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Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0
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Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 32772

Special Issue Editors

Prof. Dr. Giuseppe Biagini

E-Mail Website
Guest Editor
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
Interests: neuroscience; peptides; steroids
Special Issues, Collections and Topics in MDPI journals
Dr. Jonathan Vinet

E-Mail Website
Guest Editor
Department of Biomedical, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy
Interests: epilepsy; neuroinflammation; microglia; myeloid cells; metalloproteinases; neuroprotection
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epilepsy is a neurological disorder affecting approximately 1% of the worldwide population. Despite the availability of antiepileptic drugs, one-third of patients are considered “drug-resistant” and fail to achieve seizure control. In the last decade, many breakthroughs have been made in identifying different mutated genes linked to severe epilepsy, which have brought new molecular players as potential therapeutic targets. Moreover, a link between epilepsy and inflammation, which has now become an important component of the disorder, has brought several inflammatory-linked mediators as further potential therapeutic targets. To this regard, a critical role has also been suggested for blood vessels, as an altered vascularization or an abnormal response of the vessel wall during the seizure may participate in the progression of damage in the epileptic tissue. Finally, all these players could significantly modulate the process of epileptogenesis, for which a regulatory pathway such as that depending on the mammalian target of rapamycin (mTOR) is intensively studied to dissect the mechanisms leading to the development of an epileptogenic environment.

This Special Issue, “Epilepsy: From Molecular Mechanisms to Targeted Therapies”, of the International Journal of Molecular Sciences will comprise a selection of research papers and reviews covering various aspects of molecular and cellular biology of epilepsy models. Studies on bioactive molecules and nutraceutical treatments modulating epileptogenesis will also be considered.

Prof. Dr. Giuseppe Biagini
Dr. Jonathan Vinet
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Blood-Brain Barrier
  • Epilepsy
  • Gene mutation
  • Microglia/Monocytes
  • Neuroinflammation
  • Neuroprotection

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Published Papers (9 papers)

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Research

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15 pages, 1647 KiB  
Article
Novel Missense CACNA1G Mutations Associated with Infantile-Onset Developmental and Epileptic Encephalopathy
by Géza Berecki, Katherine L. Helbig, Tyson L. Ware, Bronwyn Grinton, Cara M. Skraban, Eric D. Marsh, Samuel F. Berkovic and Steven Petrou
Int. J. Mol. Sci. 2020, 21(17), 6333; https://doi.org/10.3390/ijms21176333 - 31 Aug 2020
Cited by 12 | Viewed by 3391
Abstract
The CACNA1G gene encodes the low-voltage-activated Cav3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Cav3.1 dysfunction [...] Read more.
The CACNA1G gene encodes the low-voltage-activated Cav3.1 channel, which is expressed in various areas of the CNS, including the cerebellum. We studied two missense CACNA1G variants, p.L208P and p.L909F, and evaluated the relationships between the severity of Cav3.1 dysfunction and the clinical phenotype. The presentation was of a developmental and epileptic encephalopathy without evident cerebellar atrophy. Both patients exhibited axial hypotonia, developmental delay, and severe to profound cognitive impairment. The patient with the L909F mutation had initially refractory seizures and cerebellar ataxia, whereas the L208P patient had seizures only transiently but was overall more severely affected. In transfected mammalian cells, we determined the biophysical characteristics of L208P and L909F variants, relative to the wild-type channel and a previously reported gain-of-function Cav3.1 variant. The L208P mutation shifted the activation and inactivation curves to the hyperpolarized direction, slowed the kinetics of inactivation and deactivation, and reduced the availability of Ca2+ current during repetitive stimuli. The L909F mutation impacted channel function less severely, resulting in a hyperpolarizing shift of the activation curve and slower deactivation. These data suggest that L909F results in gain-of-function, whereas L208P exhibits mixed gain-of-function and loss-of-function effects due to opposing changes in the biophysical properties. Our study expands the clinical spectrum associated with CACNA1G mutations, corroborating further the causal association with distinct complex phenotypes. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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19 pages, 3947 KiB  
Article
PTEN Is Required for The Anti-Epileptic Effects of AMPA Receptor Antagonists in Chronic Epileptic Rats
by Ji-Eun Kim, Hana Park, Ji-Eun Lee, Tae-Hyun Kim and Tae-Cheon Kang
Int. J. Mol. Sci. 2020, 21(16), 5643; https://doi.org/10.3390/ijms21165643 - 6 Aug 2020
Cited by 9 | Viewed by 3112
Abstract
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and [...] Read more.
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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22 pages, 9060 KiB  
Article
A Proline Derivative-Enriched Fraction from Sideroxylon obtusifolium Protects the Hippocampus from Intracerebroventricular Pilocarpine-Induced Injury Associated with Status Epilepticus in Mice
by Pedro Everson Alexandre de Aquino, Jéssica Rabelo Bezerra, Tyciane de Souza Nascimento, Juliete Tavares, Ítalo Rosal Lustosa, Adriano José Maia Chaves Filho, Melina Mottin, Danielle Macêdo Gaspar, Geanne Matos de Andrade, Kelly Rose Tavares Neves, Giuseppe Biagini, Edilberto Rocha Silveira and Glauce Socorro de Barros Viana
Int. J. Mol. Sci. 2020, 21(11), 4188; https://doi.org/10.3390/ijms21114188 - 11 Jun 2020
Cited by 7 | Viewed by 3749
Abstract
The N-methyl-(2S,4R)-trans-4-hydroxy-l-proline-enriched fraction (NMP) from Sideroxylon obtusifolium was evaluated as a neuroprotective agent in the intracerebroventricular (icv) pilocarpine (Pilo) model. To this aim, male mice were subdivided into sham (SO, vehicle), Pilo (300 µg/1 µL icv, followed by the vehicle [...] Read more.
The N-methyl-(2S,4R)-trans-4-hydroxy-l-proline-enriched fraction (NMP) from Sideroxylon obtusifolium was evaluated as a neuroprotective agent in the intracerebroventricular (icv) pilocarpine (Pilo) model. To this aim, male mice were subdivided into sham (SO, vehicle), Pilo (300 µg/1 µL icv, followed by the vehicle per os, po) and NMP-treated groups (Pilo 300 µg/1 µL icv, followed by 100 or 200 mg/kg po). The treatments started one day after the Pilo injection and continued for 15 days. The effects of NMP were assessed by characterizing the preservation of cognitive function in both the Y-maze and object recognition tests. The hippocampal cell viability was evaluated by Nissl staining. Additional markers of damage were studied—the glial fibrillary acidic protein (GFAP) and the ionized calcium-binding adaptor molecule 1 (Iba-1) expression using, respectively, immunofluorescence and western blot analyses. We also performed molecular docking experiments revealing that NMP binds to the γ-aminobutyric acid (GABA) transporter 1 (GAT1). GAT1 expression in the hippocampus was also characterized. Pilo induced cognitive deficits, cell damage, increased GFAP, Iba-1, and GAT1 expression in the hippocampus. These alterations were prevented, especially by the higher NMP dose. These data highlight NMP as a promising candidate for the protection of the hippocampus, as shown by the icv Pilo model. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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20 pages, 4963 KiB  
Article
Differential Inhibition of Human Nav1.2 Resurgent and Persistent Sodium Currents by Cannabidiol and GS967
by Emily R. Mason and Theodore R. Cummins
Int. J. Mol. Sci. 2020, 21(7), 2454; https://doi.org/10.3390/ijms21072454 - 1 Apr 2020
Cited by 24 | Viewed by 4339
Abstract
Many epilepsy patients are refractory to conventional antiepileptic drugs. Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are [...] Read more.
Many epilepsy patients are refractory to conventional antiepileptic drugs. Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are enhanced by Nav1.2 epilepsy mutations. Pharmacotherapies that specifically target aberrant resurgent and/or persistent currents would likely have fewer unwanted side effects and be effective in many patients with refractory epilepsy. This study investigated the effects of cannbidiol (CBD) and GS967 (each at 1 μM) on transient, resurgent, and persistent currents in human embryonic kidney (HEK) cells stably expressing wild-type hNav1.2 channels. We found that CBD preferentially inhibits resurgent currents over transient currents in this paradigm; and that GS967 preferentially inhibits persistent currents over transient currents. Therefore, CBD and GS967 may represent a new class of more targeted and effective antiepileptic drugs. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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17 pages, 4425 KiB  
Article
PDI-Mediated Reduction of Disulfide Bond on PSD95 Increases Spontaneous Seizure Activity by Regulating NR2A–PSD95 Interaction in Epileptic Rats Independent of S-Nitrosylation
by Duk-Shin Lee and Ji-Eun Kim
Int. J. Mol. Sci. 2020, 21(6), 2094; https://doi.org/10.3390/ijms21062094 - 18 Mar 2020
Cited by 5 | Viewed by 3218
Abstract
Postsynaptic density-95 (PSD95), a major scaffolding protein, is critical in coupling N-methyl-D-aspartate receptor (NMDAR) to cellular signaling networks in the central nervous system. A couple of cysteine residues in the N-terminus of PSD95 are potential sites for disulfide bonding, S-nitrosylation and/or palmitoylation. [...] Read more.
Postsynaptic density-95 (PSD95), a major scaffolding protein, is critical in coupling N-methyl-D-aspartate receptor (NMDAR) to cellular signaling networks in the central nervous system. A couple of cysteine residues in the N-terminus of PSD95 are potential sites for disulfide bonding, S-nitrosylation and/or palmitoylation. Protein disulfide isomerase (PDI) reduces disulfide bonds (S-S) to free thiol (-SH) on various proteins. However, the involvement of PDI in disulfide bond formation/S-nitrosylation of PSD95 and its role in epilepsy are still unknown. In the present study, acute seizure activity significantly increased the bindings of PDI to NR2A, but not to PSD95, while it decreased the NR2A–PSD95 binding. In addition, pilocarpine-induced seizures increased the amount of nitrosylated (SNO-) thiols, not total (free and SNO-) thiols, on PSD95. Unlike acute seizure, spontaneous seizing rats showed the increases in PDI–PSD95 binding, total- and SNO-thiol levels on PSD95, and NR2A–PSD95 interaction. PDI siRNA effectively reduced spontaneous seizure activity with decreases in total thiol level on PSD95 and NR2A–PSD95 association. These findings indicate that PDI-mediated reduction of disulfide-bond formations may facilitate the NR2A–PSD95 binding and contribute to spontaneous seizure generation in epileptic animals. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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28 pages, 6062 KiB  
Article
The Regional Specific Alterations in BBB Permeability are Relevant to the Differential Responses of 67-kDa LR Expression in Endothelial Cells and Astrocytes Following Status Epilepticus
by Hana Park and Tae-Cheon Kang
Int. J. Mol. Sci. 2019, 20(23), 6025; https://doi.org/10.3390/ijms20236025 - 29 Nov 2019
Cited by 7 | Viewed by 3018
Abstract
Status epilepticus (a prolonged seizure activity, SE) differently affects vasogenic edema formation and dystrophin-aquaporin 4 (AQP4) expressions between the rat hippocampus and the piriform cortex (PC). In the present study, we explored whether the 67-kDa laminin receptor (LR) expression was relevant to the [...] Read more.
Status epilepticus (a prolonged seizure activity, SE) differently affects vasogenic edema formation and dystrophin-aquaporin 4 (AQP4) expressions between the rat hippocampus and the piriform cortex (PC). In the present study, we explored whether the 67-kDa laminin receptor (LR) expression was relevant to the regional specific susceptibility of vasogenic edema at 3 days after SE. In spite of no difference in expression levels of 67-kDa LR, dystrophin, and AQP4 under physiological conditions, SE-induced serum extravasation was more severe in the PC than the hippocampus. Western blots demonstrated that SE reduced expression levels of 67-kDa LR, dystrophin, and AQP4 in the PC, but not in the hippocampus proper. Immunofluorescent studies revealed that SE increased 67-kDa LR expression in reactive CA1 astrocyte, but reduced it in the PC and the molecular layer of the dentate gyrus due to massive astroglial loss. Furthermore, SE decreased expressions of endothelial 67-kDa LR and SMI-71 (endothelial brain barrier antigen) in these regions. The 67-kDa LR neutralization evoked serum extravasation in these regions of normal animals without astroglial loss. Similar to SE, 67-kDa LR neutralization also reduced dystrophin-AQP4 expressions in the PC more than the total hippocampus. Furthermore, 67-kDa LR IgG infusion increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not c-Jun N-terminal kinase, independent of phosphoprotein enriched in astrocytes of 15 kDa (PEA15) activity. Co-treatment of U0126 (an ERK1/2 inhibitor) alleviated vasogenic edema formation and the reduced dystrophin-AQP4 expressions induced by 67-kDa LR neutralization. The 67-kDa LR IgG infusion also increased the susceptibility to SE induction. Therefore, our findings suggested that the cellular specific alterations in 67-kDa LR expression might be involved in the severity of SE-induced vasogenic edema formation in regional specific manners, which might affect the susceptibility to SE induction. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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14 pages, 1263 KiB  
Article
Neuroplasticity in Cholinergic Projections from the Basal Forebrain to the Basolateral Nucleus of the Amygdala in the Kainic Acid Model of Temporal Lobe Epilepsy
by Ítalo Rosal Lustosa, Joana I. Soares, Giuseppe Biagini and Nikolai V. Lukoyanov
Int. J. Mol. Sci. 2019, 20(22), 5688; https://doi.org/10.3390/ijms20225688 - 13 Nov 2019
Cited by 3 | Viewed by 3079
Abstract
The amygdala is a cerebral region whose function is compromised in temporal lobe epilepsy (TLE). Patients with TLE present cognitive and emotional dysfunctions, of which impairments in recognizing facial expressions have been clearly attributed to amygdala damage. However, damage to the amygdala has [...] Read more.
The amygdala is a cerebral region whose function is compromised in temporal lobe epilepsy (TLE). Patients with TLE present cognitive and emotional dysfunctions, of which impairments in recognizing facial expressions have been clearly attributed to amygdala damage. However, damage to the amygdala has been scarcely addressed, with the majority of studies focusing on the hippocampus. The aim of this study was to evaluate epilepsy-related plasticity of cholinergic projections to the basolateral nucleus (BL) of the amygdala. Adult rats received kainic acid (KA) injections and developed status epilepticus. Weeks later, they showed spontaneous recurrent seizures documented by behavioral observations. Changes in cholinergic innervation of the BL were investigated by using an antibody against the vesicular acetylcholine transporter (VAChT). In KA-treated rats, it was found that (i) the BL shrunk to 25% of its original size (p < 0.01 vs. controls, Student’s t-test), (ii) the density of vesicular acetylcholine transporter-immunoreactive (VAChT-IR) varicosities was unchanged, (iii) the volumes of VAChT-IR cell bodies projecting to the BL from the horizontal limb of the diagonal band of Broca, ventral pallidum, and subcommissural part of the substantia innominata were significantly increased (p < 0.05, Bonferroni correction). These results illustrate significant changes in the basal forebrain cholinergic cells projecting to the BL in the presence of spontaneous recurrent seizures. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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15 pages, 3418 KiB  
Article
CDDO-Me Attenuates Vasogenic Edema and Astroglial Death by Regulating NF-κB p65 Phosphorylations and Nrf2 Expression Following Status Epilepticus
by Min-Ju Kim, Hana Park, Seo-Hyeon Choi, Min-Jeong Kong, Ji-Eun Kim and Tae-Cheon Kang
Int. J. Mol. Sci. 2019, 20(19), 4862; https://doi.org/10.3390/ijms20194862 - 30 Sep 2019
Cited by 11 | Viewed by 3198
Abstract
2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that has anti-inflammatory, antioxidant, and neuroprotective activities. In the present study, we evaluate the effects of CDDO-Me on serum extravasation and astroglial death in the rat piriform cortex (PC) induced by [...] Read more.
2-Cyano-3,12-dioxo-oleana-1,9(11)-dien-28-oic acid methyl ester (CDDO-Me) is a triterpenoid analogue of oleanolic acid that has anti-inflammatory, antioxidant, and neuroprotective activities. In the present study, we evaluate the effects of CDDO-Me on serum extravasation and astroglial death in the rat piriform cortex (PC) induced by status epilepticus (a prolonged seizure activity, SE) in order to propose an underlying pharmacological mechanism of CDDO-Me and its availability for treatment of vasogenic edema. CDDO-Me effectively mitigated serum extravasation and a massive astroglial loss in the PC following SE. CDDO-Me abrogated tumor necrosis factor-α (TNF-α) synthesis in activated microglia by inhibiting nuclear factor-κB (NF-κB) p65 serine 276 phosphorylation. CDDO-Me also abolished NF-κB threonine 435 phosphorylation in endothelial cells and TNF-α-mediated-phosphatidylinositol-3-kinase (PI3K)/AKT/endothelial nitric oxide synthase (eNOS) signaling cascades, which trigger vasogenic edema following SE. Furthermore, CDDO-Me increased astroglial viability via the up-regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2) expression. Therefore, our findings suggest that CDDO-Me may ameliorate SE-induced vasogenic edema formation by regulating NF-κB p65 phosphorylations in microglia as well as endothelial cells and enhancing Nrf2 expression in astrocytes, respectively. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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Review

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27 pages, 3707 KiB  
Review
Genetics and Extracellular Vesicles of Pediatrics Sleep Disordered Breathing and Epilepsy
by Abdelnaby Khalyfa and David Sanz-Rubio
Int. J. Mol. Sci. 2019, 20(21), 5483; https://doi.org/10.3390/ijms20215483 - 4 Nov 2019
Cited by 9 | Viewed by 4533
Abstract
Sleep remains one of the least understood phenomena in biology, and sleep disturbances are one of the most common behavioral problems in childhood. The etiology of sleep disorders is complex and involves both genetic and environmental factors. Epilepsy is the most popular childhood [...] Read more.
Sleep remains one of the least understood phenomena in biology, and sleep disturbances are one of the most common behavioral problems in childhood. The etiology of sleep disorders is complex and involves both genetic and environmental factors. Epilepsy is the most popular childhood neurological condition and is characterized by an enduring predisposition to generate epileptic seizures, and the neurobiological, cognitive, psychological, and social consequences of this condition. Sleep and epilepsy are interrelated, and the importance of sleep in epilepsy is less known. The state of sleep also influences whether a seizure will occur at a given time, and this differs considerably for various epilepsy syndromes. The development of epilepsy has been associated with single or multiple gene variants. The genetics of epilepsy is complex and disorders exhibit significant genetic heterogeneity and variability in the expressivity of seizures. Phenobarbital (PhB) is the most widely used antiepileptic drug. With its principal mechanism of action to prolong the opening time of the γ-aminobutyric acid (GABA)-A receptor-associated chloride channel, it enhances chloride anion influx into neurons, with subsequent hyperpolarization, thereby reducing excitability. Enzymes that metabolize pharmaceuticals including PhB are well known for having genetic polymorphisms that contribute to adverse drug–drug interactions. PhB metabolism is highly dependent upon the cytochrome P450 (CYP450) and genetic polymorphisms can lead to variability in active drug levels. The highly polymorphic CYP2C19 isozymes are responsible for metabolizing a large portion of routinely prescribed drugs and variants contribute significantly to adverse drug reactions and therapeutic failures. A limited number of CYP2C19 single nucleotide polymorphisms (SNPs) are involved in drug metabolism. Extracellular vesicles (EVs) are circular membrane fragments released from the endosomal compartment as exosomes are shed from the surfaces of the membranes of most cell types. Increasing evidence indicated that EVs play a pivotal role in cell-to-cell communication. Theses EVs may play an important role between sleep, epilepsy, and treatments. The discovery of exosomes provides potential strategies for the diagnosis and treatment of many diseases including neurocognitive deficit. The aim of this study is to better understand and provide further knowledge about the metabolism and interactions between phenobarbital and CYP2C19 polymorphisms in children with epilepsy, interplay between sleep, and EVs. Understanding this interplay between epilepsy and sleep is helpful in the optimal treatment of all patients with epileptic seizures. The use of genetics and extracellular vesicles as precision medicine for the diagnosis and treatment of children with sleep disorder will improve the prognosis and the quality of life in patients with epilepsy. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies 2.0)
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