Epilepsy in adults

Thijs, Roland D.; Surges, Rainer; O’Brien, Terence J.; Sander, Josemir W.

doi:10.1016/s0140-6736(18)32596-0

Cited by 1,166 publications

(697 citation statements)

References 180 publications

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Section: Introductionmentioning

confidence: 99%

“…Epilepsy is one of the most common neurologic diseases worldwide, and is associated with a significant healthcare burden (Devinsky et al, 2018;Thijs et al, 2019). For most patients with epilepsy, antiepileptic drugs (AEDs) are the mainstay of therapy, which must be taken on a long-term, often lifelong basis (Trinka, 2012;Thijs et al, 2019). Antiepileptic drugs approved in the last decade display good safety and pharmacokinetic profiles; however, thus far improved efficacy over first-generation AEDs has not been demonstrated in clinical studies (Chen et al, 2018), and approximately one-third of patients with epilepsy continue to experience poorly controlled seizures despite treatment, i.e., drug-resistant epilepsy (Kwan et al, 2010;Kalilani et al, 2018;Chen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Characterization in Rodent Seizure and Epilepsy Models

Leclercq

Provins

Klitgaard

et al. 2019

J Pharmacol Exp Ther

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The antiepileptic drug (AED) candidate, (4R)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one (padsevonil), is the first in a novel class of drugs that bind to synaptic vesicle protein 2 (SV2) proteins and the GABA A receptor benzodiazepine site, allowing for pre-and postsynaptic activity, respectively. In acute seizure models, padsevonil provided potent, dose-dependent protection against seizures induced by administration of pilocarpine or 11-deoxycortisol, and those induced acoustically or through 6 Hz stimulation; it was less potent in the pentylenetetrazol, bicuculline, and maximal electroshock models. Padsevonil displayed dosedependent protective effects in chronic epilepsy models, including the intrahippocampal kainate and Genetic Absence Epilepsy Rats from Strasbourg models, which represent human mesial temporal lobe and absence epilepsy, respectively. In the amygdala kindling model, which is predictive of efficacy against focal to bilateral tonic-clonic seizures, padsevonil provided significant protection in kindled rodents; in mice specifically, it was the most potent AED compared with nine others with different mechanisms of action. Its therapeutic index was also the highest, potentially translating into a favorable efficacy and tolerability profile in humans. Importantly, in contrast to diazepam, tolerance to padsevonil's antiseizure effects was not observed in the pentylenetetrazolinduced clonic seizure threshold test. Further results in the 6 Hz model showed that padsevonil provided significantly greater protection than the combination of diazepam with either 2S-(2-oxo-1-pyrrolidinyl)butanamide (levetiracetam) or 2S-2-[(4R)-2-oxo-4-propylpyrrolidin-1-yl] butanamide (brivaracetam), both selective SV2A ligands. This observation suggests that padsevonil's unique mechanism of action confers antiseizure properties beyond the combination of compounds targeting SV2A and the benzodiazepine site. Overall, padsevonil displayed robust efficacy across validated seizure and epilepsy models, including those considered to represent drug-resistant epilepsy. SIGNIFICANCE STATEMENTPadsevonil, a first-in-class antiepileptic drug candidate, targets SV2 proteins and the benzodiazepine site of GABA A receptors. It demonstrated robust efficacy across a broad range of rodent seizure and epilepsy models, several representing drug-resistant epilepsy. Furthermore, in one rodent model, its efficacy extended beyond the combination of drugs interacting separately with SV2 or the benzodiazepine site. Padsevonil displayed a high therapeutic index, potentially translating into a favorable safety profile in humans; tolerance to antiseizure effects was not observed.All studies described in this report were funded by UCB Pharma. All authors are current or former employees of UCB Pharma.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Characterization in Rodent Seizure and Epilepsy Models

Leclercq

Provins

Klitgaard

et al. 2019

J Pharmacol Exp Ther

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“…To analyse EEG frequency, amplitude signal (power spectral density and EEG spectrogram of the data) and seizures onset, EEG data was uploaded into Labchart7 software (AD instruments Ltd, Oxford, UK). EEG total power (μV 2 ) is a function of EEG amplitude over time and was analysed by integrating frequency bands from 0 to 100 Hz. Power spectral density heat maps were generated using LabChart (spectral view), with the frequency domain filtered from 0 to 40 Hz and the amplitude domain filtered from 0 to 50 mV.…”

Section: Methodsmentioning

confidence: 99%

“…Epilepsy is one of the most common chronic neurological disorders, affecting approximately 70 million people worldwide 1,2 . Temporal lobe epilepsy (TLE) is the most common refractory form of epilepsy in adults and typically results from an earlier precipitating insult that causes structural and functional reorganisation of neuronal-glial networks within the hippocampus resulting in chronic hyperexcitability 3 .…”

Section: Introductionmentioning

confidence: 99%

Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

Parras

García

Alves

et al. 2019

Preprint

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34The molecular mechanisms that shape the gene expression landscape during the development 35 and maintenance of chronic states of brain hyperexcitability are incompletely understood. 36 Here we show that cytoplasmic mRNA polyadenylation, a posttranscriptional mechanism for 37 regulating gene expression, undergoes widespread reorganisation in temporal lobe epilepsy. 38 Specifically, over 25% of the hippocampal transcriptome displayed changes in their poly(A) 39 tail in mouse models of epilepsy, particular evident in the chronic phase. The expression of 40 cytoplasmic polyadenylation binding proteins (CPEB1-4) was found to be altered in the 41 hippocampus in mouse models of epilepsy and temporal lobe epilepsy patients and CPEB4 42 target transcripts were over-represented among those showing poly(A) tail changes. 43 Supporting an adaptive function, CPEB4-deficiency leads to an increase in seizure severity 44 and neurodegeneration in mouse models of epilepsy. Together, these findings reveal an 45 additional layer of gene expression control during epilepsy and point to novel targets for 46 seizure control and disease-modification in epilepsy. 47 48 49 50 51 52 53 54 55 56 57 58 59 Epilepsy is one of the most common chronic neurological disorders, affecting approximately 60 70 million people worldwide 1,2 . Temporal lobe epilepsy (TLE) is the most common 61 refractory form of epilepsy in adults and typically results from an earlier precipitating insult 62 that causes structural and functional reorganisation of neuronal-glial networks within the 63 hippocampus resulting in chronic hyperexcitability 3 . These network changes, which include 64 selective neuronal loss, gliosis and synaptic remodelling, are driven in part by large-scale 65 changes in gene expression 4-7 . The gene expression landscape continues to be dysregulated 66 once epilepsy is established 8 . 67 Recent studies have uncovered important roles for post-transcriptional mechanisms during 68 the development of epilepsy. These include the actions of small noncoding RNA, such as 69 microRNA and post-translational control of protein turnover via the proteasome contributing 70to altered levels of ion channels, changes in neuronal micro-and macro-structure and glial 71 responses within seizure-generating neuronal circuits 9-13 . The molecular mechanisms 72 underlying the transcriptional and translational landscape in epilepsy remain, however, 73 incompletely understood. 74In the cell nucleus, the majority of mRNAs acquire a non-templated poly(A) tail. Although 75 the addition of a poly(A) tail seems to occur by default, the subsequent control of poly(A) tail 76 length is highly regulated both in the nucleus and cytoplasm 14 . Cytoplasmic mRNA 77 polyadenylation contributes to the regulation of the stability, transport and translation of 78 mature transcripts, and is therefore an essential post-transcriptional mechanism for regulating 79 spatio-temporal gene expression 14 . 80The cytoplasmic polyadenylation element binding proteins (CPEBs) are ...

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“…Epilepsy is characterized by an enduring predisposition to increased hyperexcitability states in the brain and is one of most common chronic brain diseases affecting up to 70 million people worldwide. Despite the increasing number of anti-epileptic drugs available in the clinic, drug resistance to pharmacological interventions remains steadily at 30% (Thijs et al, 2019). Status epilepticus, medical emergency defined as prolonged continuous seizure activity lasting longer than 5 min, is associated with high mortality and can cause wide-spread brain damage and serious neurological complications including the development of epilepsy (Betjemann and Lowenstein, 2015).…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of the Metabotropic P2Y Receptor Family in the Cortex Following Status Epilepticus and Neuroprotection via P2Y1 Antagonism in Mice

2020

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Purinergic signaling via P2 receptors is now widely accepted to play a critical role during increased states of hyperexcitability and seizure-induced pathology. In the setting of seizures and epilepsy, most attention has been paid to investigating the fast-acting ATPgated P2X receptor family. More recent evidence has now also provided compelling evidence of an involvement of the slower-acting P2Y receptor family during seizures. This includes data demonstrating expression changes of P2Y receptors in the hippocampus following acute seizures and during epilepsy and anticonvulsive properties of P2Ytargeting drugs; in particular drugs targeting the P2Y 1 subtype. Seizures, however, also involve damage to extra-hippocampal brain regions such as the cortex, which is thought to contribute to the epileptic phenotype. To analyze expressional changes of the P2Y receptor family in the cortex following status epilepticus and to determine the impact of drugs interfering with P2Y 1 signaling on cortical damage, we used a unilateral mouse model of intraamygdala kainic acid-induced status epilepticus. Analysis of cortical tissue showed that status epilepticus leads to a global up-regulation of the P2Y receptor family in the cortex including P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 , with the P2Y 1 and P2Y 4 receptor subtypes showing the strongest increase. Supporting a detrimental role of P2Y 1 activation during status epilepticus, treatment with the P2Y 1 agonist MRS2365 exacerbated high frequency high amplitude spiking, synonymous with injury-causing electrographic activity, and treatment with the P2Y 1 antagonists MRS2500 protected against seizure-induced cortical damage. Suggesting P2Y 1 -mediated effects are predominantly due to increased microglia activation, treatment with the broad-spectrum anti-inflammatory drug minocycline abolished the observed neuroprotective effects of P2Y 1 antagonism. In conclusion, our results further support a role for P2Y 1 -mediated signaling during seizure generation and seizure-induced neurodegeneration, suggesting P2Y 1 -targeting therapies as novel treatment for drug-refractory status epilepticus.

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Epilepsy in adults

Cited by 1,166 publications

References 180 publications

Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Characterization in Rodent Seizure and Epilepsy Models

Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Characterization in Rodent Seizure and Epilepsy Models

Large-scale changes to mRNA polyadenylation in temporal lobe epilepsy

Differential Expression of the Metabotropic P2Y Receptor Family in the Cortex Following Status Epilepticus and Neuroprotection via P2Y1 Antagonism in Mice

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