Novel therapies for epilepsy in the pipeline

Mesraoua, Boulenouar; Deleu, Dirk; Kullmann, Dimitri M.; Shetty, Ashok K.; Boon, Paul; Perucca, Emilio; Mikati, Mohamad A.; Asadi‐Pooya, Ali A.

doi:10.1016/j.yebeh.2019.04.042

Cited by 36 publications

(41 citation statements)

References 107 publications

(132 reference statements)

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“…Hsiao et al (2016) recently tested a similar approach in a Dravet mouse model, in African Green Potential etiology-specific drugs ("precision medicine") that are currently used or discussed for treatment of severe pediatric-onset epilepsies Drugs are listed according to mutated genes. For a source of references, please refer to Wang et al (2017) and Mesraoua et al (2019). Note that mutations of the same gene may result in different clinical phenotypes, as recently shown for KCNQ2 mutation, in which the majority of patients have loss-of-function mutations but a small percentage have gain-of-function mutations associated with a different phenotype (Demarest and Brooks-Kayal, 2018).…”

Section: A Development Of New Antiseizure Drugs By Using New Drug-scmentioning

confidence: 93%

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

et al. 2020

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Significance Statement-Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome. 608 Löscher et al. Adapted from Rogawski and Löscher (2004), Rogawski et al. (2016), and Sills and Rogawski (2020) Molecular target ASDs that act on target Voltage-gated ion channels Voltage-gated sodium channels Phenytoin, fosphenytoin, a carbamazepine, oxcarbazepine, b eslicarbazepine acetate, c lamotrigine, lacosamide; possibly topiramate, zonisamide, rufinamide Voltage-gated calcium channels (T-type) Ethosuximide Voltage-gated potassium channels (K v 7) Retigabine (ezogabine) GABA-mediated inhibition GABA A receptors Phenobarbital, primidone, stiripentol, benzodiazepines, (including diazepam, lorazepam, midazolam and clonazepam), possibly topiramate, felbamate, retigabine (ezogabine) GAT1 GABA transporter Tiagabine GABA transaminase Vigabatrin Glutamic acid decarboxylase Possibly valproate, gabapentin, pregabalin Presynaptic release machinery SV2A Levetiracetam, brivaracetam a2d subunit of calcium channels Gabapentin, pregabalin Ionotropic glutamate receptors AMPA receptor Perampanel Carbonic anhydratase inhibition Acetazolamide, topiramate, zonisamide, possibly lacosamide Disease-specific mTORC1 signaling d Everolimus Lysosomal enzyme replacement e Cerliponase alfa (recombinant tripeptidyl peptidase 1) Mixed/unknown Valproate, felbamate, topiramate, zonisamide, rufinamide, adrenocorticotrophin (ACTH), cannabidiol, cenobamate AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate. a Fosphenytoin is a prodrug for phenytoin. b Oxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine. c Eslicarbarbazepine acetate is a prodrug for S-licarbazepine. d In patients with epilepsy because of tuberous sclerosis complex (TSC). e In patients with epilepsy because of neuronal ceroid lipofuscinosis type 2.

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Section: A Development Of New Antiseizure Drugs By Using New Drug-scmentioning

confidence: 93%

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

et al. 2020

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“…Another strategy that can be applied as a potential therapy for epilepsy is grafting medial ganglionic eminence (MGE) cells in the hippocampus (reviewed in References [ 93 , 94 ]). These cells are present in embryonic and fetal stages and differentiate into GABAergic interneurons.…”

Section: Adult Neurogenesis and Neural Stem/progenitor Cellsmentioning

confidence: 99%

“…MGE cells derived by either human embryonic/fetal stem cells or from human-induced pluripotent stem cells (hiPSCs) appears to alleviate spontaneous seizures [ 95 , 96 ]. Nonetheless, there are ethical issues to consider when using embryonic/fetal stem cells in clinical trials (reviewed in Reference [ 93 ]). Using hiPSCs-derived cells also raises some concerns, mainly due to their instability and possibility to suffer epigenetic alterations or their high proliferative rate (reviewed in Reference [ 93 ]).…”

Section: Adult Neurogenesis and Neural Stem/progenitor Cellsmentioning

confidence: 99%

“…Nonetheless, there are ethical issues to consider when using embryonic/fetal stem cells in clinical trials (reviewed in Reference [ 93 ]). Using hiPSCs-derived cells also raises some concerns, mainly due to their instability and possibility to suffer epigenetic alterations or their high proliferative rate (reviewed in Reference [ 93 ]).…”

Section: Adult Neurogenesis and Neural Stem/progenitor Cellsmentioning

confidence: 99%

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Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy

Lourenço

Ribeiro-Rodrigues

Sebastião

et al. 2020

IJMS

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Epilepsy is one of the most common brain diseases worldwide, having a huge burden in society. The main hallmark of epilepsy is the occurrence of spontaneous recurrent seizures, having a tremendous impact on the lives of the patients and of their relatives. Currently, the therapeutic strategies are mostly based on the use of antiepileptic drugs, and because several types of epilepsies are of unknown origin, a high percentage of patients are resistant to the available pharmacotherapy, continuing to experience seizures overtime. Therefore, the search for new drugs and therapeutic targets is highly important. One key aspect to be targeted is the aberrant adult hippocampal neurogenesis (AHN) derived from Neural Stem Cells (NSCs). Indeed, targeting seizure-induced AHN may reduce recurrent seizures and shed some light on the mechanisms of disease. The endocannabinoid system is a known modulator of AHN, and due to the known endogenous antiepileptic properties, it is an interesting candidate for the generation of new antiepileptic drugs. However, further studies and clinical trials are required to investigate the putative mechanisms by which cannabinoids can be used to treat epilepsy. In this manuscript, we will review how cannabinoid-induced modulation of NSCs may promote neural plasticity and whether these drugs can be used as putative antiepileptic treatment.

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“…However, these options offer the chance of seizure remission or reduction only for part of the patients with focal epilepsy, whose seizures continue despite ASD medications. Therefore, further alternative treatment approaches for DRE are investigated preclinically and clinically, such as neuronal transplantation, gene therapy, and the here reviewed intracranial drug delivery [12][13][14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Gernert¹,

Feja²

2020

Pharmaceutics

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Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often life-long) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood–brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies.

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Novel therapies for epilepsy in the pipeline

Cited by 36 publications

References 107 publications

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

Neural Stem Cells and Cannabinoids in the Spotlight as Potential Therapy for Epilepsy

Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

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