 4 h. At the same time point, NR2A and NR2B transcription levels were transiently increased [30]. When studied 28 d after the last evoked seizure, Kraus et al. [31] found that kindling induced a 2.8-fold increase in the number of binding sites for the competitive NMDAR antagonist 3-[(±)-2-(carboxypiperazin-4-yl)][1,2-3H-]propyl-1phosphonic acid ( 3H-CPP). This increase was confined to region CA3 within the hippocampus. However, transcription levels of the

NMDAR genes NR1, NR2A, NR2B, NR2C, and NR2D were not altered by kindling [31]. In another study, in situ hybridization revealed that in amygdaloid kindled rats, there was an increase in the NR2B and decrease in NR2D subunit mRNA levels in the neuroendocrine cells of the supraoptic nucleus one month after kindling, whereas NR1 and NR2C mRNA levels were not altered [32]. Jensen et al. [33] found that seizures result in a rapid significant increase in NR1 mRNA and protein expression in rat cerebral cortex. The NR1 subunit exists in several alternate splice isoforms. Transient reductions in specific isoforms and more sustained changes in splicing at the Cterminal have also been described [34,35]. Northern blots showed a sustained increase in cortical mRNA for NR1 in the amygdaloid kindled rat [36]. Using in situ hybridization histochemistry, GerfinMoser et al. [37] demonstrated that application of picrotoxin (500 μM) for two days led to decreases in the NR2A and NR2B mRNA levels in rat hippocampal slice cultures, whereas NR1 mRNA was not altered. Mathern et al. [38], using both kindled animals and self sustained limbic status epilepticus (SSLSE) rats, reported that the molecular layer of hippocampus in SSLSE rats with spontaneous seizures demonstrated higher levels of NR2A and NR2B immunoreactivity compared to kindled animals and controls. They suggested that hippocampal NR2A and NR2B mRNAs and proteins are differentially increased in association with spontaneous, but not kindled, seizures [38]. Another study indicated that hippocampal NR1 and NR2B mRNA levels change as rats progress from the latent to chronic seizure phase in the pilocarpine model of spontaneous limbic epilepsy and that NR1 subunit alterations correlated with mossy fiber sprouting [39]. In the KA-induced model of limbic seizures in rats, KA-induced seizures decrease NR1 mRNA levels in CA1 and CA3 pyramidal cells, but not dentate gyrus, at 24 and 72 h after drug injection [40]. Moreover, at 3 h after KA, an increase in binding of [ 3H]MK-801 in several apical dendritic fields of pyramidal cells is found [40]. However, pilocarpineinduced seizures cause a significant reduction in both CA1 pyramidal cells and dentate gyrus at 24 and 72 h, and CA3 at only 72 h after drug injection. The binding of [ 3H]MK-801 is not changed at 3 h after pilocarpine injection, whereas it is decreased in stratum lucidum at 3 and 24 h after drug injection [40]. These data point to some differences in hippocampal NMDAR regulation in the pilocarpine and KA models of limbic seizures. In DBA/2 mice, which are prone to audiogenic seizures, NR1 antisense administration resulted in short-term anticonvulsant protection; with the seizure response gradually returning to control levels 12 to 24 h following the termination of antisense administration [41]. Autoradiography ([ 3H]-MK 801 and -CGP 39653 binding) also revealed that NR1 subunit levels were significantly reduced in

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Table 3 Alteration in NMDAR subunit mRNA expression in animal models of epilepsy. NMDAR subunit

Animal model of epilepsy

Brain region

Results

Reference

NR1

Rapid partial hippocampal kindling in rats (10 stimulations) Rapid fully hippocampal kindling in rats (40 stimulations)

Granule cells of the dentate gyrus

[30]

Hippocampal kindling in rats Chronic ethanol exposure in rats Picrotoxin-induced epileptiform discharge Amygdaloid kindling in rats

CA3 pyramidal cells of hippocampus Cortex or hippocampus Rat hippocampal slice cultures (after 2 days) Supraoptic nucleus (after one month) Ipsilateral frontal and temporal cortices at 4 weeks after the last generalized seizure Bilateral piriform cortices at 4 weeks after the last generalized seizure Hippocampal dentate gyrus (after 24 and 72 h) Hippocampal CA1 and CA3 pyramidal cells (after 24 and 72 h) Hippocampal dentate gyrus, CA1 (after 24 and 72 h) and CA3 (only after 72 h) pyramidal cells Fascia dentate, CA1 and CA4 CA1

↔ ↓ Progressive ↔ ↔ ↔ ↔ ↑

Kainate-induced seizure (model of limbic seizures) in rats Pilocarpine model of limbic seizures in rats Pilocarpine model of spontaneous limbic epilepsy in rats

Latent phase (day 11) Early seizure phase (day 25) Chronic seizure phase Subiculum (day 85) Audiogenic seizures in albino Swiss mice acoustically primed at 10 days Central nucleus of the inferior colliculus NR2A

NR2B

Rapid partial hippocampal kindling in rats (10 stimulations) Rapid fully hippocampal kindling in rats (40 stimulations) Hippocampal kindling in rats Picrotoxin-induced epileptiform discharge Self sustained limbic status epilepticus rats Rapid partial hippocampal kindling in rats (10 stimulations) Rapid fully hippocampal kindling in rats (40 stimulations) Hippocampal kindling in rats Picrotoxin-induced epileptiform discharge Amygdaloid kindling in rats

NR2C

NR2D

Self sustained limbic status epilepticus in rats Pilocarpine model of spontaneous limbic Latent phase (day 11) epilepsy in rats Early seizure phase (day 25) Chronic seizure phase (day 85) Hippocampal kindling in rats Amygdaloid kindling in rats Audiogenic seizures in albino Swiss mice acoustically primed at 10 days Hippocampal kindling in rats Amygdaloid kindling in rats

the retrosplenial cortex and the overall cortex after NR1 antisense administration [41]. In albino Swiss mice acoustically primed at 10 days, some subsequently show audiogenic seizures at 20 days. These sound sensitive mice show a marked transient expression of NR2C in the central nucleus of the inferior colliculus (not seen in the non-sensitive mice) and a doubling of the expression of NR1 [42]. It was suggested that the audiogenic susceptibility may be related to the transient expression of the NR2C subunit during a brief neonatal period during which synaptic reorganization happens [42]. Pumain et al. [43] found that in the cortex of rats with absence type seizures, the response to NMDA appears to be enhanced. An evaluation of ethanol withdrawal seizures revealed that chronic ethanol administration results in increased levels of [ 3H]MK-801 recognition sites on NMDARs [44]. Because MK-801 labels all NMDARs, the change presumably involves the number of receptors, not only the recognition sites. However, NR1 subunit mRNAs were not altered following chronic ethanol exposure in rat cortex or hippocampus [44].

Granule cells of the hippocampal dentate gyrus CA3 pyramidal cells of hippocampus Rat hippocampal slice cultures (after 2 days) Molecular layer of hippocampus Granule cells of the hippocampal dentate gyrus

CA3 pyramidal cells of hippocampus Rat hippocampal slice cultures (after 2 days) Supraoptic nucleus and adjacent piriform cortex, lateral nucleus of the olfactory tract, anterior cortical amygdaloid nucleus and cortex–amygdala transition zone (after one month) Molecular layer of hippocampus Hippocampal fascia dentate Subiculum

↓ ↔ ↓ ↓

[40]

↑

[39]

↓ ↑ Transient ↓ ↑ Transient ↔ ↓ ↑ ↓ ↑ Transient ↔ ↓ ↑

[42]

↑ ↑

[38] [39]

Subiculum

↓

CA3 pyramidal cells of hippocampus Supraoptic nucleus (after one month) Central nucleus of the inferior colliculus

↔ ↔ ↑ Transient ↔ ↓

CA3 pyramidal cells of hippocampus Supraoptic nucleus (after one month)

[31] [44] [37] [32] [36]

[30] [31] [37] [38] [30]

[31] [37] [32]

[31] [32] [42] [31] [32]

5. NMDAR modulators for control of seizures 5.1. 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 Ca 2+ channels [46,47]. (b) Potentiation of GABA-induced chloride currents [48], although the direct effect on GABA receptors is unclear [49,50]. (c) Inhibition of the NMDAR. However, the exact site of action is still unclear. Some researchers reported that felbamate binds to the strychnine-insensitive glycine site [51–53]. Others have suggested that felbamate binds to a site within the NMDAR channel

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Gastaut syndrome in children [60,61], a seizure disorder characterized by multiple seizure types (i.e. atypical absence and atonic seizures), slow spike-wave electroencephalographic patterns and mental retardation. Felbamate-treated patients with Lennox–Gastaut syndrome were reported to have a robust decrease in the frequency of atonic seizures (drop attacks) and total seizures compared to placebo groups [61]. Currently, felbamate is not used as a first-line AED and generally is used only for patients with intractable partial seizures, infantile spasms, or Lennox–Gastaut syndrome [62–65]. Two rare but serious adverse effects related to felbamate, aplastic anemia and hepatotoxicity, have limited the use of this AED to patients for whom the potential benefits outweigh the risks. 5.2. Magnesium sulfate

Fig. 2. Chemical structure of some common NMDAR antagonists.

pore and acts as an open channel blocker [48]. There is also evidence that felbamate is a non-competitive, allosteric inhibitor with some modest selectivity for NR2B-containing receptors that might also be associated with the channel pore [54,55]. Felbamate was approved by the U.S. Food and Drug Administration (FDA) in 1993 [56–59]. Felbamate has also been studied in Lennox–

Clinical observations in patients [66–68] and experimental investigations in animals [69] have shown that magnesium (Mg 2+) depletion leads to a marked irritability of the nervous system, eventually resulting in seizures or increased susceptibility to seizureinducing stimuli [70,71]. The possibility that convulsions may occur in the setting of Mg 2+ deficiency led some investigators to study the metabolism of this metal in the epilepsies, and a trend towards low blood concentrations was usually found [72,73]. For example, Mg 2+ levels in serum and CSF were significantly lower in patients with tonic-clonic seizures than in controls [74–76]. Serum and CSF Mg 2+ levels fell with increasing duration of epilepsy and frequency of seizures. Within the brain, Mg 2+ preferentially accumulates within the cortex and hippocampus [77]. Magnesium sulfate enters the cerebrospinal fluid and brain after systemic administration [77]. A rise in brain Mg 2+ concentration is associated with an elevation of the seizure threshold and a marked resistance in animal models to electrically- as well as NMDA-stimulated hippocampal seizures [77]. Seizure activity facilitates blood-brain barrier penetration, leading to elevated magnesium concentrations in the cerebrospinal fluid after systemic injection [78]. Hallak et al. in 1994 [79] provided autoradiographic binding data indicating that Mg 2+ exerts its central action (beside other proposed mechanisms) through an inhibition of the NMDAR. Further experiments demonstrated that Mg 2+ blocks Ca 2+ within the NMDAR channel. When the Mg 2+ blockade is relieved by cellular depolarization, the channel is unblocked and Ca 2+ and Na + enter the postsynaptic neuron as potassium exits [80]. Systemic administration of Mg 2+ exerts an anticonvulsant effect in cats and dogs with experimentally-induced epileptic foci [81], and in models of status epilepticus [82], audiogenic and PTZ-induced clonic seizures [83–85], and NMDA-induced hippocampal seizures [86] in rodents. In humans, parenterally administered Mg 2+ is an effective treatment for the seizures of neonatal tetany [87] and eclampsia [88] and possibly for those associated with ethanol withdrawal and acute intermittent porphyria [89,90]. In spite of its effectiveness in controlling hyperexcitability and seizures associated with toxemia of pregnancy, there is still controversy over magnesium's merits as an anticonvulsant [91,92]. Nonetheless, studies have reported that Mg 2+ could be beneficial to augment the therapeutic effects of adrenocorticotropic hormone on infantile spasms (or West syndrome) [93], which is characterized by early onset (4–7 months), unusual seizure forms (repetitive flexor, extensor or flexor–extensor spasms), EEG hypsarrhythmia, and poor seizure and intellectual prognosis [94]. A recent study also reported that intravenous Mg 2+ therapy improved refractory epilepsy with recurrent status epilepticus and episodes of epilepsia partialis continua in two patients with juvenile-onset Alpers' syndrome [95]. Still, however, there are concerns regarding the possibility of hypermagnesemia toxicity in eclampsia treatment. Total magnesium serum concentrations advocated for the treatment of eclamptic convulsions are 3.5 to 7 mEq/L (4.2 to 8.4 mg/dL) [96,97]. Areflexia, particularly loss of the patellar deep tendon reflex, has been observed

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at 8 to 10 mEq/L, and respiratory paralysis occurs at N13 mEq/L [98]. Progressively higher serum magnesium levels can ultimately lead to cardiac arrest [99].

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The adverse reactions associated with remacemide include dizziness, somnolence and gastrointestinal symptoms when given as monotherapy. Adjunctive therapy with the conventional AEDs carbamazepine and/or phenytoin might result in diplopia and fatigue [116].

5.3. Remacemide 5.4. ADCI Remacemide hydrochloride [(±)-2-amino-N-(1-methyl-1,2diphenylethyl)-acetamide monohydrate] is a racemate (Fig. 2). Biotransformation of remacemide yields its desglycinated bioactive metabolite, APL 12495AA, which is about 2-fold more potent than remacemide itself. The two enantiomers of remacemide and those of APL12495AA have been tested for their anticonvulsant properties and their potencies were different depending on the route of administration and type of seizure test [100,101]. Receptor-binding studies have shown that both remacemide hydrochloride and APL 12495AA displace [ 3H]MK-801 binding from the synaptic membrane fractions of rat cerebral cortex and hippocampus [102]. Another binding study using [ 3H]desglycinylremacemide demonstrated a binding site within the NMDAR ion channel, which is thought to be associated with the benzomorphan attachment site of the NMDAR [103]. The density of binding sites for [ 3H]desglycinylremacemide was about 2-fold higher in the brainstem and cerebral cortex than in the hippocampus and cerebellum [103]. Electrophysiological studies have shown that both remacemide and APL 12495AA inhibit NMDA-induced responses in a variety of preparations such as cultured rat hippocampal neurons [104] and cortical wedges prepared from audiogenic seizure-prone DBA/2 mice [105]. Besides acting on NMDARs, both remacemide and its metabolite have been reported to be potent Na + fast-channel blockers [106,107]. It is likely that synergism between these two actions occur. Additionally, because of the relatively low affinity of remacemide and its metabolite to the NMDAR complex, the anticonvulsant effects of these agents may be due to their effects on Na + channels. A possible partial blockade of potassium channels has also been proposed [106]. Remacemide pretreatment decreased pyramidal cell damage in the CA3 and CA1 subregions of the hippocampus in a rat model of status epilepticus [108]. Remacemide and APL 12495AA have anticonvulsant actions in a number of animal models including the MES test [101,109,110]; NMDA, kainic acid, electrical kindling and 4aminopyridine-induced seizures [101,111]; cocaine-induced convulsions [112]; spike-and-wave discharges in the WAG/Rij rat; and in the GAERS rat; (which constitutes a genetic model of absence epilepsy) [113,114]. However, remacemide did not protect against bicorneal kindled seizures and those induced by PTZ, bicuculline, picrotoxin, and strychnine [101,109,110] or by acute heat stress [115]. Remacemide was also investigated as adjunctive therapy in several clinical studies of patients with drug-resistant seizures. In a doubleblind, placebo-controlled, cross-over study with remacemide hydrochloride in 28 patients with drug-resistant seizures, one-third showed a reduction in seizure frequency by 50% or more and four patients were free of seizures during remacemide treatment [116]. In an open study, Owen et al. [117] reported significant improvement. Another placebo-controlled add-on trial in adult patients with drug-resistant seizures demonstrated the percentage of responders (defined as 50% or greater reduction in seizure frequency) was significantly higher in remacemide-treated patients when compared with placebo [118]. Adjunctive remacemide treatment was similarly shown to be associated with a higher, dose-related responder rate than that observed in placebo-administered patients [119]. Another study also suggested that remacemide exhibited therapeutic activity as monotherapy in patients with drug-resistant seizures following presurgical assessment [120]. However, there is evidence that remacemide had no benefit in patients with newly diagnosed epilepsy compared to other AEDs such as carbamazepine [121], putting into question the efficacy of remacemide as monotherapy.

ADCI [(±)-5-aminocarbonyl-10,11-dihydro-5Hdibenzo[a,d]cyclohepten-5,10-imine] possesses features of carbamazepine and MK-801 [116,122] (Fig. 2). The compound is a selective, low-affinity channel blocker of the NMDAR. Sun and Lin [123] reported that ADCI could also block voltage-gated sodium channels in rat superior cervical ganglion and hippocampal neurons as well as cultured human NT2 neurons. Preclinical studies revealed the ADCI has an anticonvulsant effect in the MES test [122], as well as against 4-aminopyridine-, NMDA-, PTZ- and cocaine-induced seizures [122,124,125]; dendrotoxin-induced clonic seizures [126]; and ethanol withdrawal seizures in mice [127]. ADCI possesses an improved toxicity profile, which may be caused by its greater tendency to block NR1A/NR2B subunits (IC50 = 6.6 μM) than NR1A/NR2A subunits (IC50 = 14.3 μM) [116]. 5.5. Ketamine Ketamine hydrochloride (dl2-(o-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride or Ketalar®) was developed in 1962 (Fig. 2). Ketamine is primarily used for the induction and maintenance of general anesthesia, usually in combination with sedative drugs. The ketamine-induced anesthetic state is believed to result from functional disorganization of the CNS rather than CNS depression [128]. Ketamine has a low affinity for the NMDAR at the phencyclidine site within the ionotropic channel [129,130], with slow open-channel blocking/ unblocking kinetics, and a specific type of channel closure, called “trapping block” [131]. As early as 1965, McCarthy et al. [132] demonstrated in laboratory animals that ketamine is capable of suppressing convulsions induced by electrical stimuli as well as those induced by intravenous infusion of CNS stimulants such as PTZ or caffeine. Since then, many studies reported that ketamine exerted anticonvulsant effects in a variety of animal models of epilepsy including NMDA-, guanidinosuccinate-, p-toluidino-3-propylamino-2-propanol-, mercaptopropionate-, N-(3,5-dimethoxy-4-propoxyphenylethyl)aziridine-, lidocaine-, picrotoxin-, bicuculline-, strychnine- or PTZinduced seizures in rodents [133–148]; young chick model of epilepsy [149]; sound-induced convulsions in epilepsy prone rats [150,151]; seizures kindled by repetitive electrical stimulation of the rat motor cortex [152]; kindled amygdaloid seizures in rats [153] and kindling epileptogenesis and seizure expression in developing rats [154]; soundinduced seizures in DBA/2 mice [155]; generalized tonic–clonic seizures induced by metrazol in rats [156]; morphine-induced hind-limb myoclonic seizures [157]; limbic status epilepticus induced by 90 min continuous electrical stimulation of the hippocampus [158]; prolonged status epilepticus in rats and dogs [159,160] and pilocarpine-induced status epilepticus in rats [161]; rat model of partial status epilepticus [162]; electrically precipitated tonic hind-limb extension [163]; MES test in mice [164,165]; and the lithium–pilocarpine seizure model in rats [166]. Infusions of ketamine into the substantia nigra pars reticulata of adult rats also increase the latency of onset to seizures induced by ether flurothyl [167]. Ketamine can act synergistically with AEDs such as valproate and carbamazepine to decrease MES-induced seizures in mice [168]. Other studies demonstrated the synergistic action of diazepam and ketamine in terminating status epilepticus induced by either lithium-pilocarpine [169] or kainic acid [170]. In a model of fulminant seizures and seizure-related brain damage induced by soman poison in guinea pigs, sub-anesthetic doses of ketamine (10 mg/kg)

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prevented lethality and stopped ongoing seizures in poisoned animals and proved effective in reducing seizure-related brain damage and in increasing survival [171]. Further investigation also revealed that ketamine, either racemic or active ketamine isomer (S(+)-ketamine), in association with atropine sulfate, was highly effective in the delayed treatment of severe soman intoxication [172]. Ketamine consistently suppressed focal seizures arising from neocortical and hippocampal epileptogenic foci in cats but was ineffective in modifying interictal epileptogenic activity both at the primary and mirror focus [173]. In doses producing narcoticcataleptic effects (50–100 mg/kg, i.p.), it reduced the intensity of picrotoxin convulsions and prevented seizures caused by metrazol administration [174]. Bath application of ketamine blocked penicillininduced, synchronized afterdischarges in immature rat CA3 hippocampal neurons and depressed intracellular depolarizations produced by iontophoretic application of NMDA [175]. Ketamine decreased epileptiform activity in both CA1 and CA3 regions of the rat hippocampus [176,177]. Cunha et al. [178] demonstrated that poststatus epilepticus rats exhibited extensive gliosis and cell loss in the hippocampal CA1, CA3 (70% cell loss for both areas) and dentate gyrus (60%) and that ketamine reduced cell loss in the hippocampus [178]. Other studies revealed that ketamine blocked epileptiform activity induced by alkalosis in rat neocortical slices [179], decreased 4aminopyridine- or picrotoxin- or “magnesium free”-induced epileptogenic activity in hippocampal slices of rats [180,181], attenuated epileptogenic responses in a synaptic and a non-synaptic model of epileptogenesis in the CA1 region of the hippocampal slice [182], and had anticonvulsant effects on different patterns of epileptiform activity in rat temporal cortex slices [183]. Cortical epileptiform afterdischarges (spike-and-wave rhythms) induced by low-frequency stimulation of the sensorimotor cortex were dose-dependently shortened by ketamine [184]. Degeneration of thalamic neurons caused by persistent seizure activity in the corticothalamic tract (putative glutamergic transmitter pathway) was prevented by systemic administration of ketamine or MK-801, despite the failure of these agents to eliminate persistent electrographic seizure activity recorded from cortex and thalamus [185]. Ketamine as well as other NMDAR antagonists (MK-801 and phencyclidine) were also reported to protect against kainic acid-induced seizure-related rat brain damage [186]. A clinical study reported a 23-year-old man whose refractory status epilepticus was refractory to standard AEDs and barbiturates, and was successfully terminated only with intravenous ketamine [187]. Although the above mentioned preclinical and anecdotal clinical evidence suggests a robust anticonvulsant effect of ketamine, other studies showed contrary results. Prior studies by Winters et al. in 1972 [188] reported bursts of hippocampal seizure activity without overt behavioral manifestations in cats receiving single cataleptic doses of ketamine. In addition, Miyasaka and Domino in 1968 [189] and Winters et al. [188] demonstrated a progression of EEG changes in both the mesodiencephalon and cortex which were characterized by initial desynchronization, and then intermittent hypersynchrony (low frequency, high amplitude waves) followed by continuous hypersynchrony. Abnormal spike and hypersynchronous bursting activity was also observed during the course of chronic ketamine (30 or 80 mg/kg/day, i.p.) administration in 50% of rats [190]. Further, withdrawal of the drug for 5 days following three months of treatment resulted in the progressive increase of epileptiform activity without gross behavioral manifestations in rats [190]. Subsequent studies [191] concerned with the ketamine-induced alterations of the EEG in human volunteers showed that, under ketamine anesthesia, the EEG changed from an α rhythm to predominantly θ-wave activity, coincidentally with the loss of consciousness and establishment of “dissociative” anesthesia. Kayama and Iwanae [192] studied, also in cats, the effect of ketamine on spontaneous neocortical EEG patterns, cortical evoked potentials, and cortical single-unit activity. They interpreted

their findings as suggesting drug-induced seizure discharges, and went on to propose that the loss of consciousness in ketamine anesthesia is produced in the same manner as absence seizures interfere with consciousness. Ketamine was shown to exacerbate penicillin-induced generalized corticoreticular epilepsy in cats [193] and to increase seizure duration following electrical stimulation in a rat model of electroconvulsive therapy [194]. Observing the activation of primary and projected cortical foci by ketamine at anesthetic and non-anesthetic doses, DeVore et al. [195] speculated that ketamine is epileptogenic in certain patients with a seizure disorder. Thompson in 1972 [196] reported generalized tonic-clonic seizures in a 26-year-old woman with no past neurological history that began 2 min after an induction dose of 130 mg ketamine (i.v.) given for an elective abortion. Another study by Hirshman et al. in 1982 reported the occurrence of extensor-type seizures in 4 asthmatic patients receiving theophylline within minutes following induction of anesthesia with ketamine [197]. Another study [198] in patients who had depth electrodes implanted in the limbic and temporal regions reported that ketamine (2–4 mg/kg, i.v.) led to pronounced abnormal activity in these brain regions that progressed to electrographic seizures in some of the patients. However, Corssen et al. [199] found no evidence that ketamine (1 mg/lb. body weight, i.v.) precipitated generalized convulsions, even in patients with epilepsy and an abnormal EEG, but, on the contrary, they observed that ketamine suppressed or virtually eliminated epileptiform EEG discharges during clinical seizures. Celesia showed that ketamine neither precipitated nor aggravated seizures and was less effective than natural sleep as an activator of epileptic discharges in patients with epilepsy [200]. The anticonvulsant activity of the drug was also observed in 1968 [201]. The benefit of ketamine in severe febrile convulsions was reported by Davis and Tolstoshev in 1976 [202]. Sheth and Gidal [203] described a 13-year-old girl with seizures refractory to standard status epilepticus protocols, alternative therapeutic strategies, and 4 weeks of pentobarbital coma who achieved control of both clinical and electrographic seizures after the administration of ketamine (2 mg/kg bolus; continuous infusion to a maximum rate of 7.5 mg/kg/h for 14 days). Oral ketamine, administered to five children with severe epilepsy (Lennox–Gastaut syndrome, myoclonic-astatic epilepsy, progressive myoclonic epilepsy and pseudo-Lennox syndrome) during an episode of non-convulsive status epilepticus (NCSE) led to the resolution of NCSE in all cases clinically and electroencephalographically within 24–48 h of starting ketamine [204]. A retrospective series of 6 fatal cases of refractory status epilepticus treated with ketamine suggested some modest efficacy, although there was no mention of the dose regimen used or duration of therapy [205]. A series of seven patients treated with ketamine for refractory status epilepticus reported control of electrographic seizures in four patients on 0.3–5.8 mg/kg/h infusion [206]. Ubogu et al. [207] reported that ketamine infusion following low-dose propofol sedation in a 44-year-old man with treated neurosyphilis presenting with subclinical refractory status epilepticus resulted in the gradual control of electrographic seizures over 72 h. However, they noticed diffuse cerebellar and worsened cerebral atrophy 3 months later, consistent with animal models of NMDAR antagonist-mediated neurotoxicity [207]. A recent study reported the development of refractory status epilepticus in a 22-year-old woman with mitochondriopathy and preexisting epilepsy which was treated with administration of continuous ketamine infusion in addition to midazolam [208]. Based on these clinical observations, ketamine may be useful in controlling malignant status epilepticus. However, the response to ketamine and further characterization of adverse effects in patients need further study. 5.6. Amantadine Amantadine (1-aminoadamantane) was the first member of a class of organic molecules called aminoadamantanes to be introduced into

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clinical use. It was originally licensed to treat influenza A infections [209], and later parkinsonism [210]. Amantadine appears to act through several pharmacological mechanisms. In the early 1990s, it was shown that amantadine could block NMDARs [211,212]. Subsequent studies revealed that when bound in the channel of NMDARs, amantadine increases the rate of channel closure. As a result, the predominant inhibitory mechanism of amantadine is not blockade of current flow through open channels but rather increasing occupancy of channel closed states [213]. In the 1970s, it was reported that amantadine increased seizure susceptibility in the maximal electroshock test (MES) and PTZ-induced seizures in mice [214–216]. Amantadine (25 and 100 mg/kg) decreased the anticonvulsant effect of diphenylhydantoin in the MES [217] and inhibited the anticonvulsant effects of serotonin (5-hydroxytryptamine or 5-HT) on PTZinduced convulsions in mice at 100 mg/kg [214]. At that time, these effects were explained by its possible actions on the central dopaminergic system. However, Kleinrok et al. [218] demonstrated that although amantadine (up to 100 mg/kg) did not affect PTZinduced convulsions in mice, combined treatment of the GABAergic agonist baclofen (5 mg/kg) and amantadine (100 mg/kg) significantly decreased the number of animals with tonic seizures induced by PTZ. Subsequent studies demonstrated that amantadine had anticonvulsant properties against MES and PTZ-induced tonic convulsions and NMDA-induced lethality in mice [125,147]. Reis et al. [219] showed that oral amantadine intake (50 and 100 mg/kg) decreased human motor cortex excitability in healthy subjects. They suggested that the NMDAR antagonism was the most relevant effect on cortical excitability [219]. Rohrbacher et al. [220] found that amantadine (100 μM) decreased the synaptic excitation intrastriatally evoked in rat neostriatal slices. High doses of amantadine at 200 mg/kg were reported to induce convulsions in mice [221]. Twelve- to 16-week treatment with amantadine in 10 children with medically refractory seizures resulted in an improvement in control of myoclonic or atypical absence seizures without alteration (or even worsening) in tonic–clonic and atonic seizures. Tonic seizures were controlled in one patient, but worsened in another [222]. Another study of 10 adolescents and adults with drug-resistant generalized tonic–clonic, myoclonic, or absence seizures showed that adding amantadine to existing AED regimens in weekly increments to 400 mg/day reduced myoclonic or absence seizures in 4 patients, whereas it worsened tonic–clonic seizures in 3 patients [223]. Shahar and Brand [224], reported that add-on amantadine to four children with refractory absence epilepsy resulted in complete resolution of absence seizures within 1 week. All patients remained free of symptoms for 27 to 36 months without adverse effects related to this drug. An attempt to discontinue the medication in three children resulted in a prompt relapse [224]. Matsushige et al. [225] similarly reported a girl with refractory childhood absence epilepsy who improved with add-on amantadine therapy. These reports indicate that amantadine may be beneficial for refractory absence seizures, especially in children. However, it should be noted that high doses of amantadine could induce seizures in patients [226], consistent with animal studies [221].

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effects in MES-induced seizures with an ED50 of around 5–10 mg/kg [147,227,229–231]; tonic (but not clonic) seizures in mice induced by PTZ, bicuculline, picrotoxin, 3-mercaptopropionic acid and NMDA with an ED50 of 7–12 mg/kg [125,147,232–236]; cocaine-induced convulsions in mice [237]; ethanol withdrawal-associated audiogenic seizures in rats at 5 and 10 mg/kg [238]; soman-induced seizures in rats at 18 mg/kg [239–241]; electrically precipitated tonic hind-limb extension in mice [163]; and audiogenic convulsions in Krushinskii– Molodkina strain rats at 5 and 10 mg/kg [242,243]. Memantine was also shown to augment the anticonvulsant effects of AEDs such as valproate in the MES test [229]. Memantine depressed the spontaneous absence-like paroxysms in the cortical EEG of rats (5–10 mg/kg) [244], the synaptic excitation intrastriatally evoked in rat neostriatal slices [220], and NMDA- or Mg 2+ free-induced epileptiform activity in area CA1 of guinea pig hippocampal slices [245]. It significantly protected hippocampal and cortical neurons in culture against glutamate and NMDA excitotoxicity [240]. Memantine was also reported to protect against diisopropylphosphorofluoridate (an organophosphate compound)-induced seizures and dendritic degeneration of pyramidal neurons in the CA1 hippocampal area in rats [246]. However, Wang and Bausch in 2004 [247] showed that hippocampal cultures chronically treated with memantine showed increased mossy fiber axons, fewer granule cell layer neurons and slightly increased electrographic seizures. Another study revealed that acute memantine (20 mg/kg) significantly retarded the progression of the dystonic attack in a mutant hamster model of paroxysmal dystonia [248]. Although memantine was ineffective against amygdala kindling in rats when given alone (5–10 mg/kg) [249,250], co-administration of memantine with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [251] receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7sulfamoylbenzo[f]quinoxaline) had a supra-additive anticonvulsant effect in the kindling model of epilepsy [249]. The favorable sideeffect profile of memantine and the promising results when used together with NBQX suggest that memantine should be further studied for the treatment of epilepsy, possibly in combination with AMPA receptor blockers. Accordingly, Gmiro and Serdyuk [252] have recently reported that although memantine alone decreased the incidence of PTZ-induced generalized tonic–clonic seizures in rats by 4-fold, IEM-1913 (combined blockade of NMDA and AMPA receptors in the brain) decreased PTZ-induced clonic and tonic– clonic seizures in rats by 4- to 8-fold. The therapeutic index of IEM1913 surpassed that of memantine by 200- to 600-fold [252]. However, it is noteworthy that some studies have reported that memantine may cause seizures in patients. For instance, Peltz et al. [253] reported that a 72-year-old Caucasian woman, taking memantine for Alzheimer's disease, was admitted to the hospital with new-onset, generalized tonic–clonic seizures. After memantine was discontinued, the disturbance resolved and increased Δ waves on the patient's EEG were improved. They suggested that the newonset seizures were associated with memantine treatment [253]. The clinical data regarding the anticonvulsant effects of memantine are scarce and more investigations are clearly needed to verify whether memantine can be used as an AED for some seizure types in patients with epilepsy.

5.7. Memantine 5.8. Dextromethorphan Memantine (1-amino-3, 5-dimethyl-adamantane) is a low-affinity, noncompetitive, open-channel NMDAR antagonist that enters the receptor channel preferentially when it is excessively open, and blocks the NMDAR-associated ion channel similar to Mg 2+ by binding to or near the Mg 2+ binding site. Indeed, memantine is able to inhibit the prolonged influx of Ca 2+ ions, which forms the basis of neuronal excitotoxicity. Preliminary preclinical results in the early 1980s suggested that memantine could be beneficial as an anticonvulsant drug alone or in combination with other AEDs [227,228]. Subsequent preclinical studies revealed that memantine exerted anticonvulsant

The FDA approved dextromethorphan as an over-the-counter antitussive in 1958. Its mechanism of action is via multiple effects, including actions as a nonselective serotonin reuptake inhibitor and a sigma-1 receptor agonist [254]. Dextromethorphan can also act as a noncompetitive NMDAR antagonist; however, its metabolite (dextrorphan) is more potent than dextromethorphan in blocking the NMDAR (Fig. 2). At high doses, the pharmacology of dextromethorphan is similar to that of the controlled substances phencyclidine and ketamine, which also antagonize the NMDAR. A double-blind, crossover,

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add-on study in 9 patients with severe drug-resistant complex partial seizures reported that seizure frequency increased 25% among patients randomized to the dextromethorphan (120 mg/day) arm of the study, although this increase was not clinically significant [255]. However, in a study by Schmitt et al. [256], high doses of dextromethorphan (20–42 mg/kg/day) were given to four critically ill children with drugresistant seizures and frequent epileptiform EEG abnormalities. Treatment with dextromethorphan was started between 48 h and 14 days after onset of the illness. In three patients, the EEG improved considerably within 48 h and seizures ceased within 72 h [256]. Another study also demonstrated that adding dextromethorphan to existing AEDs at doses of 40 and 50 mg every 6 h (160 and 200 mg/day) caused a significant improvement in seizure control in sixteen patients with drug-resistant, localization-related epilepsies after 8 weeks. There were mild and transient adverse effects that were well tolerated [257]. Kazis et al. [258] showed that dextromethorphan given in doses up to 50 mg/6 h can produce plasma and brain concentrations similar to the in vitro anticonvulsant levels, without causing significant adverse effects. Dextromethorphan has anticonvulsant properties in several animal models of epilepsy including amygdaloid kindled convulsions in rats [259]; audiogenic seizures in DBA/2 mice and genetically epilepsy-prone rats [151,155]; MES in mice and rats [147,260,261]; NMDA-induced convulsions and lethality in mice [148,262,263]; PTZinduced clonic seizures in mice [147,260]; seizures induced by cocaine, lidocaine, theophylline, kainate and the calcium channel agonist BAY k-8644 in mice and rats [264–266]; ethanol withdrawal seizures in rats [267]; and soman-induced convulsions and electrographic seizure activity in guinea pigs [268]. Dextromethorphan also prevents the adverse effects of neonatal hypoxia on PTZ-induced seizure threshold in rats [269]. By contrast, dextromethorphan has limited anticonvulsant activity against morphine-induced hindlimb myoclonic seizures in mice [157]. 5.9. Riluzole Riluzole (2-amino-6-trifluoromethoxy benzothiazole) was originally synthesized by researchers in France and early studies in the 1980s suggested it had anticonvulsant properties [270]. The discovery that it can disrupt glutamate neurotransmission to prevent NMDARmediated neuronal death in experimental models [271] promoted its further development. Several mechanisms regarding the glutamatergic neurotransmission have been proposed. First, it inhibits Na + channels on glutamate-containing neurons and thereby selectively reduces presynaptic release of glutamate [272]. Second, riluzole might block NMDAR activation, preventing Ca 2+ entry via the channel. Riluzole either acts directly on the NMDAR, although a binding site for riluzole on the receptor has not been identified [273]; or indirectly, possibly via a G-protein-dependent signaling pathway [274]. Third, riluzole facilitates glutamate reuptake by increasing the activity of glutamate transporters expressed on neurons and glia [275], suggesting a modulatory action on glutamate clearance from the synaptic cleft. Preclinical data have shown that riluzole has anticonvulsant properties in a variety of seizure models such as the MES test in rodents; seizures induced by inhibitors of the synthesis of GABA; ouabain, pilocarpine, L-glutamate and kainite in rodents; seizures induced by photic stimulation in the baboon, Papio papio; sound stimuli in DBA/2 mice; postural seizures in E1 mice; seizures in WAG/Rij rats (an animal model of human absence epilepsy); kindled seizures and the development of behavioral seizures in kindling acquisition with relatively mild correlation to afterdischarge duration; and pilocarpine-induced limbic seizures, γ-hydroxybutyrate lactoneinduced absence seizures, and ethanol withdrawal-induced convulsions in mice [270,276–281]. Riluzole has been shown to augment the anticonvulsant effects of conventional AEDs such as carbamazepine, phenobarbital, valproate and diphenylhydantoin in the MES test in

mice [279], and valproate, phenobarbital, or ethosuximide in PTZinduced seizures in mice [282]. Riluzole is the only FDA-approved medication for amyotrophic lateral sclerosis. However, its benefit in controlling seizures in patients with epilepsy has not been shown in any clinical study and this issue warrants further investigation. 5.10. Cycloserine Cycloserine (4-amino-isoxazolidin-3) was historically one of the antituberculosis agents most significantly associated with CNS toxicity. Cycloserine crossreacts with the glycine site at the NMDAR and at maximally stimulating doses produces approximately half of the maximal facilitation of NMDAR function [283–285]. Under conditions where the occupancy of glycine binding sites by agonists was greater than 50%, glycine binding antagonist-like effects emerged [286]. This antagonist-like effect of cycloserine was reflected in an increase in the off-rate for glutamate from the NMDAR [287]. A number of preclinical studies have shown that cycloserine has anticonvulsant properties in tests such as sound-induced epilepsy in DBA/2J epileptic mice; seizures induced by strychnine, metrazol, isonicotinic acid hydrazide, 3-mercaptopropionic acid, cocaine, kainate and NMDA; tonic convulsions induced by 120 mg/kg of PTZ; and focal seizures in amygdala-kindled rats [233,288–301]. DCycloserine in subprotective doses (2.5 and 10 mg/kg) was also shown to potentiate the anticonvulsant action of phenytoin and carbamazepine in the MES test in mice [300]. D-Cycloserine (2.5 mg/kg) also potentiates the anticonvulsant activity of carbamazepine, diazepam, felbamate, lamotrigine, phenytoin, phenobarbital and valproate against sound-induced seizures in DBA/2 mice [302]. Despite the accumulating evidence regarding the anticonvulsant effects of cycloserine in animal studies, some clinical evidence has suggested that cycloserine, especially in patients with tuberculosis, could have adverse effects including exacerbation of psychiatric conditions as well as seizures [303]. Therefore it is generally not used in patients with convulsions and psychiatric states characterized by signification agitation [303]. 5.11. Dizocilpine Dizocilpine or MK-801 {(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate} is a potent noncompetitive NMDAR antagonist. MK-801 binds inside the ion channel of the receptor at the phencyclidine binding site and thus prevents the flow of ions, including an influx of Ca 2+, through the channel. A large number of preclinical investigations demonstrated anticonvulsant properties in several models including seizures induced by NMDA, quinolinic acid, lindane, 4-aminopyridine, caffeine, picrotoxin, bicuculline, cocaine, kainic acid, strychnine, PTZ or hyperbaric oxygen in rodents [125,135,142,147,234,237,263,304–315]; sensory-evoked electromyographic activity induced by catechol in urethane-anesthetized rats [316]; limbic kindling and kindled seizures in rats [317– 319]; limbic status epilepticus induced by 90 min of continuous electrical stimulation of the hippocampus [158]; chemical kindling induced by PTZ in rats [320]; soman-induced seizures in guinea pigs [321]; alcohol withdrawal seizures in rats [322]; febrile seizures in epileptic chicks [323]; hypoxic stress-induced convulsions and death in mice [324]; electrically precipitated tonic hind-limb extension in mice [163]; kindling epileptogenesis and seizure expression in developing rats [154]; focal seizure activity from the feline hippocampus [325]; seizures induced by putrescine in the deep prepiriform cortex [326]; audiogenic seizures in genetically epilepsy-prone rats [151]; sound-induced seizures in DBA/2 mice [155]; generalized tonic–clonic convulsions in genetically epileptic E1 mice [327]; enflurane-induced opisthotonus in mice [328]; hippocampal seizure threshold and afterdischarge in rats implanted with intracranial electrodes [329]; limbic status epilepticus induced by 90 min of

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continuous electrical stimulation of the hippocampus [158]; pilocarpine-induced status epilepticus in rats [330]; the MES test in mice [147,305,318,331]; and the lithium-pilocarpine seizure model in rats [332]. Combined treatment of MK-801 and nimodipine has anticonvulsant effects against PTZ- and strychnine-induced seizures in mice [306]. Doses of 0.0031 and 0.0125 mg/kg enhanced the protective activity of valproate against MES-induced convulsions in mice [333]. MK-801 (0.0125 and 0.05 mg/kg) potentiated the anticonvulsant action of phenobarbital, totally eliminating phenobarbital-induced motor impairment at 0.05 mg/kg, but did not influence the protection offered by carbamazepine and diphenylhydantoin at 0.05 mg/kg [333]. Sub-effective doses of MK-801 and lithium also exert anticonvulsant effects in the PTZ model of clonic seizures in mice [135]. Moreover, MK-801 improved the antiepileptic activity of phenobarbital, valproate and nicardipine in the rat amygdala kindling models [334]. These findings offer the possibility that a combination of MK-801 with selected conventional AEDs might have clinical benefit. Troupin et al. in 1986 studied the effects of MK-801 and standard AEDs in human epilepsy. They reported considerable improvement in more than 50% of patients in seizure frequency, mood, and alertness. The promising start of this trial faded with time. However, the patients were primarily receiving carbamazepine or diphenylhydantoin therapy [335]. 5.12. Ifenprodil Ifenprodil (4-[2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol) selectively blocks the polyamine site at the NR2B subunit of the NMDAR. Several preclinical studies have shown that ifenprodil exerts anticonvulsant effects in a variety of animal models of epilepsy including seizures induced by NMDA, spermine, lindane, and PTZ in rodents [336–340]; spinal seizures in mice induced by handling following pretreatment with a sub-convulsive dose of strychnine [341]; the MES test [230,336,342]; audiogenic seizures in genetically epilepsy-prone rats [151,343]; motor and electrocortical seizures induced by unilateral local injection of putrescine into the rat deep prepiriform cortex [326]; ethanol withdrawal seizures in mice [344]; amygdala-kindling development [345]; proconvulsive effects of interleukin(IL)-1β on electrographic seizures induced by intrahippocampal injection of kainic acid in C57BL6 adult mice [346]; PTZinduced seizures in spermidine/spermine N1-acetyltransferase transgenic mice [347]; cocaine-induced convulsions and lethality in mice [237]; prolonged status epilepticus induced by continuous hippocampal stimulation [348]; and activity evoked by intracortical stimulation in brain slices from freeze-lesioned rat neocortex [349]. However, it is noteworthy that ifenprodil had no effect in some animal models. Some of these studies [350,351] demonstrated that ifenprodil was unable to protect against seizures induced by imipenem or pefloxacin in DBA/2 mice [230], suggesting that the polyamine site did not exert a principal role in the genesis of seizures induced by imipenem or pefloxacin. Another study showed that ifenprodil had no effect on DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3carboxylate)-induced seizures in mice [352]. Burket et al. [353] demonstrated that ifenprodil was ineffective against electricallyprecipitated tonic hindlimb extension. Although ifenprodil increased the threshold for electroconvulsions when applied at 20 and 40 mg/kg (i.p.), when combined with AEDs (carbamazepine, diphenylhydantoin, phenobarbital and valproate), it did not influence their anticonvulsant actions [342]. Similarly Kleinrok et al. [230] showed that ifenprodil failed to enhance the antielectroshock efficacy of conventional AEDs. In a further study, the combined treatment of ifenprodil with L-701,324, a brain penetrating glycineB antagonist, was examined for anticonvulsive effectiveness in fully amygdala-kindled rats [354]. Both drugs, when given separately up to doses causing severe motor impairment,

627

did not significantly affect seizure parameters comprising focal afterdischarge threshold, seizure severity, duration of seizures and afterdischarges. Coadministration of ifenprodil (10 mg/kg, i.p.) and L-701,324 (5 mg/kg, i.p.) resulted in an increased anticonvulsant effect in afterdischarge threshold, while generalized seizure activity was suppressed [354]. These results indicate that combinations of drugs targeting different sites may offer an advantage compared with a single compound. 5.13. Eliprodil Eliprodil or SL-82.0715 (1-(4-chlorophenyl)-2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]ethanol) is an NMDAR antagonist that binds to the polyamine modulatory site. It has neuroprotective and anticonvulsant effects in animal studies and does not produce sedation or amnesia [355]. It was evaluated for the treatment of stroke but human trials failed to show clear benefits [356]. Eliprodil has anticonvulsant effects against ethanol withdrawal seizures [357] and amygdala kindling model in rats [358]. It also potentiates anticonvulsant effects of other NMDAR antagonists against electroshock-induced seizures in mice [359] and in the rat amygdala kindling model [358]. Side effects of the drug combination were low-grade ataxia and slight hyperlocomotion. However, no detectable changes in motor coordination (as assessed with the rotarod test) could be observed [358]. These side effect data are encouraging for further clinical development of combined treatment with polyamine site antagonists and glycineB receptor antagonists. 5.14. Other NMDAR antagonists in preclinical studies In addition to the above-mentioned NMDAR antagonists and modulators that were used in clinical settings, a variety of NMDAR antagonists have been evaluated in preclinical studies during the last 30 years. The results of these studies have been summarized in Table 4. These findings suggest that NMDAR antagonism at different sites of the receptor, such as the pore channel, the glycine/D-serine site at the NR1 subunit, and the glutamate/NMDA site at the NR2 subunit could have anticonvulsant activity in several animal models of epilepsy. However, these agents have not been examined in clinical settings yet (Table 4). Side effects occurring with the application of NMDAR antagonists might be an important obstacle to evaluating these agents in the clinical trials. In experimental models of epilepsy, the combinations of conventional AEDs with low doses of NMDAR antagonists have shown a marked benefit with less severe side effects compared with monotherapy [231], suggesting a potential advantage that requires clinical validation. 6. 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 of common AEDs with NMDAR antagonists could be beneficial in controlling epileptic seizures. 7. 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

628

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Table 4 Anticonvulsant effects of several NMDAR antagonists in a variety of animal behavioral experiments. Substance

Effect

Seizure models

Reference

ACEA-1021 (5-Nitro-6,7-dichloro-1,4dihydro-2,3-quinoxalinedione), ACEA1031, ACEA-1328 (5-Nitro-6,7-dimethyl1,4-dihydro-2, 3-quinoxalinedione) ACPC (1-Aminocyclopropane carboxylic acid)

Competitive strychnineinsensitive glycine site antagonist

Cocaine-induced convulsions and lethality in mice

[237,300,391]

Strychnine-insensitive glycine site partial agonist

Aminocyclobutane carboxylic acid

Strychnine-insensitive glycine site partial agonist Competitive NMDAR antagonist

Audiogenic seizures in genetically epilepsy-prone rats Lithium-pilocarpine status epilepticus in rats MES in rats NMDA-induced seizures in mice and rats NMDA-induced hippocampal seizures in mice NMDA-induced seizures in mice and rats

[392] [393] [299] [233] [394] [233]

Audiogenic seizures in DBA/2 mice

[395]

Aminophylline-induced seizures in mice Febrile seizures in epileptic chicks Aminophylline-induced seizures in mice 4-Aminopyridine-induced seizures in rats Amygdaloid kindled convulsions in rats Audiogenic seizures in DBA/2 mice or genetically epilepsy-prone rats Barbital withdrawal-induced convulsions in rats Cocaine-induced convulsions and lethality in mice Electrically kindled seizures in the rat prepyriform cortex Epileptogenic responses in a synaptic and a non-synaptic model of epileptogenesis in the CA1 region of the hippocampal slice Febrile seizures in epileptic chicks Flurothyl-induced clonic seizures in rats Homocysteine-induced seizures in immature rats Hyperbaric oxygen-induced seizures in rats Insulin-induced convulsions in rats Kindled hippocampal seizures MES in rats Metaphit-induced audiogenic seizures in rats Motor and electrocortical seizures, elicited by administration of the polyamine putrescine into the deep prepiriform cortex Penicillin-induced, synchronized afterdischarges in immature rat CA3 hippocampal neurons Pilocarpine-induced limbic seizures in rats PTZ-induced seizures in mice Seizures in baboons, Papio papio, with photosensitive epilepsy Seizures induced by injection of quinolinic acid into the rat dorsal hippocampus Seizures induced by NMDA, 3MPA, TSC, DMCM, picrotoxin, bicuculline and ibotenate in mice MES in rats and mice

[396] [323] [396] [397] [398] [399–402] [403] [237] [404] [182]

γ-D-glutamylaminomethylphosphonate (Glu-Amp), β-Daspartylaminomethylphosphonate (Asp-Amp) AP-5 (2-Amino-5-phosphonoheptanoic acid) AP-7 (2-Amino-7-phosphonoheptanoic acid)

Competitive NMDAR antagonist Competitive NMDAR antagonist

Biphenyl-analogs of AP-7 (SDZ 220–581) Competitive NMDAR antagonist APV (2-Amino-5-phosphonovalerate) Competitive NMDAR antagonist

CGP 37849 (DL-(E)-2-Amino-4-methyl5-phosphono-3-pentonoic acid)

Competitive strychnineinsensitive glycine site antagonist

CGP 39551 (Carboxyethylester of CGP 37849)

Competitive NMDAR antagonist

CGP 40116 ((R)-Enantiomer of CGP 37849)

Competitive NMDAR antagonist

Amygdaloid kindled convulsions in rats Catechol-induced sensory-evoked electromyographic activity in rats Guanidinosuccinate-induced convulsions in mice Metaphit-induced audiogenic seizures in rats NMDA-induced convulsions and lethality in mice Picrotoxin-induced epileptiform activity in the hippocampal CA1 and CA3 regions Seizures induced by picrotoxin microperfusion in the hippocampus of freely moving rats Spinal seizure model in mice Amygdaloid kindled convulsions in rats Audiogenic seizures in DBA/2 mice and genetically epilepsy-prone rats Electroshock or MES-induced seizures in mice and rats Guanidinosuccinate-induced convulsions in mice NMDA-induced seizures in mice and rats Photically induced myoclonus in Papio papio Amygdaloid kindled convulsions in rats Audiogenic or imipenem-induced seizures in DBA/2 mice or genetically epilepsy-prone rats Electroshock or MES-induced seizures in mice and rats Ethanol withdrawal seizures in mice Photically induced myoclonus in Papio papio PTZ-induced seizures in developing, 7 to 90-day-old rats Bicuculline- or pilocarpine-evoked seizures in mice exposed to transient episode of brain oligemia or ischemia Homocysteine-induced seizures in immature rats Lithium-pilocarpine-induced status epilepticus MES in mice NMDA-induced generalized tonic–clonic seizures in mice

[323] [167,405,406] [407] [315] [408] [409] [410,411] [412–414] [326] [175] [415] [399] [416] [417] [310,418–421] [422] [423] [316] [140] [413] [148,424] [176,181] [425] [341] [426,427] [392,402,428] [359,429–431] [140] [233] [428] [426,427] [351,402,428] [429–431] [432–434] [428] [435] [436,437] [407] [438] [301] [439]

M. Ghasemi, S.C. Schachter / Epilepsy & Behavior 22 (2011) 617–640

629

Table 4 (continued) Substance

Effect

CGP 43487 (Carboxylester of CGP 40116) Competitive NMDAR antagonist CGS 19755 or Selfotel (Cis-4phosphonomethyl-2-piperidine carboxylic acid)

7-CKA (7-chlorokynurenic acid) and Kynurenic acid

Co 101022 CP101,606 (Traxoprodil) CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid)

Competitive NMDAR antagonist

Strychnine-insensitive glycine site antagonist

Competitive NMDAR antagonist NR2B subunit NMDAR antagonist Competitive NMDAR antagonist

CPPene ((E)-4-(3-phophonoprop-2enyl)-piperazine-2-carboxylic acid)

Competitive NMDAR antagonist

DCQX (6,7-dichloroquinoxaline-2,3dione)

Competitive strychnineinsensitive glycine site antagonist NMDAR antagonist at glycine site

5,7-DCK (5,7-Dichlorokynurenic acid)

Gacyclidine (GK-11) (+,R)-HA-966 ((+,R)-3-amino-1hydroxy-2-pyrrolidine)

Ibogaine [(−)-12-Methoxyibogamine]

L-701,324 (7-Chloro-4-hydroxy-3-(3phenoxy)phenylquinolin-2-[1H]-one)

Non-competitive NMDAR antagonist Strychnine-insensitive glycine site partial agonist

Low-affinity noncompetitive NMDAR antagonist Strychnine-insensitive glycine site antagonist

Seizure models

Reference

Pilocarpine-induced motor seizures in mice PTZ-induced clonic and generalized tonic–clonic seizures Seizure threshold for tonic hindlimb extension Spontaneously recurrent absence seizures in GAERS Wistar rats γ-Hydroxybutyrate model of generalized absence seizures in rats Lithium-pilocarpine-induced status epilepticus in rats Seizure threshold for tonic hindlimb extension in mice Amygdaloid kindled convulsions in rats Audiogenic seizures in DBA/2 mice Focal hippocampal seizures in freely moving rats elicited by low-frequency stimulation Lidocaine-induced seizures in rats MES in rats and mice NMDA-induced seizures in mice Picrotoxin-induced seizures in rats and mice Amygdaloid kindled convulsions in rats Audiogenic seizures in DBA/2 mice Cocaine-induced convulsions and lethality in mice Electroshock-induced seizures or MES in rats Focal hippocampal seizures in freely moving rats elicited by low-frequency stimulation PTZ-induced diazepam-withdrawal seizures in mice Seizures evoked by focal application of bicuculline into the area tempestas of rat deep prepiriform cortex Seizures induced by bicuculline, DMCM and NMDA in mice Cocaine-induced convulsions and lethality in mice

[440] [441] [442] [443] [444,445] [438] [442] [446] [447,448] [449]

Cocaine-induced convulsions and lethality in mice

[237]

4-Aminopyridine-induced seizures in mice and rats Amygdaloid kindled convulsions in rats Audiogenic or imipenem-induced seizures in DBA/2 mice or genetically epilepsy-prone rats Cocaine-induced convulsions and lethality in mice Dendrotoxin-induced clonic seizures in mice Electrically kindled seizures at the rat prepyriform cortex Febrile seizures in epileptic chicks γ-Hydroxybutyrate model of generalized absence seizures in rats MES in mice NMDA-induced seizures in mice PTZ-induced clonic or tonic extensor seizures in mice Status epilepticus induced by continuous electrical stimulation of the hippocampus in rats Audiogenic seizures in genetically epilepsy-prone rats Imipenem-induced seizures in DBA/2 mice MES in mice Spinal seizure model in mice Cocaine-induced convulsions and lethality in mice

[397,461] [446] [351,392,402,455]

[450] [451] [448,452] [451] [297,453,454] [455,456] [237] [457,458] [449] [459] [460] [310,337,352,452] [237]

[237,462] [126] [404] [323] [444,445] [260,299] [262,337,424,452,456] [260,463] [158,348] [151,392] [351] [230] [341] [237,300]

NMDA-induced seizures in mice and rats Self-sustaining status epilepticus induced in rats by brief intermittent electrical stimulation of the perforant path Spontaneously recurrent absence seizures in GAERS Wistar rats Tonic hindlimb extension in MES Soman-induced seizures and EEG activity in primates

[233] [464]

Amygdaloid kindled convulsions in rats Cocaine-induced convulsions and lethality in mice γ-Hydroxybutyrate model of generalized absence seizures in rats Imipenem/cilastatin-induced seizures in rats MES in rats NMDA-induced seizures in mice and rats Pilocarpine-induced motor seizures in mice Seizures evoked by focal application of bicuculline into the area tempestas of rat deep prepiriform cortex Spinal seizure model in mice Tonic extensor seizures from low-intensity electroshock in rats NMDA-induced seizures in mice

[296,297,467] [237,300] [444,445] [468] [299] [233,452] [440] [460]

Amygdaloid kindled convulsions in rats Audiogenic seizures in DBA-2 mice Ethanol withdrawal seizures in rats MES in mice Seizures induced by NMDA, PTZ and electroshock in mice and rats

[354,358,471,472] [473] [357] [301] [473]

[443] [299] [465,466]

[341] [469] [125,470]

(continued on next page)

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M. Ghasemi, S.C. Schachter / Epilepsy & Behavior 22 (2011) 617–640

Table 4 (continued) Substance

Effect

Seizure models

Reference

MNQX (5,7-dinitroquinoxaline-2,3dione) MRZ 21579 or Neramexane (1-amino1,3,3,5,5-pentamethyl-cyclohexane hydrochloride) Tiletamine

Strychnine-insensitive glycine site antagonist Low-to-moderate affinity non-competitive NMDAR antagonist Non-competitive NMDAR antagonist

Audiogenic seizures in DBA-2 mice NMDA-induced seizures in mice and rats Ethanol withdrawal seizures in rats

[474] [233] [238,475]

Audiogenic seizures in DBA/2 mice NMDA and quinolinate-induced seizure in mice

[155] [476]

Abbreviations: DMCM, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; 3MPA, 3-mercaptopropionic acid; TSC, thiosemicarbazide; MES, maximal electroshock; PTZ, pentylenetetrazole.

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 intractable epilepsy are considerably higher than the general population [360–362]. A lifetime history of depression may predict persistent auras in the absence of disabling seizures and a failure to achieve freedom from disabling seizures [361,363]. Recently, a bidirectional relationship between depressive disorders and epilepsy has been suggested, as not only are people with epilepsy at greater risk of developing depressive disorders, but patients with depression have a three- to seven-fold higher risk of developing epilepsy [364–366]. These results may suggest the existence of common pathogenic mechanisms underlying both conditions. In recent decades, glutamate and glutamate-mediated activation of NMDARs have become potential therapeutic targets in many neuropsychiatric diseases including mood disorders. Using a variety of methods such as NMDAR subunit gene expression, immunoblotting, binding affinities and autoradiography, several laboratories have demonstrated a significant alteration in functioning and expression of NMDARs in both patients and suicidal victims with major depressive disorder [367]. Various NMDAR antagonists exert antidepressant-like effects in several animal models of depression [368,369]. Moreover, clinical studies revealed that NMDAR antagonists including ketamine [370,371], memantine [372], amantadine [373,374] and traxoprodil [375] are able to significantly improve depressive symptoms in patients with either major depression or bipolar disorder. Therefore, further studies should explore whether using NMDAR antagonists may be beneficial in improving both seizures and depression in comorbid patients whose symptoms are resistant to conventional AEDs. 8. 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 neurotoxicity, cause generalized inhibition of NMDAR function. While open-channel block with the noncompetitive antagonists is the most appealing strategy for therapeutic intervention during excessive NMDAR activation, as this action of blockade requires prior activation of the receptor [376], progressive increase in the severity of NMDAR hypofunction can lead to an increasing range of effects on brain function. Underexcitation of the NMDAR, induced by even relatively low doses of NMDAR antagonists, can cause memory dysfunction and learning deficits without clinically evident psychosis. More severe NMDAR hypofunction can produce psychosis [377] characterized by hallucinations,

paranoid delusions, confusion, difficulty in concentration, alterations in mood, agitation, nightmares, catatonia, ataxia, and loss of sensation [378,379]. Therefore, there should be considerable caution regarding the use of NMDAR antagonists, especially at high doses in clinical settings and particularly in children. This issue stems from the fact that NMDAR function plays a critical role in brain development, longterm potentiation, and neuronal migration and synaptic pruning [380]. Accordingly, NMDAR blockers could potentially result in neurodegeneration in the cingulate and retrosplenial cortex [381]. Several lines of evidence have demonstrated that strychnineinsensitive glycine site NMDAR antagonists (glycineB antagonists) lack neuronal vacuolization and a psychotomimetic potential, indicating a more acceptable adverse effect profile over NMDAR antagonists at other sites (for a review see [382]). The route of administration may also influence the appearance of side effects. For example, NMDAR antagonists could result in spinal cord pathology when given intrathecally. Brock-Utne et al. [383] showed that intrathecal administration of ketamine to monkeys caused focal degeneration with loss of myelin and axoplasm within a solitary nerve root. Another study by Errando et al. [384] demonstrated that subarachnoid ketamine without preservative did not show significant neurotoxic effects, whereas ketamine with preservative produced minimal changes. Vranken et al. reported that intrathecal administration of preservative-free ketamine in a clinically relevant concentration and dosage had a toxic effect on the CNS of rabbits [385]. Other investigators indicated that chronic intrathecal administration of pharmacologically active doses of NMDAR antagonists including CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid), kynurenic acid and ketamine in rats or rabbits did not produce significant neurotoxic effects in the spinal cord [386–388]. However, a blood– brain barrier study showed evidence of neurotoxicity for ketamine after intrathecal administration in rabbits [389]. Moreover, Karpinski et al. [390] reported post-mortem CNS histopathological changes of subpial spinal cord vacuolation in a terminally ill cancer patient who received continuous infusion of intrathecal ketamine at a rate of 5 mg/day for a duration of 3 weeks. 9. 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 further studied as possible treatments for controlling status epilepticus and eclampsia-related seizures, respectively, whereas a vast majority of agents have not been evaluated in clinical trials yet. Moreover, some NMDAR antagonists (e.g. D-cycloserine) have proconvulsant activity in animal models, in vitro models or even in patients with epilepsy. Several conventional AEDs have been shown to affect

M. Ghasemi, S.C. Schachter / Epilepsy & Behavior 22 (2011) 617–640

631

Table 5 Effect of common AEDs on NMDARs. Drug

Species

Carbamazepine Rat fetus Fetal mouse Rat pup Genetically epilepsyprone mouse Guinea pig Rabbit Rat

Ethosuximide

Mouse Rat

Gabapentin

Rat

Lamotrigine

– Rats with inflammation induced by injection of CFA to hindpaw Rat

[477] [478] [479,480] [481]

NMDA-mediated incease in the frequency of occurrence of low Mg2+ induced EFP NMDA-mediated induction of long-term potentiation NMDA-evoked excitatory postsynaptic potential NMDA-evoked responses NMDA-, glutamate- or kainate-induced increase in [Ca2+] NMDA component of fPSP response NMDA-induced cytoplasmic vacuolization NMDA-induced regional arachidonic acid incorporation coefficients k* Release of preloaded D-[3H]aspartate NMDAR hypofunction neurotoxicity

Hippocampal CA3

↓ ↓ ↓ ↓ ↑ ↔

Perforant path-dentate gyrus pathway Hippocampal and amygdaloid slices Cortical wedge Cultured hippocampal neurons Hippocampal slices Primary hippocampal neurons Brain

↓ ↓ ↓ ↓ ↓ ↓ ↓

[483] [484,485] [486] [487] [488] [489] [490]

Cerebral cortical slices ↓ Layer IV–Va pyramidal neurons of retrosplenial ↓ cortex Epileptiform field potential discharges evoked by removing Hippocampal slices ↓ 2+ Mg from perfusion fluid NMDA-evoked depolarizations Cultured cortical neurons ↔ NMDA-induced presynaptic glutamate release Entorhinal cortex ↔ NMDA-evoked excitatory postsynaptic currents Superficial horn neurons of spinal cord slices ↓ Presynaptically NMDA-induced axon excitability Presynaptic fiber volley in the hippocampal ↓ CA1 slices NMDA-induced excitotoxicity Hippocampal CA1 neurons ↓ NMDAR currents Xenopus laevis oocytes ↓ NMDA-evoked currents Single dorsal horn neurons ↑

Kainate-induced neurotoxicity Quinolinic acid- or ibotenic acid-induced neurotoxicity Veratrine-evoked release of glutamate and aspartate NMDA-evoked responses Evoked NMDA-mediated excitatory postsynaptic currents Release of preloaded D-[3H]aspartate NMDA-induced epileptiform activity NMDA-evoked EPSC Specific binding of [3H]-MK-801 and [3H]-glycine

Striatum

↓ ↔ ↓

[482]

[491] [492] [493] [494] [495] [496] [497]

[498] [499]

[500]

↔ ↓ ↓ ↓ ↓ ↔ ↓

[508]

Caudate–putamen, hippocampal CA1 and CA3 Striatal synapses Primary hippocampal neurons 3 week old primary hippocampal cultures Entorhinal cortex Hippocampal CA1 region

↓ ↔ ↓ ↔ ↔ ↔

[509] [510] [511] [512] [495] [513]

Hippocampus Forebrain membranes Cortical wedge Layer IV–Va pyramidal neurons of retrosplenial cortex Epileptiform field potential discharges evoked by removing Hippocampal slices Mg2+ from perfusion fluid Rat NMDAR-mediated trafficking and release of synaptic Cultured hippocampal neurons vesicles Rat L-Glutamate- or NMDA-induced paroxysms Planarians (Dugesia dorotocephala) Rat NMDA-induced cytoplasmic vacuolization Primary hippocampal neurons NMDA-induced regional arachidonic acid incorporation Brain coefficients k* 2-week-old rats prenatally NR2A and NR2B mRNA expression Neocortex exposed to the drug Somatosensory cortex

↔ ↔ ↓ ↓

[514] [515] [486] [492]

↓

[493]

↓

[516,517]

↓ ↓ ↓

[518,519] [489] [520]

↑ ↔

[521] [522]

Olanzapine

Rat

Topiramate Valproic acid

Result Reference

Cultured hippocampal pyramidal neurons Cultured spinal neurons Primary cultures of cerebellar granule cells Cortical wedges

[501] [502] [486] [503] [491,504] [505] [506] [507]

Mouse Rat

Pregabalin

Region/cells

Glutamate-induced neurotoxicity NMDA-activated membrane currents Kainate- and NMDA-induced intracellular Ca2+ levels NMDA-induced depolarizations

Cortical slices Forebrain slices Cortical wedge Granule cells in the dentate gyrus Cerebral cortical slices CA3 subfield of hippocampal slices Hippocampal dentate gyrus Synaptic plasma membranes prepared from medial prefrontal cortex Pyramidal cell of the medial prefrontal cortex

Levetiracetam

Oxcarbazepine Phenytoin

Measurement

Rat 19 day embryonic rat Rat

Phencyclidine-evoked increase in excitatory postsynaptic currents NMDAR binding Protein levels of NR1, NR2A and NR2B subunits kainic acid-induced apoptosis NMDA-induced neurotoxicity NMDA-induced presynaptic glutamate release NMDA receptor-mediated epileptiform population response NMDAR-dependent LTP [3H]glycine binding NMDA-evoked responses NMDAR hypofunction neurotoxicity

Abbreviations: CFA, complete Freund adjuvant; EFP, extracellular field potentials; EPSC, excitatory postsynaptic currents; fPSP, field excitatory postsynaptic potentials; I/R, ischemia/reperfusion; LTP, long-term potentiation; PKC, protein kinase C.

NMDAR function and some studies indicate that combinations of AEDs with NMDAR antagonists may be a promising strategy to increase clinical benefit. However, establishing the safety of NMDARs alone or in combination with AEDs requires further investigation.

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