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Epilepsy: From Molecular Mechanisms to Targeted Therapies

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 (30 April 2019) | Viewed by 46457

Special Issue Editors

Department of Biomedical, Universita degli Studi di Modena e Reggio Emilia, Modena, Italy
Interests: epilepsy; extracellular matrix; glia; hippocampus; neuroprotection; neurosteroids; seizure; stroke
Special Issues, Collections and Topics in MDPI journals
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 to the progression of damage in the epileptic tissue. Finally, all these players could significantly modulate the process of epileptogenesis, for which regulatory pathway such as that depending on the mammalian target of rapamycin (mTOR) are 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.

Dr. Giuseppe Biagini
Dr. Jonathan Vinet
Guest Editors

Manuscript Submission Information

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Keywords

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

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Published Papers (9 papers)

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Research

Jump to: Review

18 pages, 4065 KiB  
Article
Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features
by Maria Virginia Soldovieri, Paolo Ambrosino, Ilaria Mosca, Francesco Miceli, Cristina Franco, Lorella Maria Teresa Canzoniero, Beth Kline-Fath, Edward C. Cooper, Charu Venkatesan and Maurizio Taglialatela
Int. J. Mol. Sci. 2019, 20(14), 3382; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143382 - 10 Jul 2019
Cited by 13 | Viewed by 3391
Abstract
Kv7.2 subunits encoded by the KCNQ2 gene provide a major contribution to the M-current (IKM), a voltage-gated K+ current crucially involved in the regulation of neuronal excitability. Heterozygous missense variants in Kv7.2 are responsible for epileptic diseases characterized by highly [...] Read more.
Kv7.2 subunits encoded by the KCNQ2 gene provide a major contribution to the M-current (IKM), a voltage-gated K+ current crucially involved in the regulation of neuronal excitability. Heterozygous missense variants in Kv7.2 are responsible for epileptic diseases characterized by highly heterogeneous genetic transmission and clinical severity, ranging from autosomal-dominant Benign Familial Neonatal Seizures (BFNS) to sporadic cases of severe epileptic and developmental encephalopathy (DEE). Here, we describe a patient with neonatal onset DEE, carrying a previously undescribed heterozygous KCNQ2 c.418G > C, p.Glu140Gln (E140Q) variant. Patch-clamp recordings in CHO cells expressing the E140Q mutation reveal dramatic loss of function (LoF) effects. Multistate structural modelling suggested that the E140Q substitution impeded an intrasubunit electrostatic interaction occurring between the E140 side chain in S2 and the arginine at position 210 in S4 (R210); this interaction is critically involved in stabilizing the activated configuration of the voltage-sensing domain (VSD) of Kv7.2. Functional results from coupled charge reversal or disulfide trapping experiments supported such a hypothesis. Finally, retigabine restored mutation-induced functional changes, reinforcing the rationale for the clinical use of Kv7 activators as personalized therapy for DEE-affected patients carrying Kv7.2 LoF mutations. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
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13 pages, 2199 KiB  
Article
Kinase Inhibitors with Antiepileptic Properties Identified with a Novel in Vitro Screening Platform
by Jing Liu, Madison Schenker, Shabnam Ghiasvand and Yevgeny Berdichevsky
Int. J. Mol. Sci. 2019, 20(10), 2502; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102502 - 21 May 2019
Cited by 7 | Viewed by 2883
Abstract
Kinase signaling plays an important role in acquired epilepsy, but only a small percentage of the total kinome has been investigated in this context. A major roadblock that prevents the systematic investigation of the contributions of kinase signaling networks is the slow speed [...] Read more.
Kinase signaling plays an important role in acquired epilepsy, but only a small percentage of the total kinome has been investigated in this context. A major roadblock that prevents the systematic investigation of the contributions of kinase signaling networks is the slow speed of experiments designed to test the chronic effects of target inhibition in epilepsy models. We developed a novel in vitro screening platform based on microwire recordings from an organotypic hippocampal culture model of acquired epilepsy. This platform enables the direct, parallel determination of the effects of compounds on spontaneous epileptiform activity. The platform also enables repeated recordings from the same culture over two-week long experiments. We screened 45 kinase inhibitors and quantified their effects on seizure duration, the frequency of paroxysmal activity, and electrographic load. We identified several inhibitors with previously unknown antiepileptic properties. We also used kinase inhibition profile cross-referencing to identify kinases that are inhibited by seizure-suppressing compounds, but not by compounds that had no effect on seizures. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
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14 pages, 1653 KiB  
Article
Differential Effects of a Full and Biased Ghrelin Receptor Agonist in a Mouse Kindling Model
by An Buckinx, Yana Van Den Herrewegen, Anouk Pierre, Eleonora Cottone, Khoubaib Ben Haj Salah, Jean-Alain Fehrentz, Ron Kooijman, Dimitri De Bundel and Ilse Smolders
Int. J. Mol. Sci. 2019, 20(10), 2480; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102480 - 20 May 2019
Cited by 11 | Viewed by 3403
Abstract
The ghrelin system has received substantial recognition as a potential target for novel anti-seizure drugs. Ghrelin receptor (ghrelin-R) signaling is complex, involving Gαq/11, Gαi/o, Gα12/13, and β-arrestin pathways. In this study, we aimed to deepen our understanding [...] Read more.
The ghrelin system has received substantial recognition as a potential target for novel anti-seizure drugs. Ghrelin receptor (ghrelin-R) signaling is complex, involving Gαq/11, Gαi/o, Gα12/13, and β-arrestin pathways. In this study, we aimed to deepen our understanding regarding signaling pathways downstream the ghrelin-R responsible for mediating anticonvulsive effects in a kindling model. Mice were administered the proconvulsive dopamine 1 receptor-agonist, SKF81297, to gradually induce a kindled state. Prior to every SKF81297 injection, mice were treated with a ghrelin-R full agonist (JMV-1843), a Gαq and Gα12 biased ligand unable to recruit β-arrestin (YIL781), a ghrelin-R antagonist (JMV-2959), or saline. Mice treated with JMV-1843 had fewer and less severe seizures compared to saline-treated controls, while mice treated with YIL781 experienced longer and more severe seizures. JMV-2959 treatment did not lead to differences in seizure severity and number. Altogether, these results indicate that the Gαq or Gα12 signaling pathways are not responsible for mediating JMV-1843′s anticonvulsive effects and suggest a possible involvement of β-arrestin signaling in the anticonvulsive effects mediated by ghrelin-R modulation. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
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13 pages, 5604 KiB  
Article
The Neuroprotective Effect of Hericium erinaceus Extracts in Mouse Hippocampus after Pilocarpine-Induced Status Epilepticus
by Hyun-Jong Jang, Ji-Eun Kim, Kyoung Hoon Jeong, Sung Chul Lim, Seong Yun Kim and Kyung-Ok Cho
Int. J. Mol. Sci. 2019, 20(4), 859; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040859 - 16 Feb 2019
Cited by 24 | Viewed by 7348
Abstract
Hericium erinaceus (HE), a culinary-medicinal mushroom, has shown therapeutic potential in many brain diseases. However, the role of HE in status epilepticus (SE)-mediated neuronal death and its underlying mechanisms remain unclear. We investigated the neuroprotective effects of HE using a pilocarpine-induced SE model. [...] Read more.
Hericium erinaceus (HE), a culinary-medicinal mushroom, has shown therapeutic potential in many brain diseases. However, the role of HE in status epilepticus (SE)-mediated neuronal death and its underlying mechanisms remain unclear. We investigated the neuroprotective effects of HE using a pilocarpine-induced SE model. Male C57BL/6 mice received crude extracts of HE (60 mg/kg, 120 mg/kg, or 300 mg/kg, p.o.) for 21 d from 14 d before SE to 6 d after SE. At 7 d after SE, cresyl violet and immunohistochemistry of neuronal nuclei revealed improved hippocampal neuronal survival in animals treated with 60 mg/kg and 120 mg/kg of HE, whereas those treated with 300 mg/kg of HE showed similar neuronal death to that of vehicle-treated controls. While seizure-induced reactive gliosis, assessed by immunohistochemistry, was not altered by HE, the number of hippocampal cyclooxygenase 2 (COX2)-expressing cells was significantly reduced by 60 and 120 mg/kg of HE. Triple immunohistochemistry demonstrated no overlap of COX2 labeling with Ox42, in addition to a decrease in COX2/GFAP-co-immunoreactivity in the group treated with 60 mg/kg HE, suggesting that the reduction of COX2 by HE promotes neuroprotection after SE. Our findings highlight the potential application of HE for preventing neuronal death after seizures. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
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16 pages, 4420 KiB  
Article
A Hydroxypyrone-Based Inhibitor of Metalloproteinase-12 Displays Neuroprotective Properties in Both Status Epilepticus and Optic Nerve Crush Animal Models
by Jonathan Vinet, Anna-Maria Costa, Manuel Salinas-Navarro, Giuseppina Leo, Lieve Moons, Lutgarde Arckens and Giuseppe Biagini
Int. J. Mol. Sci. 2018, 19(8), 2178; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19082178 - 25 Jul 2018
Cited by 14 | Viewed by 5354
Abstract
Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood–brain barrier (BBB) leakage and subsequent neuronal cell death that follows status epilepticus (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor [...] Read more.
Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood–brain barrier (BBB) leakage and subsequent neuronal cell death that follows status epilepticus (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor selective for MMP-12 in the pilocarpine-induced SE rat model to determine hippocampal cell survival. In the hippocampus of rats treated with pilocarpine, intra-hippocampal injections of the MMP-12 inhibitor protected Cornu Ammonis 3 (CA3) and hilus of dentate gyrus neurons against cell death and limited the development of the ischemic-like lesion that typically develops in the CA3 stratum lacunosum-moleculare of the hippocampus. Furthermore, we showed that MMP-12 inhibition limited immunoglobulin G and albumin extravasation after SE, suggesting a reduction in BBB leakage. Finally, to rule out any possible involvement of seizure modulation in the neuroprotective effects of MMP-12 inhibition, neuroprotection was also observed in the retina of treated animals after optic nerve crush. Overall, these results support the hypothesis that MMP-12 inhibition can directly counteract neuronal cell death and that the specific hydroxypyrone-based inhibitor used in this study could be a potential therapeutic agent against neurological diseases/disorders characterized by an important inflammatory response and/or neuronal cell loss. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
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Review

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10 pages, 224 KiB  
Review
Update on the Genetic Basis of Sudden Unexpected Death in Epilepsy
by Monica Coll, Antonio Oliva, Simone Grassi, Ramon Brugada and Oscar Campuzano
Int. J. Mol. Sci. 2019, 20(8), 1979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20081979 - 23 Apr 2019
Cited by 34 | Viewed by 3571
Abstract
Epilepsy is a common neurological disorder associated with increased morbidity and mortality. Sudden unexpected death in epilepsy, also known as SUDEP, is the main cause of death in patients with epilepsy. SUDEP has an incidence of 1.2 per 1000 person-years in adults and [...] Read more.
Epilepsy is a common neurological disorder associated with increased morbidity and mortality. Sudden unexpected death in epilepsy, also known as SUDEP, is the main cause of death in patients with epilepsy. SUDEP has an incidence of 1.2 per 1000 person-years in adults and 0.2 per 1000 person-years in children. SUDEP accounts for 8–17% of deaths in patients with epilepsy. It is commonly associated with a history of generalized tonic-clonic seizures, and its risk may be increased by other factors such as postictal electroencephalographic suppression, prone sleeping position, altered heart rate variability, conduction abnormalities, gender, or antiepileptic medications. Recently, electrocardiograms, electroencephalograms, and imaging markers have helped clinicians stratify SUDEP risk and identify patients in need of close monitoring. However, the pathophysiology of SUDEP is likely multifactorial and still unknown. Improving the knowledge of SUDEP incidence, risk factors, and biomarkers can help design and implement effective prevention strategies. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
22 pages, 2175 KiB  
Review
Extracellular Vesicles as Diagnostics and Therapeutics for Structural Epilepsies
by Jenni Karttunen, Mette Heiskanen, Anssi Lipponen, David Poulsen and Asla Pitkänen
Int. J. Mol. Sci. 2019, 20(6), 1259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061259 - 13 Mar 2019
Cited by 19 | Viewed by 5717
Abstract
Extracellular vesicles (EVs) are small vesicles involved in intercellular communication. Data is emerging that EVs and their cargo have potential as diagnostic biomarkers and treatments for brain diseases, including traumatic brain injury and epilepsy. Here, we summarize the current knowledge regarding changes in [...] Read more.
Extracellular vesicles (EVs) are small vesicles involved in intercellular communication. Data is emerging that EVs and their cargo have potential as diagnostic biomarkers and treatments for brain diseases, including traumatic brain injury and epilepsy. Here, we summarize the current knowledge regarding changes in EV numbers and cargo in status epilepticus (SE) and traumatic brain injury (TBI), which are clinically significant etiologies for acquired epileptogenesis in animals and humans. We also review encouraging data, which suggests that EVs secreted by stem cells may serve as recovery-enhancing treatments for SE and TBI. Using Gene Set Enrichment Analysis, we show that brain EV-related transcripts are positively enriched in rodent models of epileptogenesis and epilepsy, and altered in response to anti-seizure drugs. These data suggest that EVs show promise as biomarkers, treatments and drug targets for epilepsy. In parallel to gathering conceptual knowledge, analytics platforms for the isolation and analysis of EV contents need to be further developed. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
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17 pages, 1412 KiB  
Review
Role of the Angiotensin Pathway and its Target Therapy in Epilepsy Management
by Shaip Krasniqi and Armond Daci
Int. J. Mol. Sci. 2019, 20(3), 726; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030726 - 08 Feb 2019
Cited by 30 | Viewed by 6034
Abstract
Despite extensive research on epileptogenesis, there is still a need to investigate new pathways and targeted therapeutic approaches in this complex process. Inflammation, oxidative stress, neurotoxicity, neural cell death, gliosis, and blood–brain barrier (BBB) dysfunction are the most common causes of epileptogenesis. Moreover, [...] Read more.
Despite extensive research on epileptogenesis, there is still a need to investigate new pathways and targeted therapeutic approaches in this complex process. Inflammation, oxidative stress, neurotoxicity, neural cell death, gliosis, and blood–brain barrier (BBB) dysfunction are the most common causes of epileptogenesis. Moreover, the renin–angiotensin system (RAS) affects the brain’s physiological and pathological conditions, including epilepsy and its consequences. While there are a variety of available pharmacotherapeutic approaches, information on new pathways is in high demand and the achievement of treatment goals is greatly desired. Therefore, targeting the RAS presents an interesting opportunity to better understand this process. This has been supported by preclinical studies, primarily based on RAS enzyme, receptor-inhibition, and selective agonists, which are characterized by pleiotropic properties. Although there are some antiepileptic drugs (AEDs) that interfere with RAS, the main targeted therapy of this pathway contributes in synergy with AEDs. However, the RAS-targeted treatment alone, or in combination with AEDs, requires clinical studies to contribute to, and clarify, the evidence on epilepsy management. There is also a genetic association between RAS and epilepsy, and an involvement of pharmacogenetics in RAS, so there are possibilities for the development of new diagnostic and personalized treatments for epilepsy. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
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18 pages, 970 KiB  
Review
The Paroxysmal Depolarization Shift: Reconsidering Its Role in Epilepsy, Epileptogenesis and Beyond
by Helmut Kubista, Stefan Boehm and Matej Hotka
Int. J. Mol. Sci. 2019, 20(3), 577; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030577 - 29 Jan 2019
Cited by 22 | Viewed by 7888
Abstract
Paroxysmal depolarization shifts (PDS) have been described by epileptologists for the first time several decades ago, but controversy still exists to date regarding their role in epilepsy. In addition to the initial view of a lack of such a role, seemingly opposing hypotheses [...] Read more.
Paroxysmal depolarization shifts (PDS) have been described by epileptologists for the first time several decades ago, but controversy still exists to date regarding their role in epilepsy. In addition to the initial view of a lack of such a role, seemingly opposing hypotheses on epileptogenic and anti-ictogenic effects of PDS have emerged. Hence, PDS may provide novel targets for epilepsy therapy. Evidence for the roles of PDS has often been obtained from investigations of the multi-unit correlate of PDS, an electrographic spike termed “interictal” because of its occurrence during seizure-free periods of epilepsy patients. Meanwhile, interictal spikes have been found to be associated with neuronal diseases other than epilepsy, e.g., Alzheimer’s disease, which may indicate a broader implication of PDS in neuropathologies. In this article, we give an introduction to PDS and review evidence that links PDS to pro- as well as anti-epileptic mechanisms, and to other types of neuronal dysfunction. The perturbation of neuronal membrane voltage and of intracellular Ca2+ that comes with PDS offers many conceivable pathomechanisms of neuronal dysfunction. Out of these, the operation of L-type voltage-gated calcium channels, which play a major role in coupling excitation to long-lasting neuronal changes, is addressed in detail. Full article
(This article belongs to the Special Issue Epilepsy: From Molecular Mechanisms to Targeted Therapies)
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