International Journal of Molecular Sciences

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Molecular and Cellular Mechanisms of Epilepsy 2.0

by Aleksey V. Zaitsev

Int. J. Mol. Sci. 2023, 24(24), 17464; https://doi.org/10.3390/ijms242417464 - 14 Dec 2023

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Abstract

Epilepsy is a prevalent neurological disorder [...] Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

Research

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15 pages, 4466 KiB

Open AccessArticle

Alterations in Rat Hippocampal Glutamatergic System Properties after Prolonged Febrile Seizures

by Alexandra V. Griflyuk, Tatyana Y. Postnikova, Sergey L. Malkin and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2023, 24(23), 16875; https://doi.org/10.3390/ijms242316875 - 28 Nov 2023

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Abstract

Febrile seizures during early childhood may result in central nervous system developmental disorders. However, the specific mechanisms behind the impact of febrile seizures on the developing brain are not well understood. To address this gap in knowledge, we employed a hyperthermic model of [...] Read more.

Febrile seizures during early childhood may result in central nervous system developmental disorders. However, the specific mechanisms behind the impact of febrile seizures on the developing brain are not well understood. To address this gap in knowledge, we employed a hyperthermic model of febrile seizures in 10-day-old rats and tracked their development over two months. Our objective was to determine the degree to which the properties of the hippocampal glutamatergic system are modified. We analyzed whether pyramidal glutamatergic neurons in the hippocampus die after febrile seizures. Our findings indicate that there is a reduction in the number of neurons in various regions of the hippocampus in the first two days after seizures. The CA1 field showed the greatest susceptibility, and the reduction in the number of neurons in post-FS rats in this area appeared to be long-lasting. Electrophysiological studies indicate that febrile seizures cause a reduction in glutamatergic transmission, leading to decreased local field potential amplitude. This impairment could be attributable to diminished glutamate release probability as evidenced by decreases in the frequency of miniature excitatory postsynaptic currents and increases in the paired-pulse ratio of synaptic responses. We also found higher threshold current causing hind limb extension in the maximal electroshock seizure threshold test of rats 2 months after febrile seizures compared to the control animals. Our research suggests that febrile seizures can impair glutamatergic transmission, which may protect against future seizures. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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22 pages, 15465 KiB

Open AccessArticle

Antiepileptogenic Effects of Anakinra, Lamotrigine and Their Combination in a Lithium–Pilocarpine Model of Temporal Lobe Epilepsy in Rats

by Olga E. Zubareva, Denis S. Sinyak, Alisa D. Kalita, Alexandra V. Griflyuk, Georgy P. Diespirov, Tatiana Y. Postnikova and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2023, 24(20), 15400; https://doi.org/10.3390/ijms242015400 - 20 Oct 2023

Cited by 1 | Viewed by 1663

Abstract

Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite [...] Read more.

Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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21 pages, 2291 KiB

Open AccessArticle

EpiPro, a Novel, Synthetic, Activity-Regulated Promoter That Targets Hyperactive Neurons in Epilepsy for Gene Therapy Applications

by Cassidy T. Burke, Iuliia Vitko, Justyna Straub, Elsa O. Nylund, Agnieszka Gawda, Kathryn Blair, Kyle A. Sullivan, Lara Ergun, Matteo Ottolini, Manoj K. Patel and Edward Perez-Reyes

Int. J. Mol. Sci. 2023, 24(19), 14467; https://doi.org/10.3390/ijms241914467 - 23 Sep 2023

Viewed by 1880

Abstract

Epileptogenesis is characterized by intrinsic changes in neuronal firing, resulting in hyperactive neurons and the subsequent generation of seizure activity. These alterations are accompanied by changes in gene transcription networks, first with the activation of early-immediate genes and later with the long-term activation [...] Read more.

Epileptogenesis is characterized by intrinsic changes in neuronal firing, resulting in hyperactive neurons and the subsequent generation of seizure activity. These alterations are accompanied by changes in gene transcription networks, first with the activation of early-immediate genes and later with the long-term activation of genes involved in memory. Our objective was to engineer a promoter containing binding sites for activity-dependent transcription factors upregulated in chronic epilepsy (EpiPro) and validate it in multiple rodent models of epilepsy. First, we assessed the activity dependence of EpiPro: initial electrophysiology studies found that EpiPro-driven GFP expression was associated with increased firing rates when compared with unlabeled neurons, and the assessment of EpiPro-driven GFP expression revealed that GFP expression was increased ~150× after status epilepticus. Following this, we compared EpiPro-driven GFP expression in two rodent models of epilepsy, rat lithium/pilocarpine and mouse electrical kindling. In rodents with chronic epilepsy, GFP expression was increased in most neurons, but particularly in dentate granule cells, providing in vivo evidence to support the “breakdown of the dentate gate” hypothesis of limbic epileptogenesis. Finally, we assessed the time course of EpiPro activation and found that it was rapidly induced after seizures, with inactivation following over weeks, confirming EpiPro’s potential utility as a gene therapy driver for epilepsy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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17 pages, 4216 KiB

Open AccessArticle

Drug-Inducible Gene Therapy Effectively Reduces Spontaneous Seizures in Kindled Rats but Creates Off-Target Side Effects in Inhibitory Neurons

by Kyle A. Sullivan, Iuliia Vitko, Kathryn Blair, Ronald P. Gaykema, Madison J. Failor, Jennifer M. San Pietro, Deblina Dey, John M. Williamson, Ruth L. Stornetta, Jaideep Kapur and Edward Perez-Reyes

Int. J. Mol. Sci. 2023, 24(14), 11347; https://doi.org/10.3390/ijms241411347 - 12 Jul 2023

Cited by 3 | Viewed by 1925

Abstract

Over a third of patients with temporal lobe epilepsy (TLE) are not effectively treated with current anti-seizure drugs, spurring the development of gene therapies. The injection of adeno-associated viral vectors (AAV) into the brain has been shown to be a safe and viable [...] Read more.

Over a third of patients with temporal lobe epilepsy (TLE) are not effectively treated with current anti-seizure drugs, spurring the development of gene therapies. The injection of adeno-associated viral vectors (AAV) into the brain has been shown to be a safe and viable approach. However, to date, AAV expression of therapeutic genes has not been regulated. Moreover, a common property of antiepileptic drugs is a narrow therapeutic window between seizure control and side effects. Therefore, a long-term goal is to develop drug-inducible gene therapies that can be regulated by clinically relevant drugs. In this study, a first-generation doxycycline-regulated gene therapy that delivered an engineered version of the leak potassium channel Kcnk2 (TREK-M) was injected into the hippocampus of male rats. Rats were electrically stimulated until kindled. EEG was monitored 24/7. Electrical kindling revealed an important side effect, as even low expression of TREK M in the absence of doxycycline was sufficient to cause rats to develop spontaneous recurring seizures. Treating the epileptic rats with doxycycline successfully reduced spontaneous seizures. Localization studies of infected neurons suggest seizures were caused by expression in GABAergic inhibitory neurons. In contrast, doxycycline increased the expression of TREK-M in excitatory neurons, thereby reducing seizures through net inhibition of firing. These studies demonstrate that drug-inducible gene therapies are effective in reducing spontaneous seizures and highlight the importance of testing for side effects with pro-epileptic stressors such as electrical kindling. These studies also show the importance of evaluating the location and spread of AAV-based gene therapies in preclinical studies. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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17 pages, 4334 KiB

Open AccessArticle

Of the Mechanisms of Paroxysmal Depolarization Shifts: Generation and Maintenance of Bicuculline-Induced Paroxysmal Activity in Rat Hippocampal Cell Cultures

by Denis P. Laryushkin, Sergei A. Maiorov, Valery P. Zinchenko, Valentina N. Mal’tseva, Sergei G. Gaidin and Artem M. Kosenkov

Int. J. Mol. Sci. 2023, 24(13), 10991; https://doi.org/10.3390/ijms241310991 - 1 Jul 2023

Cited by 4 | Viewed by 1825

Abstract

Abnormal depolarization of neuronal membranes called paroxysmal depolarization shift (PDS) represents a cellular correlate of interictal spikes. The mechanisms underlying the generation of PDSs or PDS clusters remain obscure. This study aimed to investigate the role of ionotropic glutamate receptors (iGluRs) in the [...] Read more.

Abnormal depolarization of neuronal membranes called paroxysmal depolarization shift (PDS) represents a cellular correlate of interictal spikes. The mechanisms underlying the generation of PDSs or PDS clusters remain obscure. This study aimed to investigate the role of ionotropic glutamate receptors (iGluRs) in the generation of PDS and dependence of the PDS pattern on neuronal membrane potential. We have shown that significant depolarization or hyperpolarization (by more than ±50 mV) of a single neuron does not change the number of individual PDSs in the cluster, indicating the involvement of an external stimulus in PDS induction. Based on this data, we have suggested reliable protocols for stimulating single PDS or PDS clusters. Furthermore, we have found that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are necessary for PDS generation since AMPAR antagonist NBQX completely suppresses bicuculline-induced paroxysmal activity. In turn, antagonists of NMDA (N-methyl-D-aspartate) and kainate receptors (D-AP5 and UBP310, respectively) caused a decrease in the amplitude of the first action potential in PDSs and in the amplitude of the oscillations of intracellular Ca²⁺ concentration occurring alongside the PDS cluster generation. The effects of the NMDAR (NMDA receptor) and KAR (kainate receptor) antagonists indicate that these receptors are involved only in the modulation of paroxysmal activity. We have also shown that agonists of some G_i-coupled receptors, such as A₁ adenosine (A₁Rs) or cannabinoid receptors (CBRs) (N₆-cyclohexyladenosine and WIN 55,212-2, respectively), completely suppressed PDS generation, while the A₁R agonist even prevented it. We hypothesized that the dynamics of extracellular glutamate concentration govern paroxysmal activity. Fine-tuning of neuronal activity via action on G_i-coupled receptors or iGluRs paves the way for the development of new approaches for epilepsy pharmacotherapy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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24 pages, 5747 KiB

Open AccessArticle

Alpha2 Adrenergic Modulation of Spike-Wave Epilepsy: Experimental Study of Pro-Epileptic and Sedative Effects of Dexmedetomidine

by Evgenia Sitnikova, Maria Pupikina and Elizaveta Rutskova

Int. J. Mol. Sci. 2023, 24(11), 9445; https://doi.org/10.3390/ijms24119445 - 29 May 2023

Cited by 6 | Viewed by 1768

Abstract

In the present report, we evaluated adrenergic mechanisms of generalized spike-wave epileptic discharges (SWDs), which are the encephalographic hallmarks of idiopathic generalized epilepsies. SWDs link to a hyper-synchronization in the thalamocortical neuronal activity. We unclosed some alpha2-adrenergic mechanisms of sedation and provocation of [...] Read more.

In the present report, we evaluated adrenergic mechanisms of generalized spike-wave epileptic discharges (SWDs), which are the encephalographic hallmarks of idiopathic generalized epilepsies. SWDs link to a hyper-synchronization in the thalamocortical neuronal activity. We unclosed some alpha2-adrenergic mechanisms of sedation and provocation of SWDs in rats with spontaneous spike-wave epilepsy (WAG/Rij and Wistar) and in control non-epileptic rats (NEW) of both sexes. Dexmedetomidine (Dex) was a highly selective alpha-2 agonist (0.003–0.049 mg/kg, i.p.). Injections of Dex did not elicit de novo SWDs in non-epileptic rats. Dex can be used to disclose the latent form of spike-wave epilepsy. Subjects with long-lasting SWDs at baseline were at high risk of absence status after activation of alpha2- adrenergic receptors. We create the concept of alpha1- and alpha2-ARs regulation of SWDs via modulation of thalamocortical network activity. Dex induced the specific abnormal state favorable for SWDs—“alpha2 wakefulness”. Dex is regularly used in clinical practice. EEG examination in patients using low doses of Dex might help to diagnose the latent forms of absence epilepsy (or pathology of cortico-thalamo-cortical circuitry). Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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18 pages, 2843 KiB

Open AccessArticle

GABA_A Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut Syndrome

by Gerald Ikemefuna Nwosu, Wangzhen Shen, Kirill Zavalin, Sarah Poliquin, Karishma Randhave, Carson Flamm, Marshall Biven, Katherine Langer and Jing-Qiong Kang

Int. J. Mol. Sci. 2023, 24(9), 8458; https://doi.org/10.3390/ijms24098458 - 8 May 2023

Cited by 1 | Viewed by 2480

Abstract

Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in GABRB3 that encodes the GABA_A receptor (GABA_AR) β₃ [...] Read more.

Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in GABRB3 that encodes the GABA_A receptor (GABA_AR) β₃ subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate Gabrb3^+/N328D knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing Gabrb3 (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated Gabrb3^+/N328D mice for features of LGS. In 2–4-month-old male and female C57BL/J6 wild-type and Gabrb3^+/N328D mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABA_AR subunit expression by Western blot. Gabrb3^+/N328D mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, Gabrb3^+/N328D mice showed reduced β₃ subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that Gabrb3^+/N328D mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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27 pages, 3966 KiB

Open AccessArticle

Beneficial Effects of Probiotic Bifidobacterium longum in a Lithium–Pilocarpine Model of Temporal Lobe Epilepsy in Rats

by Olga E. Zubareva, Alexandra V. Dyomina, Anna A. Kovalenko, Anna I. Roginskaya, Tigran B. Melik-Kasumov, Marina A. Korneeva, Alesya V. Chuprina, Alesya A. Zhabinskaya, Stepan A. Kolyhan, Maria V. Zakharova, Marusya O. Gryaznova and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2023, 24(9), 8451; https://doi.org/10.3390/ijms24098451 - 8 May 2023

Cited by 16 | Viewed by 2890

Abstract

Epilepsy is a challenging brain disorder that is often difficult to treat with conventional therapies. The gut microbiota has been shown to play an important role in the development of neuropsychiatric disorders, including epilepsy. In this study, the effects of Bifidobacterium longum, [...] Read more.

Epilepsy is a challenging brain disorder that is often difficult to treat with conventional therapies. The gut microbiota has been shown to play an important role in the development of neuropsychiatric disorders, including epilepsy. In this study, the effects of Bifidobacterium longum, a probiotic, on inflammation, neuronal degeneration, and behavior are evaluated in a lithium–pilocarpine model of temporal lobe epilepsy (TLE) induced in young adult rats. B. longum was administered orally at a dose of 10⁹ CFU/rat for 30 days after pilocarpine injection. The results show that B. longum treatment has beneficial effects on the TLE-induced changes in anxiety levels, neuronal death in the amygdala, and body weight recovery. In addition, B. longum increased the expression of anti-inflammatory and neuroprotective genes, such as Il1rn and Pparg. However, the probiotic had little effect on TLE-induced astrogliosis and microgliosis and did not reduce neuronal death in the hippocampus and temporal cortex. The study suggests that B. longum may have a beneficial effect on TLE and may provide valuable insights into the role of gut bacteria in epileptogenesis. In addition, the results show that B. longum may be a promising drug for the comprehensive treatment of epilepsy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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17 pages, 9219 KiB

Open AccessArticle

Deregulation of Astroglial TASK-1 K⁺ Channel Decreases the Responsiveness to Perampanel-Induced AMPA Receptor Inhibition in Chronic Epilepsy Rats

by Duk-Shin Lee, Tae-Hyun Kim, Hana Park and Tae-Cheon Kang

Int. J. Mol. Sci. 2023, 24(6), 5491; https://doi.org/10.3390/ijms24065491 - 13 Mar 2023

Cited by 1 | Viewed by 1419

Abstract

Tandem of P domains in a weak inwardly rectifying K⁺ channel (TWIK)-related acid sensitive K⁺-1 channel (TASK-1) is activated under extracellular alkaline conditions (pH 7.2–8.2), which are upregulated in astrocytes (particularly in the CA1 region) of the [...] Read more.

Tandem of P domains in a weak inwardly rectifying K⁺ channel (TWIK)-related acid sensitive K⁺-1 channel (TASK-1) is activated under extracellular alkaline conditions (pH 7.2–8.2), which are upregulated in astrocytes (particularly in the CA1 region) of the hippocampi of patients with temporal lobe epilepsy and chronic epilepsy rats. Perampanel (PER) is a non-competitive α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) antagonist used for the treatment of focal seizures and primary generalized tonic–clonic seizures. Since AMPAR activation leads to extracellular alkaline shifts, it is likely that the responsiveness to PER in the epileptic hippocampus may be relevant to astroglial TASK-1 regulation, which has been unreported. In the present study, we found that PER ameliorated astroglial TASK-1 upregulation in responders (whose seizure activities were responsive to PER), but not non-responders (whose seizure activities were not responsive to PER), in chronic epilepsy rats. ML365 (a selective TASK-1 inhibitor) diminished astroglial TASK-1 expression and seizure duration in non-responders to PER. ML365 co-treatment with PER decreased spontaneous seizure activities in non-responders to PER. These findings suggest that deregulation of astroglial TASK-1 upregulation may participate in the responsiveness to PER, and that this may be a potential target to improve the efficacies of PER. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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Review

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Open AccessReview

Fluid Biomarkers of Neuro-Glial Injury in Human Status Epilepticus: A Systematic Review

by Giada Giovannini and Stefano Meletti

Int. J. Mol. Sci. 2023, 24(15), 12519; https://doi.org/10.3390/ijms241512519 - 7 Aug 2023

Cited by 7 | Viewed by 1714

Abstract

As per the latest ILAE definition, status epilepticus (SE) may lead to long-term irreversible consequences, such as neuronal death, neuronal injury, and alterations in neuronal networks. Consequently, there is growing interest in identifying biomarkers that can demonstrate and quantify the extent of neuronal [...] Read more.

As per the latest ILAE definition, status epilepticus (SE) may lead to long-term irreversible consequences, such as neuronal death, neuronal injury, and alterations in neuronal networks. Consequently, there is growing interest in identifying biomarkers that can demonstrate and quantify the extent of neuronal and glial injury. Despite numerous studies conducted on animal models of status epilepticus, which clearly indicate seizure-induced neuronal and glial injury, as well as signs of atrophy and gliosis, evidence in humans remains limited to case reports and small case series. The implications of identifying such biomarkers in clinical practice are significant, including improved prognostic stratification of patients and the early identification of those at high risk of developing irreversible complications. Moreover, the clinical validation of these biomarkers could be crucial in promoting neuroprotective strategies in addition to antiseizure medications. In this study, we present a systematic review of research on biomarkers of neuro-glial injury in patients with status epilepticus. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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16 pages, 5282 KiB

Open AccessReview

Forward Genetics-Based Approaches to Understanding the Systems Biology and Molecular Mechanisms of Epilepsy

by Anton D. Shevlyakov, Tatiana O. Kolesnikova, Murilo S. de Abreu, Elena V. Petersen, Konstantin B. Yenkoyan, Konstantin A. Demin and Allan V. Kalueff

Int. J. Mol. Sci. 2023, 24(6), 5280; https://doi.org/10.3390/ijms24065280 - 9 Mar 2023

Cited by 4 | Viewed by 2664

Abstract

Epilepsy is a highly prevalent, severely debilitating neurological disorder characterized by seizures and neuronal hyperactivity due to an imbalanced neurotransmission. As genetic factors play a key role in epilepsy and its treatment, various genetic and genomic technologies continue to dissect the genetic causes [...] Read more.

Epilepsy is a highly prevalent, severely debilitating neurological disorder characterized by seizures and neuronal hyperactivity due to an imbalanced neurotransmission. As genetic factors play a key role in epilepsy and its treatment, various genetic and genomic technologies continue to dissect the genetic causes of this disorder. However, the exact pathogenesis of epilepsy is not fully understood, necessitating further translational studies of this condition. Here, we applied a computational in silico approach to generate a comprehensive network of molecular pathways involved in epilepsy, based on known human candidate epilepsy genes and their established molecular interactors. Clustering the resulting network identified potential key interactors that may contribute to the development of epilepsy, and revealed functional molecular pathways associated with this disorder, including those related to neuronal hyperactivity, cytoskeletal and mitochondrial function, and metabolism. While traditional antiepileptic drugs often target single mechanisms associated with epilepsy, recent studies suggest targeting downstream pathways as an alternative efficient strategy. However, many potential downstream pathways have not yet been considered as promising targets for antiepileptic treatment. Our study calls for further research into the complexity of molecular mechanisms underlying epilepsy, aiming to develop more effective treatments targeting novel putative downstream pathways of this disorder. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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12 pages, 594 KiB

Open AccessReview

Polymorphisms Affecting the Response to Novel Antiepileptic Drugs

by Valentina Urzì Brancati, Tiziana Pinto Vraca, Letteria Minutoli and Giovanni Pallio

Int. J. Mol. Sci. 2023, 24(3), 2535; https://doi.org/10.3390/ijms24032535 - 28 Jan 2023

Cited by 8 | Viewed by 2560

Abstract

Epilepsy is one of the most frequent chronic neurologic disorders that affects nearly 1% of the population worldwide, especially in developing countries. Currently, several antiepileptic drugs (AEDs) are available for its therapy, and although the prognosis is good for most patients, 20%–30% amongst [...] Read more.

Epilepsy is one of the most frequent chronic neurologic disorders that affects nearly 1% of the population worldwide, especially in developing countries. Currently, several antiepileptic drugs (AEDs) are available for its therapy, and although the prognosis is good for most patients, 20%–30% amongst them do not reach seizure freedom. Numerous factors may explain AED-resistance such as sex, age, ethnicity, type of seizure, early epilepsy onset, suboptimal dosing, poor drug compliance, alcohol abuse, and in particular, genetic factors. Specifically, the interindividual differences in drug response can be caused by single nucleotide polymorphisms (SNPs) in genes encoding for drug efflux transporters, for the brain targets of AEDs, and for enzymes involved in drug metabolism. In this review, we used the PubMed database to retrieve studies that assessed the influence of SNPs on the pharmacokinetic (PK), pharmacodynamic (PD), and efficacy of new antiepileptic drugs. Our results showed that polymorphisms in the ABCB1, ABCC2, UGT1A4, UGT2B7, UGT2B15, CYP2C9, and CYP2C19 genes have an influence on the PK and efficacy of AEDs, suggesting that a genetic pre-evaluation of epileptic patients could help clinicians in prescribing a personalized treatment to improve the efficacy and the safety of the therapy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

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