Noncompetitive AMPA Receptor Antagonist Research Articles

An In Vivo Electroencephalographic Analysis of the Effect of Riluzole against Limbic and Absence Seizure and Comparison with Glutamate Antagonists.

Riluzole (RLZ) has demonstrated neuroprotective effects in several neurological disorders. These neuroprotective effects seem to be mainly due to its ability to inhibit the excitatory glutamatergic neurotransmission, acting on different targets located both at the presynaptic and postsynaptic levels. In the present study, we evaluated the effects of Riluzole (RLZ) against limbic seizures, induced by AMPA, kainate, and NMDA receptor agonists in Sprague-Dawley rats, and in a well-validated genetic model of absence epilepsy, the WAG/Rij rat. Furthermore, in this latter model, we also studied the effect of RLZ in co-administration with the competitive NMDA receptor antagonist, CPP, or the non-competitive AMPA receptor antagonist, THIQ-10c, on spike-wave discharges (SWDs) in WAG/Rij rats, to understand the potential involvement of AMPA and NMDA receptors in the anti-absence effect of RLZ. In Sprague-Dawley rats, RLZ pretreatment significantly reduced the limbic seizure severity induced by glutamatergic agonists, suggesting an antagonism of RLZ mainly on NMDA rather than non-NMDA receptors. RLZ also reduced SWD parameters in WAG/Rij rats. Interestingly, the co-administration of RLZ with CPP did not increase the anti-absence activity of RLZ in this model, advocating a competitive effect on the NMDA receptor. In contrast, the co-administration of RLZ with THIQ-10c induced an additive effect against absence seizure in WAG/Rij rats. these results suggest that the antiepileptic effects of RLZ, in both seizure models, can be mainly due to the antagonism of the NMDA glutamatergic receptors.

EARLY ONSET AGGRESSIVE BEHAVIOR INDUCED BY PERAMPANEL IN THE TREATMENT OF CHRONIC INSOMNIA: A CASE REPORT

IntroductionChronic insomnia, resistant to different treatments (pharmacological, sleep hygiene and cognitive-behavioral therapy) remains one of the greatest challenges in our daily practice as psychiatrists. The pharmacological options include benzodiazepines and their analogues (zolpidem, zopiclone, etc.). However, when trying to treat chronic insomnia the use of off-label drugs, including antidepressants with sedative action (such as trazodone), antipsychotics or antiepiletic drugs, is not uncommon.Perampanel is a non-competitive AMPA receptor antagonist, marketed for the treatment of partial onset epilepsy and primary generalized tonic-clonic seizures. It has been used in the treatment of chronic insomnia with positive results and it has shown to improve the quality of sleep in a recent observational retrospective cohort study.The most frequent adverse effects of Perampanel include dizziness and drowsiness. Perampanel can also cause psychiatric and behavioral adverse effects, aggression and irritability in up to 10% of patients, as well as depression, and suicidal ideation, with higher rates in patients with psychiatric history.ObjectivesTo draw attention to possible adverse effects of Perampanel and to add knowledge to improve the treatment for chronic insomnia.MethodsCase report and non-systematic literature review of the current data.ResultsA 33 year old woman with Anorexia Nervosa was admitted to the psychiatric hospitalization unit due to suicidal ideation and a history of chronic insomnia. Perampanel was started at a dose of 2mg/day, progressively titrated to 6mg/day, following patient’s informed consent. A week after the initiation of treatment, her sleep pattern had improved but she became aggressive, showed low tolerability to minor frustrations and suffered from an intensification of suicidal ideation. She became extremely hostile to the personnel, had severe tantrums and deliberate self injurious behavior. Perampanel was discontinued and in less than a week her aggressive behavior succumbed. Although she was not re-exposed to Perampanel the symptoms she presented are considered a very likely adverse drug reaction. Levomepromazine 20mg/day and Lormetazepam 0.5mg/day were reinstated as a treatment for insomnia.ConclusionsPsychiatric comorbidity is known to be a risk factor for behavioral adverse effects of Perampanel. Therefore Perampanel as a treatment for chronic insomnia needs a careful individual benefit-risk assessment and monitoring for adverse effects.Disclosure of InterestNone Declared

Effectiveness and tolerability of perampanel in сhildren and adolescents (own experience of Svt. Luka’s Institute of Child Neurology and Epilepsy)

Effectiveness and tolerability of perampanel in сhildren and adolescents (own experience of Svt. Luka’s Institute of Child Neurology and Epilepsy)

Treatment of epilepsy associated with primary and metastatic brain tumors

There is a number of unsolved issues in management of epilepsy associated with primary and metastatic brain tumors (BTs). In particular, no consensus approaches to treatment of patients with epilepsy associated with BTs have been proposed regarding use of current anti-epileptic drugs (AEDs). The review presents the relevant data on epidemiology, features of clinically manifested epilepsy at varying stages of BTs, aspects of drug-drug interaction between AEDs and anti-tumor agents, AED-related effects on cognitive functions as well as quality of life in patients with epilepsy associated with BTs. Levetiracetam and valproic acid comprise the first-line drugs for treating seizures in patients with BTs. It is unreasonable to use AEDs acting as hepatic microsomal enzyme inducers for therapy of epileptic seizures in BTs, because it may decrease efficacy of chemotherapy agents and glucocorticoids along with elevated rate of side effects. Perampanel acting as a selective noncompetitive AMPA receptor antagonist, may be one of the drugs of choice for the adjunctive therapy of epileptic seizures associated with BTs.

Effects of the noncompetitive AMPA receptor antagonist perampanel on thalamo-cortical excitability: A study of high-frequency oscillations in somatosensory evoked potentials

We designed a longitudinal cohort study on People with Epilepsy (PwE) with the aim of assessing the effect of Perampanel (PER) on cortico-subcortical networks, as measured by high-frequency oscillations of somatosensory evoked potentials (SEP-HFOs). SEP-HFOs measure the excitability of both thalamocortical projections (early HFOs) and intracortical GABAergic synapses (late HFOs), thus they could be used to study the anti-glutamatergic action of PER, a selective antagonist of the AMPA receptor.

Multiple synaptic connections into a single cortical pyramidal cell or interneuron in the anterior cingulate cortex of adult mice

The ACC is an important brain area for the processing of pain-related information. Studies of synaptic connections within the ACC provide an understanding of basic cellular and molecular mechanisms for brain functions such as pain, emotion and related cognitive functions. Previous study of ACC synaptic transmission mainly focused on presumably thalamic inputs into pyramidal cells. In the present study, we developed a new mapping technique by combining single neuron whole-cell patch-clamp recording with 64 multi-channel field potential recording (MED64) to examine the properties of excitatory inputs into a single neuron in the ACC. We found that a single patched pyramidal neuron or interneuron simultaneously received heterogeneous excitatory synaptic innervations from different subregions (ventral, dorsal, deep, and superficial layers) in the ACC. Conduction velocity is faster as stimulation distance increases in pyramidal neurons. Fast-spiking interneurons (FS-IN) show slower inactivation when compared to pyramidal neurons and regular-spiking interneurons (RS-IN) while pyramidal neurons displayed the most rapid activation. Bath application of non-competitive AMPA receptor antagonist GYKI 53655 followed by CNQX revealed that both FS-INs and RS-INs have AMPA and KA mediated components. Our studies provide a new strategy and technique for studying the network of synaptic connections.

Effects of the noncompetitive AMPA receptor antagonist perampanel on thalamo-cortical excitability: A study of high-frequency oscillations in somatosensory evoked potentials

ObjectiveWedesignedalongitudinalcohortstudyon People with Epilepsy (PwE) with the aimofassessingthe effect of Perampanel (PER) oncortico-subcortical networks, as measured by high-frequency oscillations of somatosensory evoked potentials (SEP-HFOs). SEP-HFOs measure the excitability of both thalamo-corticalprojections(early HFOs) and intracortical GABAergic synapses (late HFOs), thus they could be used to study the anti-glutamatergic action of PER, a selective antagonist of the AMPA receptor. Methods15 PwE eligible for PER add-on therapy, were enrolled prospectively. Subjects underwent SEPs recording from the dominant hand at two times: PwET0 (baseline, before PER titration) and PwET1 (therapeutic dose of 4 mg). HFOs were obtained by filtering N20 scalp response in the 400–800 Hz range. Patients were compared with a normative population of 15 healthy controls (HC) matched for age and sex. ResultsWe found a significant reduction ofTotal HFOs and mostly early HFOs area between PwET0 and PwET1 (p = 0.05 and p = 0.045 respectively) and between HC and PwET1 (p = 0.01). Furthermore, we found a significant reduction of P24/N24 Amplitude between PwET0 and HC and between PwET0 and PwET1 (p = 0.006 and p = 0.032, respectively). ConclusionsIntroduction of PER as add-on therapy reduced the area of total HFOs, acting mainly on the early burst, related to thalamo-cortical pathways. Furthermore P24/N24 amplitude, which seems to reflect a form of cortico-subcortical integration, resulted increased in PwE at T0 and normalized at T1. SignificanceOur findings suggest that PER acts on cortico-subcortical excitability. This could explain the broad spectrum of PER and its success in forms of epilepsy characterized by thalamo-cortical hyperexcitability.

An Evidence-Based Review On The Use Of Perampanel For The Treatment Of Focal-Onset Seizures In Pediatric Patients.

Perampanel, a non-competitive AMPA receptor antagonist, is a once-daily oral antiepileptic drug approved for the treatment of focal seizures and primary generalized tonic–clonic seizures in children 12 years of age and over. We conducted a systematic review of the data on perampanel in children and adolescents with focal-onset seizures. We found 21 published papers on the pediatric use of perampanel for focal-onset seizures, including 9 papers on clinical trials and ancillary studies of these trials, of which 2 focused on pharmacokinetics, 1 was a meta-analysis, and 9 were real-life studies (1 was prospective). Perampanel, as an adjunctive treatment for uncontrolled focal-onset seizures, results in an improvement of seizure control with a generally good safety profile. Evidence-based data are currently available for children 12 years of age and over. Higher amounts of perampanel might be required in patients taking enzyme-inducing antiepileptic drugs. The most common adverse events are somnolence, dizziness and behavioral adverse events. The latter seems more frequent in adolescents than in adults and in adolescents with preexisting behavioral comorbidities. Current studies did not identify any short-term impact of perampanel on cognitive functions. Its long half-life allows once-daily administration. Real-life studies further established that a decrease of the dose frequently resolves adverse events, as demonstrated in pivotal studies. Pharmacokinetic and safety studies are still ongoing in the younger population, down to 4 years of age, in order to apply for approval in this age group.

TARP mediation of accelerated and more regular locus coeruleus network bursting in neonatal rat brain slices

Transmembrane AMPA receptor (AMPAR) regulatory proteins (TARP) increase neuronal excitability. However, it is unknown how TARP affect rhythmic neural network activity. Here we studied TARP effects on local field potential (LFP) bursting, membrane potential and cytosolic Ca2+ (Cai) in locus coeruleus neurons of newborn rat brain slices. LFP bursting was not affected by the unselective competitive ionotropic glutamate receptor antagonist kynurenic acid (2.5 mM). TARP-AMPAR complex activation with 25 μM CNQX accelerated LFP rhythm 2.2-fold and decreased its irregularity score from 63 to 9. Neuronal spiking was correspondingly 2.3-fold accelerated in association with a 2–5 mV depolarization and a modest Cai rise whereas Cai was unchanged in neighboring astrocytes. After blocking rhythmic activities with tetrodotoxin (1 μM), CNQX caused a 5–8 mV depolarization and also the Cai rise persisted. In tetrodotoxin, both responses were abolished by the non-competitive AMPAR antagonist GYKI 53655 (25 μM) which also reversed stimulatory CNQX effects in control solution. The CNQX-evoked Cai rise was blocked by the L-type voltage-activated Ca2+ channel inhibitor nifedipine (100 μM). The findings show that ionotropic glutamate receptor-independent neonatal locus coeruleus network bursting is accelerated and becomes more regular by activating a TARP-AMPAR complex. The associated depolarization-evoked L-type Ca2+ channel-mediated neuronal Cai rise may be pivotal to regulate locus coeruleus activity in cooperation with SK-type K+ channels. In summary, this is the first demonstration of TARP-mediated stimulation of neural network bursting. We hypothesize that TARP-AMPAR stimulation of rhythmic locus coeruleus output serves to fine-tune its control of multiple brain functions thus comprising a target for drug discovery.

Modulation of AMPA Receptor Gating by the Anticonvulsant Drug, Perampanel.

Postsynaptic AMPA/glutamate receptors, essential for neuronal excitability, are important targets for anticonvulsant therapy. This single channel study of the selective noncompetitive AMPA receptor antagonist, perampanel, was performed on homotetrameric GluA3 receptor-channels that open in a stepwise manner to four distinct conductance levels through independent subunit activation. Previous structural studies show that perampanel binds to four sites located within the extracellular/transmembrane boundary of closed AMPA receptor-channel subunits. We found that channels exposed to 1 or 2 μM perampanel opened mainly to the two lower conductance levels in a dose-dependent manner. Comparison of the single channel results in the structures of the full length AMPA receptor in the closed state bound to perampanel, and the open state provide insights into the mechanism of allosteric reduction of AMPA-receptor-mediated excitation in epilepsy.

Phthalazine-1,4-dione derivatives as non-competitive AMPA receptor antagonists: design, synthesis, anticonvulsant evaluation, ADMET profile and molecular docking.

In view of the anticonvulsant activity reported for phthalazine derivatives as non-competitive AMPA receptor antagonists, a new series of phthalazine-1,4-diones (2-12) were designed and synthesized. The neurotoxicity was assessed using rotarod test. The molecular docking was performed for the synthesized compounds to assess their binding affinities toward AMPA receptor as non-competitive antagonists. The molecular modeling data were strongly interrelated to biological screening data. Compounds 8, 7b, 7a, 10 and 3a exhibited the highest binding affinities as non-competitive AMPA receptor antagonists and also showed the highest relative potencies of 1.78, 1.66, 1.60, 1.59 and 1.29, respectively, as anticonvulsants in comparison with diazepam. The most active compounds 8, 7b, 7a, 10 and 3a were further tested against maximal electroshock seizure (MES). Compounds 8 and 7b and 3a showed 100% protection at a dose level of 125µgm/kg, while compounds 7a and 10 exhibited 83.33% protection at the same dose level. These agents exerted low neurotoxicity and high safety margin in comparison with valproate as a reference drug. Most of our designed compounds exhibited good ADMET profile.

Perampanel, an AMPA receptor antagonist: From clinical research to practice in clinical settings.

Epileptic seizures are refractory to treatment in approximately one-third of patients despite the recent introduction of many newer antiepileptic drugs (AEDs). Development of novel AEDs therefore remains a high priority. Perampanel is a first-in-class non-competitive selective AMPA receptor antagonist with a unique mechanism of action. Clinical efficacy and safety of perampanel as adjunctive treatment for focal seizures with/without secondary generalization (±SG) and primary generalized tonic-clonic (PGTC) seizures have been established in five phase 3 randomized controlled trials (RCTs), and a long-term extension study, and perampanel is approved as monotherapy for focal seizures ±SG in the USA. In patients with focal seizures ±SG, add-on perampanel resulted in median percent reduction in seizure frequency 23.3%-34.5% and ≥50% responder rate 28.5%-37.6%; in PGTC seizures, these results were 76.5% and 64.2%, respectively. Efficacy among adolescents (reduction in seizure frequency 34.8%-35.6%; ≥50% responder rate 40.9%-45.0%) and elderly people (reduction in seizure frequency 12.5%-16.9%; ≥50% responder rate 22.2%-42.9%) is similar to those in adults, and results remain comparable between Asian (reduction in seizure frequency 17.3%-38.0%) and global populations. Perampanel has been extensively studied in real-world clinical practice, with similar efficacy and safety results to the RCTs (≥50% responder rate 12.8%-75.0%; adverse events of somnolence/sedation, dizziness, ataxia, and behavioral changes). Real-world observational studies suggest that perampanel tolerability can be improved by slow titration (2mg every 2-4weeks), and bedtime administration can mitigate somnolence and dizziness. Counseling about the potential for behavioral changes and close monitoring are recommended.

Pahse 2 clinical trial with perampanel for sporadic ayotrophic lateral sclerosis

Background: Perampanel, a selective non-competitive AMPA receptor antagonist, has been reported to prevent the progression of the model mouse for sporadic amyotrophic lateral sclerosis (ALS) (AR2 mice), in which an RNA editing enzyme adenosine deaminase acting on RNA2 (ADAR2) is conditionally knocked out in the motor neurons. Because of therapeutic potency of perampanel for sporadic ALS, we planned to perform a clinical trial with perampanel for sporadic ALS.

Effect of enzyme inhibition on perampanel pharmacokinetics: Why study design matters

ObjectivesPerampanel, a selective, noncompetitive AMPA receptor antagonist, is indicated as adjunctive therapy for the treatment of partial seizures with or without secondarily generalized seizures and primary generalized tonic-clonic seizures in patients with epilepsy aged 12years and older. In vitro studies and Phase I trials indicate that perampanel is metabolized almost exclusively by CYP3A, with an elimination half-life (t1/2) averaging approximately 105h. Understanding of pharmacokinetic (PK) interactions—enzyme inhibition or induction—and anticipating their occurrence are important for management of patients with epilepsy. Here we report PK results from a Phase I drug-drug interaction (DDI) study (Study 005) combining perampanel with the CYP3A inhibitor ketoconazole, as well as supplementary in silico predictions further exploring this interaction. MethodsA Phase I, randomized, open-label, two-period, two-treatment, two-way crossover study was conducted in 26 healthy adult male volunteers. Subjects were randomized to 1 of 2 treatment sequences. In one period, subjects received a single 1-mg fasting dose of perampanel (Day1); in the other period, subjects received ketoconazole 400mg once daily for 10days with a single 1-mg perampanel dose while fasting (Day3). Blood samples were drawn at multiple time points up to 288h after the perampanel dose. Pharmacokinetic parameters of perampanel were calculated by noncompartmental analysis, and safety was recorded. An integrated, physiologically based PK model built in Simcyp® provided additional insight into this interaction. Drug-drug interaction intensity was measured by the ratio of systemic exposure (area under plasma concentration-time curve [AUC]) of perampanel in the presence or absence of concomitant ketoconazole. ResultsSingle oral doses of 1mg perampanel and once-daily oral doses of ketoconazole 400mg were safe and well tolerated. Maximum perampanel plasma concentration (Cmax) and time to Cmax showed no apparent differences when perampanel was administered alone versus with ketoconazole. Ketoconazole co-administration resulted in an approximate 20% increase in perampanel AUC (P<0.001). This increase, although statistically significant, was a<2.0-fold AUC change and alone would suggest a modest effect of ketoconazole. To further explore these results, DDI simulations were performed to query the findings and test additional study conditions. Using the actual trial conditions of Study 005, the simulations also predicted an AUC ratio increase <2-fold, providing verification of the simulation assumptions and the modest effect of ketoconazole for 10days. Simulations further suggested that an interaction effect of ketoconazole on perampanel exposure (>2-fold) of potential clinical significance could be predicted when using larger doses of ketoconazole (e.g., 200mg every 6h) coadministered for a greater time period (e.g., 30days), with AUC ratio as high as 3.36. Additionally, simulations suggested that a significant interaction with co-administration of perampanel and an inhibitor more potent than ketoconazole (such as itraconazole) could not be ruled out. ConclusionsSelecting an appropriate study design is critical to fully characterize the PK interaction for drugs such as perampanel that have a long t1/2. Although a negligible effect on perampanel PK was observed following co-administration of ketoconazole 400mg/day for 10days, this is likely due in part to the relatively brief co-administration period of ketoconazole and perampanel (<3 times the t1/2 of perampanel). While short-term administration of a CYP3A inhibitor may not significantly increase perampanel exposure, such increases may be expected following chronic and larger dosing or with a more potent inhibitor.

Perampanel in the treatment of patients with epilepsy

Development of new antiepileptic drugs (AED) does not stop due to the fact that the number of patients with pharmacoresistant epilepsy remains at about 30%. One of the newest AEDs is perampanel (PER), a selective, non-competitive AMPA receptor antagonist to target post-synaptic glutamate transmission. PER is approved in the Russian Federation as adjunctive treatment for focal seizures with or without secondarily generalized seizures and for primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE) in patients with epilepsy aged ≥12 years. The drug is effective and well-tolerated in the dose of 4-8 mg/day, and most side effects are dose-dependent. The high efficacy of PER combined with the good tolerability, absence of life-threatening adverse reactions and convenient intake allow us to recommend PER as the first choice additional drug in treatment of patients with epilepsy.

The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice.

Both TDP-43 pathology and failure of RNA editing of AMPA receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of the majority of patients with amyotrophic lateral sclerosis (ALS). AR2 mice, in which an RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is conditionally knocked out in the motor neurons, exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons through a Ca2+-permeable AMPA receptor-mediated mechanism. Therefore, amelioration of the increased Ca2+ influx by AMPA receptor antagonists may be a potential ALS therapy. Here, we showed that orally administered perampanel, a selective, non-competitive AMPA receptor antagonist significantly prevented the progression of the ALS phenotype and normalized the TDP-43 pathology-associated death of motor neurons in the AR2 mice. Given that perampanel is an approved anti-epileptic drug, perampanel is a potential candidate ALS drug worthy of a clinical trial.

Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8

Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.

Efficacy and tolerability of adjunct perampanel based on number of antiepileptic drugs at baseline and baseline predictors of efficacy: A phase III post-hoc analysis

Perampanel is a selective, noncompetitive AMPA receptor antagonist with demonstrated efficacy and tolerability in partial seizures in patients aged ≥12 years in Phase III studies. Post-hoc analysis of these studies was conducted to determine the efficacy and tolerability of perampanel based on the number of concomitant antiepileptic drugs (AEDs) at baseline, as well as to examine which baseline characteristics, if any, were predictors of efficacy. Efficacy parameters were based on the number of baseline AEDs, and logistic regression analyses were used to evaluate the association of demographic and baseline clinical factors with probability of ≥50% reduction in seizure frequency. Patients on 1 AED at baseline were significantly more likely to have reduced seizure frequency (P<0.02) and improved 50% responder rate (P<0.02) than patients on 3 AEDs at baseline. Secondarily generalized seizures at baseline, unknown etiology, and use of concomitant non-inducer AEDs were also established as positive predictors of efficacy (50% responder rate; P<0.01). Patients with more AEDs at baseline were associated with greater use of inducers (P<0.01), which may result in decreased exposure of perampanel in these patients and lower efficacy. Patients with 1 AED at baseline had a significantly shorter time since diagnosis compared with patients in the 3 (P<0.01) AEDs group, as well as a lower median seizure frequency at baseline compared to patients on 3 AEDs (P<0.05), suggesting that the reduced efficacy of perampanel with 3 AEDs may also be associated with the greater severity of seizures in the patient groups. The incidence of adverse events in perampanel-treated patients was similar regardless of the number of AEDs at baseline. Greater efficacy is predicted for patients receiving fewer concomitant AEDs when starting perampanel, as well as for those receiving concomitant treatment with AEDs that are not CYP3A4 enzyme-inducers, compared to patients treated with multiple concomitant AEDs. The results of this study provide additional information for clinicians considering adding perampanel to their patients’ treatment regimen earlier rather than later, and offer evidence regarding the potential for increased efficacy with a decreased medication burden.

The Noncompetitive AMPAR Antagonist Perampanel Abrogates Brain Endothelial Cell Permeability in Response to Ischemia: Involvement of Claudin-5.

The blood-brain barrier (BBB) is formed by brain endothelial cells, and decreased BBB integrity contributes to vasogenic cerebral edema and increased mortality after stroke. In the present study, we investigated the protective effect of perampanel, an orally active noncompetitive AMPA receptor antagonist, on BBB permeability in an in vitro ischemia model in murine brain endothelial cells (mBECs). The results showed that perampanel significantly attenuated oxygen glucose deprivation (OGD)-induced loss of cell viability, release of lactate dehydrogenase, and apoptotic cell death in a dose-dependent manner. Perampanel treatment did not alter the expression and surface distribution of various glutamate receptors. Furthermore, the results of calcium imaging showed that perampanel had no effect on OGD-induced increase in intracellular Ca(2+) concentrations. Treatment with perampanel markedly reduced the paracellular permeability of mBECs after OGD in different time points, as measured by transepithelial electrical resistance assay. In addition, the expression of claudin-5 at protein level, but not at mRNA level, was increased by perampanel treatment after OGD. Knockdown of claudin-5 partially prevented perampanel-induced protection in cell viability and BBB integrity in OGD-injured mBECs. These data show that the noncompetitive AMPA receptor antagonist perampanel affords protection against ischemic stroke through caludin-5 mediated regulation of BBB permeability.

Perampanel in patients with refractory and super-refractory status epilepticus in a neurological intensive care unit.

In refractory status epilepticus (SE), because of subcellular maladaptive changes, GABAergic drugs are no longer effective, and the excitatory neurotransmitter glutamate (Glu) plays a major role in seizure perpetuation. Perampanel (PER, licensed since 09/2012) is the first orally active noncompetitive AMPA receptor antagonist for adjunctive treatment of refractory focal epilepsy. We analyzed treatment response, seizure outcome, and adverse effects of add-on treatment with perampanel in patients with refractory status epilepticus in the Neurological Intensive Care Unit (NICU), Salzburg, Austria between 09/2012 and 11/2014 by retrospective chart review. Twelve patients (75% women) with refractory status epilepticus were treated with PER administered per nasogastric tube between 09/2012 and 11/2014. Median age was 75 years [range: 60-91]. The most frequent SE type was nonconvulsive SE (NCSE) with (5/12, 42%) and without coma (6/12, 50%). In seven patients (58%), SE arose de novo, with an acute symptomatic cause in five patients (42%). Cerebrovascular diseases (4/12, 33%) and cerebral tumors (4/12, 33%) were the most common etiologies. Perampanel was given after a median number of four antiepileptic drugs [range: 2-7] and a median time of 1.5 days [range: 0.8-18.3]. In one patient (8%), clinical improvement was observed within 24h and EEG improvement within 60 h after administration of PER, while in another patient (8%), clinical and EEG improvement was observed more than 48 h after administration. Median initial dose was 4 mg [range: 2-12; SD: 4.11], titrated up to a median of 12 mg [range: 4-12] in steps of 2 to 4 mg per day. No adverse effects were reported regarding cardiorespiratory changes or laboratory parameters. Outcomes after SE were moderate disability in five patients (42%), death in three patients (25%), and persistent vegetative state in two patients (17%). Though glutamate plays a major role in seizure perpetuation, the noncompetitive AMPA receptor antagonist PER could only ameliorate seizure activity in a few patients with refractory SE. The long duration of SE before the administration of PER via nasogastric tube, as well as relatively low doses of PER, might be responsible for the modest result. Perampanel was well tolerated, and no adverse events were reported. This article is part of a Special Issue entitled Status Epilepticus.