Drugs Targeting the Disease Progression, Cognitive Impairment, Anxiety and Other Co-morbidities in Epilepsy: From Bench to Bedside

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: 15 June 2024 | Viewed by 2944

Special Issue Editors

Departamento de Química e Bioquímica and Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal
Interests: neuroscience pharmacology; toxicology and pharmaceutics chemistry psychology biochemistry; genetics and molecular biology arts and humanities
ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
Interests: adenosine; neuromodulation; neuromuscular junction; epilepsy; osteogenic differentiation; fibrosis; mesenchymal stem cells (MSCs)

Special Issue Information

Dear Colleagues,

Until now, epilepsy therapy has mainly focused on anticonvulsant drugs with negligible disease modifying properties.  Despite the increasing implication of non-canonical neurotransmitter systems in epilepsy, this knowledge has not been sufficiently translated into clinical practice to decrease epileptogenesis progression and accompanying neuropsychiatric co-morbidities. For instance, brain monoaminergic circuits are important regulators of synaptic plasticity and acute stress responses ultimately involved in epilepsy-induced anxiety and memory impairment, but only a few studies have proven that these circuits are altered in epilepsy. Likewise, central cholinergic system adaptations are also associated with epileptogenesis. Both monoaminergic and cholinergic brain circuits frequently target cortical interneurons, expressing a myriad of neuropeptide co-transmitters in distinct cortical areas including the hippocampus, the amygdala, and the prefrontal cortex, all involved in emotional control of cognition. On the other hand, brain neuropeptides released during high-frequency and repetitive discharges may also foster neuronal hyperexcitability states, thus facilitating seizures recurrence and chronic epilepsy. This Special Issue aims to receive high-quality original research papers and review articles focusing on novel drug targets to control epilepsy progression and neuropsychiatric co-morbidities from bench to bedside and bedside to bench perspectives.

Dr. Diana Cunha-Reis
Dr. Paulo Correia-de-Sá
Guest Editors

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Keywords

  • epilepsy and epileptogenesis
  • aminergic neurotransmission
  • neuropeptidergic neuromodulation
  • interneurons
  • neuroprotection
  • neuroplasticity
  • cognitive impairment
  • anxiety
  • neuropsychiatric co-morbidities

Published Papers (3 papers)

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Research

20 pages, 2164 KiB  
Article
Impaired Response to Mismatch Novelty in the Li2+-Pilocarpine Rat Model of TLE: Correlation with Hippocampal Monoaminergic Inputs
by Carlos Nascimento, Vasco Guerreiro-Pinto, Seweryn Pawlak, Ana Caulino-Rocha, Laia Amat-Garcia and Diana Cunha-Reis
Biomedicines 2024, 12(3), 631; https://doi.org/10.3390/biomedicines12030631 - 12 Mar 2024
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Abstract
Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that activates the hippocampal CA1 area in humans and is vital for memory reformulation and reconsolidation, is also impaired in patients with hippocampal [...] Read more.
Novelty detection, crucial to episodic memory formation, is impaired in epileptic patients with mesial temporal lobe resection. Mismatch novelty detection, that activates the hippocampal CA1 area in humans and is vital for memory reformulation and reconsolidation, is also impaired in patients with hippocampal lesions. In this work, we investigated the response to mismatch novelty, as occurs with the new location of known objects in a familiar environment, in the Li2+-pilocarpine rat model of TLE and its correlation with hippocampal monoaminergic markers. Animals showing spontaneous recurrent seizures (SRSs) for at least 4 weeks at the time of behavioural testing showed impaired spatial learning in the radial arm maze, as described. Concurrently, SRS rats displayed impaired exploratory responses to mismatch novelty, yet novel object recognition was not significantly affected in SRS rats. While the levels of serotonin and dopamine transporters were mildly decreased in hippocampal membranes from SRS rats, the levels on the norepinephrine transporter, tyrosine hydroxylase and dopamine-β-hydroxylase were enhanced, hinting for an augmentation, rather than an impairment in noradrenergic function in SRS animals. Altogether, this reveals that mismatch novelty detection is particularly affected by hippocampal damage associated to the Li2+-pilocarpine model of epilepsy 4–8 weeks after the onset of SRSs and suggests that deficits in mismatch novelty detection may substantially contribute to cognitive impairment in MTLE. As such, behavioural tasks based on these aspects of mismatch novelty may prove useful in the development of cognitive therapy strategies aiming to rescue cognitive deficits observed in epilepsy. Full article
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15 pages, 18142 KiB  
Article
Identification of CYFIP2 Arg87Cys Ligands via In Silico and In Vitro Approaches
by Ísis Venturi Biembengut, Emanuella de Castro Andreassa and Tatiana A. C. B. de Souza
Biomedicines 2024, 12(3), 479; https://doi.org/10.3390/biomedicines12030479 - 21 Feb 2024
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Abstract
The advancement of next-generation sequencing has enabled the identification of specific mutations associated with early infantile epileptic encephalopathies (EIEEs). In EIEE, epileptic spasms and seizures that occur since early childhood lead to impaired neurological development. The CYFIP2 p.Arg87Cys variant was recently related to [...] Read more.
The advancement of next-generation sequencing has enabled the identification of specific mutations associated with early infantile epileptic encephalopathies (EIEEs). In EIEE, epileptic spasms and seizures that occur since early childhood lead to impaired neurological development. The CYFIP2 p.Arg87Cys variant was recently related to EIEE. CYFIP2 participates in the Wave Regulatory Complex (WRC), which is related to the regulation of actin dynamics. The variant residue is at the interface between the CYFIP2 protein and WAVE1 protein inside the WRC. Thus, the weakening of this interaction induced by the residue modification, which also causes the flexibilization of the loop 80–110 within the CYFIP2 structure, allows the constant activation of the WCR. This study aimed to identify ligands for CYFIP2 p.Arg87Cys and potential therapy targets using in silico in vitro approaches. Models of different CYFIP2 versions were constructed, and molecular docking analyses were conducted. A total of 3946 ligands from the PDE3 and Drugbank databases were screened, leading to the identification of 11 compounds that selectively bind to the variant protein. The impact of binding in CYFIP2 was also evaluated using a thermal stability assay. These findings contribute to a better understanding of CYFIP2’s functional role in pathology and can guide more in vitro experiments, facilitating the development of targeted therapies for CYFIP2-related conditions. Full article
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16 pages, 1811 KiB  
Article
Evaluation of the Antioxidant Activity of Levetiracetam in a Temporal Lobe Epilepsy Model
by Iván Ignacio-Mejía, Itzel Jatziri Contreras-García, Julieta Griselda Mendoza-Torreblanca, Omar Noel Medina-Campos, José Pedraza-Chaverri, Mercedes Edna García-Cruz, Antonio Romo-Mancillas, Saúl Gómez-Manzo, Cindy Bandala, María Elena Sánchez-Mendoza, Luz Adriana Pichardo-Macías and Noemí Cárdenas-Rodríguez
Biomedicines 2023, 11(3), 848; https://doi.org/10.3390/biomedicines11030848 - 10 Mar 2023
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Abstract
Epilepsy is a neurological disorder in which it has been shown that the presence of oxidative stress (OS) is implicated in epileptogenesis. The literature has shown that some antiseizure drugs (ASD) have neuroprotective properties. Levetiracetam (LEV) is a drug commonly used as an [...] Read more.
Epilepsy is a neurological disorder in which it has been shown that the presence of oxidative stress (OS) is implicated in epileptogenesis. The literature has shown that some antiseizure drugs (ASD) have neuroprotective properties. Levetiracetam (LEV) is a drug commonly used as an ASD, and in some studies, it has been found to possess antioxidant properties. Because the antioxidant effects of LEV have not been demonstrated in the chronic phase of epilepsy, the objective of this study was to evaluate, for the first time, the effects of LEV on the oxidant–antioxidant status in the hippocampus of rats with temporal lobe epilepsy (TLE). The in vitro scavenging capacity of LEV was evaluated. LEV administration in rats with TLE significantly increased superoxide dismutase (SOD) activity, increased catalase (CAT) activity, but did not change glutathione peroxidase (GPx) activity, and significantly decreased glutathione reductase (GR) activity in comparison with epileptic rats. LEV administration in rats with TLE significantly reduced hydrogen peroxide (H2O2) levels but did not change lipoperoxidation and carbonylated protein levels in comparison with epileptic rats. In addition, LEV showed in vitro scavenging activity against hydroxyl radical (HO•). LEV showed significant antioxidant effects in relation to restoring the redox balance in the hippocampus of rats with TLE. In vitro, LEV demonstrated direct antioxidant activity against HO•. Full article
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