Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status

Introduction: Several drugs targeting the GABAergic system are used in the treatment of epilepsy, but only one drug targeting glutamate receptors is on the market. This is surprising because an imbalance between excitatory and inhibitory neurotransmission lies at the core of the pathophysiology of epilepsy. One possible explanation is that drug development has been directed towards the synthesis of molecules that inhibit the activity of ionotropic glutamate receptors. These receptors mediate fast excitatory synaptic transmission in the central nervous system (CNS) and their blockade may cause severe adverse effects such as sedation, cognitive impairment, and psychotomimetic effects. Metabotropic glutamate (mGlu) receptors are more promising drug targets because these receptors modulate synaptic transmission rather than mediate it.

Areas covered: We review the current evidence that links mGlu receptor subtypes to the pathophysiology and experimental treatment of convulsive and absence seizures.

Expert opinion: While mGlu₅ receptor negative allosteric modulators have the potential to be protective against convulsive seizures and hyperactivity-induced neurodegeneration, drugs that enhance mGlu₅ and mGlu₇ receptor function may have beneficial effects in the treatment of absence epilepsy. Evidence related to the other mGlu receptor subtypes is more fragmentary; further investigations are required for an improved understanding of their role in the generation and propagation of seizures.     

The Management and Alternative Therapies for Comorbid Sleep Disorders in Epilepsy

Background There is a complex and interactive relationship between sleep and epilepsy. Sleep disorders are common in patients with epilepsy, and methods for managing sleep disorders in patients with epilepsy are limited.Objective This review addresses the relationship among sleep, sleep disorders, and epilepsy, focusing on the management of sleep disorders in epilepsy, including some complementary and alternative therapies.Methods The terms related to “sleep” and “epilepsy” were searched in “Pubmed” and “Cochrane Library”.Results Sleep stages differently affect both seizures and interictal epileptiform discharges. Seizures disrupt sleep architecture greatly, especially when occurring during sleep in the night. Insomnia and obstructive sleep apnea (OSA) are the most frequent types of comorbid sleep disorders in patients with epilepsy. Pharmacological agents with both anti-convulsant and sedative effects are the priorities for comorbid sleep disorders in epilepsy. Continuous positive airway pressure (CPAP) therapy is the most effective non-pharmacological method to improve OSA and reduce seizures. Complementary and alternative therapies such as Chinese traditional medicine, cognitive behavioral therapy, meditation, yoga, neurofeedback, and acupuncture may have benefits in reducing seizures and improving sleep quality simultaneously by alleviating stress and seizure triggers; however, evidence-based therapies are still deficient.Conclusion Management of sleep disorders in patients with epilepsy is challenging. Large-scale randomized controlled clinical trials are in demand to guide the treatments in the future.     

The Role of ASIC1a in Epilepsy: A Potential Therapeutic Target

Background Epilepsy represents one of the most common brain diseases among humans. Tissue acidosis is a common phenomenon in epileptogenic foci. Moreover, its role in epileptogenesis remains unclear. Acid-sensing ion channel-1a (ASIC1a) represents a potential way to assess new therapies. ASIC1a, mainly expressed in the mammalian brain, is a type of protein-gated cation channel. It has been shown to play an important role in the pathological mechanism of various diseases, including stroke, epilepsy, and multiple sclerosis.Methods Data were collected from Web of Science, Medline, PubMed, through searching for these keywords: “Acid-sensing ion channels 1a” or “ASIC1a” and “epilepsy” or “seizure”.Results The role of ASIC1a in epilepsy remains controversial; it may represent a promising therapeutic target of epilepsy.Conclusion This review is intended to provide an overview of the structure, trafficking, and molecular mechanisms of ASIC1a in order to elucidate the role of ASIC1a in epilepsy further.     

Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures

Individual metabotropic glutamate (mGlu) receptor subtypes have been implicated in the pathophysiology of epileptic seizures, and are potential targets for novel antiepileptic drugs. Here, we examined the role of the mGlu4 receptor subtype in absence seizures using as models: (i) WAG/Rij rats, which develop spontaneous absence seizures after 2-3months of age; and (ii) mice treated with pentylentetrazole (PTZ, 30mg/kg, s.c.). Expression of mGlu4 receptors was enhanced in the reticular thalamic nucleus (RTN) of symptomatic WAG/Rij rats as compared with age-matched controls, as assessed by immunoblotting and immunohistochemistry. No changes were found in other regions of WAG/Rij rats including ventrobasal thalamic nuclei, somatosensory cortex, and hippocampus. Electron microscopy and in situ hybridization data suggested that mGlu4 receptors in the RTN are localized on excitatory cortical afferents. Systemic injection of the selective mGlu4 receptor positive allosteric modulator, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen1a-carboxamide (PHCCC, 10mg/kg, s.c.), substantially enhanced the number of spike-and-wave discharges (SWDs) in WAG/Rij rats. Injection of PHCCC also enhanced absence-like seizures in PTZ-treated mice, whereas it was totally inactive in mGlu4 receptor knockout mice, which were intrinsically resistant to PTZ-induced seizures, as expected. This data supports the hypothesis that activation of mGlu4 receptors participates in the generation of absence seizures which can be exacerbated with the use of a positive allosteric modulator.     

Glutamate receptor channels: novel properties and new clones.

Glutamate is the principal excitatory neurotransmitter in the brain. Glutamate activates cation-selective receptor channels carried by nearly every neuron and by glial cells. Bernd Sommer and Peter Seeburg describe how our concepts concerning the molecular and functional design of ionotropic glutamate receptors are rapidly progressing, with the recent discovery of novel receptor properties and new subunits following the landmark cloning of the first receptor subunit by M. Hollmann and his colleagues. New properties currently revealed by the cloned receptor channels may guide physiologists in characterizing the elementary steps in synaptic transmission, help neurologists to define the role of glutamate receptors in acute and chronic neuropathologies, and enlighten all neuroscientists whose models for learning and memory involve the idiosyncracies of particular channel subtypes.     

AMPA receptors and perampanel behind selected epilepsies: current evidence and future perspectives

Introduction: The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are the major mediators of glutamate-mediated excitatory neurotransmission, and are critical for synchronization and spread of epileptic activity.

Areas covered: AMPA receptor antagonists have been also developed as antiepileptic drugs and perampanel (PER) is the first highly selective, non-competitive AMPA-type glutamate receptor antagonist that is available on the market. It is approved as adjunctive therapy for the treatment of partial-onset seizures with or without secondary generalization, and for primary generalized tonic-clonic seizures in idiopathic generalized epilepsy, in patients aged ≥ 12 years. This article reviews the role of AMPA receptors in the neuronal hyperexcitability underlying epilepsy, the mechanism of action and clinical experience on the anti-seizure activity of PER. Moreover, the rationale for targeting AMPA receptor in specific epileptic disorders, including brain tumor-related epilepsy, mesial temporal lobe epilepsy with/without hippocampal sclerosis, and status epilepticus is evaluated. Finally, the pharmacological rationale for the development of AMPA receptor antagonists in other neurological disorders beyond epilepsy is considered.

Expert opinion: Further research aimed at better understanding the pharmacology and blocking mechanism of PER and other AMPA receptor antagonists will drive future development of therapeutic agents that target epilepsy and other neurological diseases.     

The glutamate story

Glutamatergic synaptic transmission in the mammalian central nervous system was slowly established over a period of some 20 years, dating from the 1950s. Realisation that glutamate and like amino acids (collectively known as excitatory amino acids (EAA)) mediated their excitatory actions via multiple receptors preceded establishment of these receptors as synaptic transmitter receptors. EAA receptors were initially classified as N-methyl-D-aspartate (NMDA) and non-NMDA receptors, the latter subdivided into quisqualate (later AMPA) and kainate receptors after agonists that appeared to activate these receptors preferentially, and by their sensitivity to a range of differentially acting antagonists developed progressively during the 1970s. NMDA receptors were definitively shown to be synaptic receptors on spinal neurones by the sensitivity of certain excitatory pathways in the spinal cord to a range of specific NMDA receptor antagonists. Importantly, specific NMDA receptor antagonists appeared to be less effective at synapses in higher centres. In contrast, antagonists that also blocked non-NMDA as well as NMDA receptors were almost universally effective at blocking synaptic excitation within the brain and spinal cord, establishing both the existence and ubiquity of non-NMDA synaptic receptor systems throughout the CNS. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways, acting in concert with non-NMDA receptors under conditions where a protracted excitatory postsynaptic potential was effected in response to intense stimulation of presynaptic fibres. Such activation of NMDA receptors together with non-NMDA receptors led to the phenomenon of long-term potentiation (LTP), associated with lasting changes in synaptic efficacy (synaptic plasticity) and considered to be an important process in memory and learning. During the 1980s, it was shown that certain glutamate receptors in the brain mediated biochemical changes that were not susceptible to NMDA or non-NMDA receptor antagonists. This dichotomy was resolved in the early 1990s by the techniques of molecular biology, which identified two families of glutamate-binding receptor proteins (ionotropic (iGlu) and metabotropic (mGlu) receptors). Development of antagonists binding to specific protein subunits is currently enabling precise identification of discrete iGlu or mGlu receptor subtypes that participate in a range of central synaptic processes, including synaptic plasticity.     

Activation of NMDA receptors reduces metabotropic glutamate receptor-induced long-term depression in the nucleus accumbens via a CaMKII-dependent mechanism

Glutamate is the major excitatory neurotransmitter in the brain and exerts its actions through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluR). Although functional interplay between ionotropic N-methyl-d-aspartate receptors (NMDAR) and mGluR has been convincingly demonstrated in native and recombinant systems, the mechanism by which NMDAR activation leads to modulation of mGluR function has yet to be elucidated. Using whole-cell patch-clamp recordings in mouse nucleus accumbens (NAc) slices, we found that tetanic stimulation (TS) of excitatory afferents with a naturally occurring frequency (10 min at 13 Hz) reliably induces a mGluR1/5-dependent long-term depression (mGluR1/5-LTD) of excitatory synaptic transmission. Blockade of NMDAR during but not after TS showed enhanced mGluR1/5-LTD induction, which is associated with its antagonism of TS-induced calcium/calmodulin-dependent protein kinase II (CaMKII) activation. The ability of NMDAR antagonists to promote mGluR1/5-LTD induction was mimicked by a selective CaMKII inhibitor KN-62. However, the induction of mGluR1/5-LTD by bath-applied agonist (S)-3,5-dihydrophenylglycine was not affected by NMDAR blockade. We also observed that NMDAR or CaMKII blockade during TS significantly blunted TS-induced increased serine/threonine phosphorylation of the scaffold protein Homer1b/c and resulted in an increased interaction of mGluR5 with the Homer1b/c. These results indicate that synaptically released glutamate during TS of excitatory afferents can activate both NMDAR and mGluR1/5 in NAc neurons concomitantly and that activation of NMDAR may stimulate CaMKII-mediated phosphorylation of Homer1b/c and impair the interaction between mGluR5 and Homer1b/c, thereby attenuating mGluR1/5-LTD induction. This study provides a novel molecular mechanism by which NMDAR could regulate mGluR5 function.     

Etomidate reduces glutamate uptake in rat cultured glial cells: involvement of PKA

Background and purpose:

Glutamate is the main excitatory neurotransmitter in the vertebrate CNS. Removal of the transmitter from the synaptic cleft by glial and neuronal glutamate transporters (GLTs) has an important function in terminating glutamatergic neurotransmission and neurological disorders. Five distinct excitatory amino-acid transporters have been characterized, among which the glial transporters excitatory amino-acid transporter 1 (EAAT1) (glutamate aspartate transporter) and EAAT2 (GLT1) are most important for the removal of extracellular glutamate. The purpose of this study was to describe the effect of the commonly used anaesthetic etomidate on glutamate uptake in cultures of glial cells.

Experimental approach:

The activity of the transporters was determined electrophysiologically using the whole cell configuration of the patch-clamp recording technique.

Key results:

Glutamate uptake was suppressed by etomidate (3–100 μM) in a time- and concentration-dependent manner with a half-maximum effect occurring at 2.4±0.6 μM. Maximum inhibition was approximately 50% with respect to the control. Etomidate led to a significant decrease of V_max whereas the K_m of the transporter was unaffected. In all cases, suppression of glutamate uptake was reversible within a few minutes upon washout. Furthermore, both GF 109203X, a nonselective inhibitor of PKs, and H89, a selective blocker of PKA, completely abolished the inhibitory effect of etomidate.

Conclusion and implications:

Inhibition of glutamate uptake by etomidate at clinically relevant concentrations may affect glutamatergic neurotransmission by increasing the glutamate concentration in the synaptic cleft and may compromise patients suffering from acute or chronic neurological disorders such as CNS trauma or epilepsy.     

Efficiency and safety of desloratadine in combination with compound glycyrrhizin in the treatment of chronic urticaria: a meta-analysis and systematic review of randomised controlled trials

ContextDesloratadine, an H1 receptor antagonist, is suggested as an effective first-line drug for chronic urticarial (CU). However, the efficacy of desloratadine alone is limited, and the recurrence rate of CU is relatively high.ObjectiveWe sought to evaluate the efficacy and clinical feasibility of desloratadine in combination with compound glycyrrhizin in the treatment of CU.Materials and methodsA systematic literature search was conducted in the databases of the China National Knowledge Infrastructure Database, VIP, WanFang, PubMed, and Web of Science using subject terms: “Chronic urticaria”, “Loratadine”, and “Compound glycyrrhizin”. Randomised controlled trials (RCTs) that compared the efficiency and safety of the combination treatment with desloratadine alone starting from January 1, 2014 until February 10, 2021 were selected by two co-first authors independently, and the extracted data were analysed using Rev Man 5.3 software.ResultsFourteen RCTs were included in our meta-analysis with a total of 1501 patients. The results showed that the combination treatment yielded a better treatment effect (total response rate: RR = 1.23, 95% CI: 1.17 to 1.29, p < 0.00001; cure rate: RR = 1.50, 95% CI: 1.30 to 1.73, p < 0.00001), lower recurrence rate as well as superior immune improvement than the treatment with desloratadine alone. In addition, there was no significant difference in the safety of the two treatments.Discussion and ConclusionThe combination of desloratadine and compound glycyrrhizin is a promising treatment for CU and is associated with decreased serum IgE level and improved proportions of CD4+ T and CD8+ T cells.     

The effects of excitatory amino acids on isolated gut segments of the rat.

Glutamate and aspartate are excitatory neurotransmitters in both central and peripheral nervous systems, acting on ionotropic and metabotropic receptors. In our study we have examined the effects of glutamate, aspartate, N-methyl-d-aspartate (NMDA), kainic acid and (+/-)-1-aminocyclopentane-cis-1,3-dicarboxylic acid (ACPD) on tone and spontaneous activity of isolated rat gastric fundus, jejunum, ileum, ascending colon and rectum. Both glutamate and aspartate produced concentration-dependent tonic contractions of rat fundus and rectum; the other gut segments used in the study were not responsive. While only NMDA and kainic acid produced concentration-dependent tonic contractions of isolated rat gastric fundus, all three type-selective agonists of glutamate receptors (NMDA, kainic acid and ACPD) produced tonic contractions of isolated rat rectum. The results of our study suggest that glutamate and aspartate in rat gastric fundus activate excitatory intrinsic neurons through only ionotropic receptors (NMDA and non-NMDA receptors), while the same action in rat rectum is mediated through both ionotropic and metabotropic receptors.     

Elevated Serum Purine Levels in Schizophrenia: A Reverse Translational Study to Identify Novel Inflammatory Biomarkers

BackgroundImmunological markers and related signaling molecules in the blood are altered in schizophrenia mouse models, in acutely relapsed patients with schizophrenia, and in persons at a clinically high risk for subsequently developing psychosis, highlighting their potential as prognostic and theranostic biomarkers. Therefore, we herein aimed to identify novel potential biomarkers in the serum that are associated with purinergic signaling.MethodsTo our knowledge, this is the first study to assess the correlations among the levels of human serum adenine nucleotides (ATP, ADP), adenosine, P2X7 receptor, and disease activity in patients hospitalized due to an acute relapse of schizophrenia (n = 53) and healthy controls (n = 47). In addition, to validate these findings using a reverse translational approach, we examined the same parameters in an acute phencyclidine-induced schizophrenia mouse model.ResultsWe found consistently elevated levels of ATP, ADP, interleukin (IL)-6, and IL-10 in both schizophrenia groups compared with the controls. The levels of adenosine, IL-1β, IL-12, and C-reactive protein were also increased in the human patient samples. Moreover, ATP and ADP were significantly positively correlated with the Positive and Negative Symptom Scale item “lack of judgment and insight”; IL-1β, IL-12, and tumour necrosis factor alpha were significantly positively correlated with “tension” and “depression”; and “disorientation” and “poor attention” were correlated significantly with IL-6 and IL-8.ConclusionsOur study suggests the promising potential of blood purines and inflammatory markers as future prognostic tools.     

Glutamate receptors and persistent pain: targeting forebrain NR2B subunits

Glutamate is the fast excitatory transmitter in mammalian brains. It binds to two major classes of glutamate receptors: ionotropic and metabotropic receptors. Ionotropic receptors contain three subtype receptors, including N-methyl-d-aspartate (NMDA) receptors. Activation of NMDA receptors is important for initiating long-lasting changes in synapses. In the forebrain structures that are known to contribute to the formation and storage of information, NMDA receptors have an important role in persistent inflammatory pain by reinforcing glutamate sensory transmission. Mice with enhanced forebrain NMDA receptor function demonstrate selective enhancement of persistent pain and allodynia. Drugs targeting NMDA NR2B subunits in the forebrain could serve as a new class of medicine for controlling persistent pain in humans.     

Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson’s disease, Alzheimer’s disease and pain.     

Glutamate receptors and nociception: implications for the drug treatment of pain

Evidence from the last several decades indicates that the excitatory amino acid glutamate plays a significant role in nociceptive processing. Glutamate and glutamate receptors are located in areas of the brain, spinal cord and periphery that are involved in pain sensation and transmission. Glutamate acts at several types of receptors, including ionotropic (directly coupled to ion channels) and metabotropic (directly coupled to intracellular second messengers). Ionotropic receptors include those selectively activated by N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate. Metabotropic glutamate receptors are classified into 3 groups based on sequence homology, signal transduction mechanisms and receptor pharmacology. Glutamate also interacts with the opioid system, and intrathecal or systemic coadministration of glutamate receptor antagonists with opioids may enhance analgesia while reducing the development of opioid tolerance and dependence. The actions of glutamate in the brain seem to be more complex. Activation of glutamate receptors in some brain areas seems to be pronociceptive (e.g. thalamus, trigeminal nucleus), although activation of glutamate receptors in other brain areas seems to be antinociceptive (e.g. periaqueductal grey, ventrolateral medulla). Application of glutamate, or agonists selective for one of the several types of glutamate receptor, to the spinal cord or periphery induces nociceptive behaviours. Inhibition of glutamate release, or of glutamate receptors, in the spinal cord or periphery attenuates both acute and chronic pain in animal models. Similar benefits have been seen in studies involving humans (both patients and volunteers); however, results have been inconsistent. More research is needed to clearly define the role of existing treatment options and explore the possibilities for future drug development.     

S-palmitoylation regulates AMPA receptors trafficking and function: a novel insight into synaptic regulation and therapeutics

Glutamate acting on AMPA-type ionotropic glutamate receptor (AMPAR) mediates the majority of fast excitatory synaptic transmission in the mammalian central nervous system. Dynamic regulation of AMPAR by post-translational modifications is one of the key elements that allow the nervous system to adapt to environment stimulations. S-palmitoylation, an important lipid modification by post-translational addition of a long-chain fatty acid to a cysteine residue, regulates AMPA receptor trafficking, which dynamically affects multiple fundamental brain functions, such as learning and memory. In vivo, S-palmitoylation is controlled by palmitoyl acyl transferases and palmitoyl thioesterases. In this review, we highlight advances in the mechanisms for dynamic AMPA receptors palmitoylation, and discuss how palmitoylation affects AMPA receptors function at synapses in recent years. Pharmacological regulation of S-palmitoylation may serve as a novel therapeutic strategy for neurobiological diseases.KEY WORDS: Palmitoylation, AMPA receptors, Trafficking, DHHCAbbreviations: ABE, acyl-biotinyl exchange; ABP, AMPA receptor binding protein; AD, Alzheimer׳s disease; AKAP79/150, A-kinase anchoring protein 79/150; AMPAR, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; APT1, acyl-protein thioesterase-1; APT2, acyl-protein thioesterase-2; CP-AMPARs, Ca²⁺-permeable AMPARs; DHHC, aspartate-histidine-histidine-cysteine; FMRP, fragile X mental retardation protein; FXS, Fragile X syndrome; GAP-43, growth associated protein-43; GRIP, glutamate receptor interacting protein; LTD, long-term depression; LTP, long-term potentiation; 17-ODYA, 17-octadecynoic acid; PATs, palmitoyl acyl transferases; PDZ, postsynaptic density-95/discs large/zona occludens-1; PICK1, protein interacting with C-kinase 1; PKA, protein kinase A; PKC, protein kinase C; PPT1, palmitoyl-protein thioesterase-1; PSD-95, postsynaptic density-95; Ras, rat sarcoma; SNAP-23, soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptor protein-23     

Structure of glutamate receptors

Glutamate receptors mediate a vast array of processes in plants, animals and bacteria. In particular, the ionotropic glutamate receptors (iGluRs) are the most abundant excitatory neurotransmitter receptors in the mammalian central nervous system. Because these proteins are constructed from distinct folding domains, most of which can be traced to bacterial precursors, the analyses of these important receptor proteins has been performed on a variety of levels ranging from atomic structure and dynamics to behavioral studies. This review will focus on the structure and dynamics of iGluRs, with particular emphasis on the role that the glutamate-binding domain (S1S2) plays in receptor function.     

Novel metabotropic glutamate receptor 4 and glutamate receptor 8 therapeutics for the treatment of anxiety

Introduction: The fast actions of the excitatory neurotransmitter glutamate are mediated by glutamate-gated ion channels (ionotropic Glu receptors). Metabotropic glutamate receptors (mGlus) are coupled to second messenger pathways via G proteins and modulate glutamatergic and GABAergic neurotransmission. Of the eight different types of mGlus (mGlu1–mGlu8), mGlu4, mGlu6, mGlu7 and mGlu8 are members of group III. Except for mGlu6, group III receptors are generally located presynaptically and regulate neurotransmitter release. Because of their role in modulating excitatory neurotransmission, mGlus are attractive targets for therapies aimed at treating anxiety disorders.

Areas covered: In this review, the authors discuss the role of mGlu4 and mGlu8 in anxiety disorders. They also discuss how mGlu4 and mGlu8 have distinct expression patterns in the brain, which might have related functions. Finally, the authors discuss how compounds that target more than one mGlu receptor might be therapeutically more effective.

Expert opinion: mGlu4 might compensate for mGlu8 deficiency, and deficiency of both receptors might result in a more pronounced phenotype than deficiency of either receptor alone. The distinct and overlapping anatomical distribution and functions of mGlu4 and mGlu8 suggest that both receptors, either individually or combined, are attractive therapeutic targets in anxiety disorders, post-traumatic stress disorder, Parkinson’s disease, and multiple sclerosis.     

Rat brain gaba and glutamate content in m-fluorotyrosine convulsions

The relationship between m-fluorotyrosine convulsions and brain γ-aminobutyric acid (GABA) and glutamate levels was examined in rats. Glutamate and GABA contents in the cerebellum or cerebral cortex were unaffected. Decreases in GABA occurred in the thalamus before convulsion as well as during its course. Hippocampal GABA was elevated throughout the experiment. The GABA content in the nucleus decreased and increased respectively during early and late convulsions. Reductions occurred in hippocampal glutamate during convulsive and postconvulsive periods. Glutamate content in the caudate nucleus was reduced during late convulsive and postconvulsive periods. The data suggest that subcortical alterations in the GABA system are important etiologic factors in m-fluorotyrosine seizures.     

New and investigational antiepileptic drugs

In the last fifteen years, new antiepileptic medications have been offered for the treatment of patients with epilepsy. Nevertheless, despite optimal medical treatment, up to 30% of patients still experience recurrent seizures and the challenge for new, more efficacious and better-tolerated drugs continues. New antiepileptic drugs include the evolution of pre-existing drugs and new compounds identified through the investigation of additional molecular targets, such as SV2A synaptic vesicle protein, voltage-gated potassium channels, ionotropic and metabotropic glutamate receptors, and gap junctions. This paper reviews the available information on various classes of molecules that are in the pipeline as well as on the innovative approaches to the treatment of epilepsy.