Research

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23 pages, 3371 KiB

Open AccessArticle

In Vivo and In Vitro Characterization of Close Analogs of Compound KA-11, a New Antiseizure Drug Candidate

by Marta Andres-Mach, Mirosław Zagaja, Joanna Szala-Rycaj, Aleksandra Szewczyk, Michał Abram, Marcin Jakubiec, Katarzyna Ciepiela, Katarzyna Socała, Piotr Wlaź, Gniewomir Latacz, Nadia Khan and Krzysztof Kaminski

Int. J. Mol. Sci. 2023, 24(9), 8302; https://doi.org/10.3390/ijms24098302 - 05 May 2023

Viewed by 1735

Abstract

Epilepsy is a neurological disorder involving a number of disease syndromes with a complex etiology. A properly matched antiseizure drug (ASD) gives remission in up to 70% of patients. Nevertheless, there is still a group of about 30% of patients suffering from drug-resistant [...] Read more.

Epilepsy is a neurological disorder involving a number of disease syndromes with a complex etiology. A properly matched antiseizure drug (ASD) gives remission in up to 70% of patients. Nevertheless, there is still a group of about 30% of patients suffering from drug-resistant epilepsy. Consequently, the development of new more effective and/or safer ASDs is still an unmet clinical need. Thus, our current studies were focused on the structural optimization/modifications of one of the leading compounds, KA-11, aiming at the improvement of its antiseizure activity. As a result, we designed and synthesized two close analogs with highly pronounced drug-like physicochemical properties according to in silico predictions, namely KA-228 and KA-232, which were subsequently tested in a panel of animal seizure models, i.e., MES, 6 Hz (32 mA), scPTZ and ivPTZ. Among these compounds, KA-232, which was designed as a water-soluble salt, was distinctly more effective than KA-228 and assured similar antiseizure protection as its chemical prototype KA-11. With the aim of a more detailed characterization of both new molecules, in vitro binding tests were performed to evaluate the potential mechanisms of action. Furthermore, KA-232 was also evaluated in several ADME-Tox studies, and the results obtained strongly supported its drug-like potential. The proposed chemical modification of KA-11 enabled the identification of new pharmacologically active chemotypes, particularly water-soluble KA-232, which, despite the lack of better efficacy than the leading compound, may be used as a chemical prototype for the development of new ASDs, as well as substances potentially active in other neurological or neurodegenerative conditions. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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19 pages, 3279 KiB

Open AccessArticle

Thalidomide Attenuates Epileptogenesis and Seizures by Decreasing Brain Inflammation in Lithium Pilocarpine Rat Model

by Irán M. Cumbres-Vargas, Sergio R. Zamudio, Luz A. Pichardo-Macías and Eduardo Ramírez-San Juan

Int. J. Mol. Sci. 2023, 24(7), 6488; https://doi.org/10.3390/ijms24076488 - 30 Mar 2023

Cited by 1 | Viewed by 1609

Abstract

Thalidomide (TAL) has shown potential therapeutic effects in neurological diseases like epilepsy. Both clinical and preclinical studies show that TAL may act as an antiepileptic drug and as a possible treatment against disease development. However, the evidence for these effects is limited. Therefore, [...] Read more.

Thalidomide (TAL) has shown potential therapeutic effects in neurological diseases like epilepsy. Both clinical and preclinical studies show that TAL may act as an antiepileptic drug and as a possible treatment against disease development. However, the evidence for these effects is limited. Therefore, the antiepileptogenic and anti-inflammatory effects of TAL were evaluated herein. Sprague Dawley male rats were randomly allocated to one of five groups (n = 18 per group): control (C); status epilepticus (SE); SE-TAL (25 mg/kg); SE-TAL (50 mg/kg); and SE-topiramate (TOP; 60mg/kg). The lithium-pilocarpine model was used, and one day after SE induction the rats received pharmacological treatment for one week. The brain was obtained, and the hippocampus was micro-dissected 8, 18, and 28 days after SE. TNF-α, IL-6, and IL-1β concentrations were quantified. TOP and TAL (50 mg/kg) increased the latency to the first of many spontaneous recurrent seizures (SRS) and decreased SRS frequency, as well as decreasing TNF-α and IL-1β concentrations in the hippocampus. In conclusion, the results showed that both TAL (50 mg/kg) and TOP have anti-ictogenic and antiepileptogenic effects, possibly by decreasing neuroinflammation. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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21 pages, 5191 KiB

Open AccessArticle

Altered GABA_A Receptor Expression in the Primary Somatosensory Cortex of a Mouse Model of Genetic Absence Epilepsy

by Muhammad Hassan, Nadia K. Adotevi and Beulah Leitch

Int. J. Mol. Sci. 2022, 23(24), 15685; https://doi.org/10.3390/ijms232415685 - 10 Dec 2022

Cited by 2 | Viewed by 2682

Abstract

Absence seizures are hyperexcitations within the cortico-thalamocortical (CTC) network, however the underlying causative mechanisms at the cellular and molecular level are still being elucidated and appear to be multifactorial. Dysfunctional feed-forward inhibition (FFI) is implicated as one cause of absence seizures. Previously, we [...] Read more.

Absence seizures are hyperexcitations within the cortico-thalamocortical (CTC) network, however the underlying causative mechanisms at the cellular and molecular level are still being elucidated and appear to be multifactorial. Dysfunctional feed-forward inhibition (FFI) is implicated as one cause of absence seizures. Previously, we reported altered excitation onto parvalbumin-positive (PV⁺) interneurons in the CTC network of the stargazer mouse model of absence epilepsy. In addition, downstream changes in GABAergic neurotransmission have also been identified in this model. Our current study assessed whether dysfunctional FFI affects GABA_A receptor (GABA_AR) subunit expression in the stargazer primary somatosensory cortex (SoCx). Global tissue expression of GABA_AR subunits α1, α3, α4, α5, β2, β3, γ2 and δ were assessed using Western blotting (WB), while biochemically isolated subcellular fractions were assessed for the α and δ subunits. We found significant reductions in tissue and synaptic expression of GABA_AR α1, 18% and 12.2%, respectively. However, immunogold-cytochemistry electron microscopy (ICC-EM), conducted to assess GABA_AR α1 specifically at synapses between PV⁺ interneurons and their targets, showed no significant difference. These data demonstrate a loss of phasic GABA_AR α1, indicating altered GABAergic inhibition which, coupled with dysfunctional FFI, could be one mechanism contributing to the generation or maintenance of absence seizures. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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18 pages, 3796 KiB

Open AccessArticle

Blockade of Kv1.3 Potassium Channel Inhibits Microglia-Mediated Neuroinflammation in Epilepsy

by Xinyi Zhang, Peiyu Liang, Yahui Zhang, Yifan Wu, Yinghao Song, Xueyang Wang, Taoxiang Chen, Biwen Peng, Wanhong Liu, Jun Yin, Song Han and Xiaohua He

Int. J. Mol. Sci. 2022, 23(23), 14693; https://doi.org/10.3390/ijms232314693 - 24 Nov 2022

Cited by 6 | Viewed by 2432

Abstract

Epilepsy is a chronic neurological disorder whose pathophysiology relates to inflammation. The potassium channel Kv1.3 in microglia has been reported as a promising therapeutic target in neurological diseases in which neuroinflammation is involved, such as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease [...] Read more.

Epilepsy is a chronic neurological disorder whose pathophysiology relates to inflammation. The potassium channel Kv1.3 in microglia has been reported as a promising therapeutic target in neurological diseases in which neuroinflammation is involved, such as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and middle cerebral artery occlusion/reperfusion (MCAO/R). Currently, little is known about the relationship between Kv1.3 and epilepsy. In this study, we found that Kv1.3 was upregulated in microglia in the KA-induced mouse epilepsy model. Importantly, blocking Kv1.3 with its specific small-molecule blocker 5-(4-phenoxybutoxy)psoralen (PAP-1) reduced seizure severity, prolonged seizure latency, and decreased neuronal loss. Mechanistically, we further confirmed that blockade of Kv1.3 suppressed proinflammatory microglial activation and reduced proinflammatory cytokine production by inhibiting the Ca²⁺/NF-κB signaling pathway. These results shed light on the critical function of microglial Kv1.3 in epilepsy and provided a potential therapeutic target. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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22 pages, 3825 KiB

Open AccessArticle

GDNF Increases Inhibitory Synaptic Drive on Principal Neurons in the Hippocampus via Activation of the Ret Pathway

by Apostolos Mikroulis, Eliška Waloschková, Johan Bengzon, David Woldbye, Lars H. Pinborg, Bo Jespersen, Anna Sanchez Avila, Zsofia I. Laszlo, Christopher Henstridge, Marco Ledri and Merab Kokaia

Int. J. Mol. Sci. 2022, 23(21), 13190; https://doi.org/10.3390/ijms232113190 - 29 Oct 2022

Cited by 1 | Viewed by 1617

Abstract

Glial cell line-derived neurotrophic factor (GDNF) has been shown to counteract seizures when overexpressed or delivered into the brain in various animal models of epileptogenesis or chronic epilepsy. The mechanisms underlying this effect have not been investigated. We here demonstrate for the first [...] Read more.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to counteract seizures when overexpressed or delivered into the brain in various animal models of epileptogenesis or chronic epilepsy. The mechanisms underlying this effect have not been investigated. We here demonstrate for the first time that GDNF enhances GABAergic inhibitory drive onto mouse pyramidal neurons by modulating postsynaptic GABA_A receptors, particularly in perisomatic inhibitory synapses, by GFRα1 mediated activation of the Ret receptor pathway. Other GDNF receptors, such as NCAM or Syndecan3, are not contributing to this effect. We observed similar alterations by GDNF in human hippocampal slices resected from epilepsy patients. These data indicate that GDNF may exert its seizure-suppressant action by enhancing GABAergic inhibitory transmission in the hippocampal network, thus counteracting the increased excitability of the epileptic brain. This new knowledge can contribute to the development of novel, more precise treatment strategies based on a GDNF gene therapy approach. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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16 pages, 5346 KiB

Open AccessArticle

Relationship between Neuroglial Apoptosis and Neuroinflammation in the Epileptic Focus of the Brain and in the Blood of Patients with Drug-Resistant Epilepsy

by Tatiana V. Sokolova, Yulia M. Zabrodskaya, Anastasia V. Litovchenko, Natalia M. Paramonova, Vugar R. Kasumov, Svetlana V. Kravtsova, Ekaterina N. Skiteva, Daria A. Sitovskaya and Elena D. Bazhanova

Int. J. Mol. Sci. 2022, 23(20), 12561; https://doi.org/10.3390/ijms232012561 - 19 Oct 2022

Cited by 9 | Viewed by 2159

Abstract

Neuroglial apoptosis and neuroinflammation play an important role in epileptogenesis. The aim of this study is to evaluate neuronal and glial apoptosis in association with neuroinflammation in brain epileptic focus and inflammatory changes in blood in patients with focal drug-resistant epilepsy (DRE). Pathological [...] Read more.

Neuroglial apoptosis and neuroinflammation play an important role in epileptogenesis. The aim of this study is to evaluate neuronal and glial apoptosis in association with neuroinflammation in brain epileptic focus and inflammatory changes in blood in patients with focal drug-resistant epilepsy (DRE). Pathological changes in the temporal lobe in epilepsy (histology, transmission electron microscopy), levels of apoptotic and neuroinflammatory proteins: active caspase-3 (immunohistochemistry), full-length form caspase-3, caspase-9, FAS, FAS-L, NF-kB, TNF-α, p53 (Western blot), and cytokine levels in blood: IL-1β, IL-2, IL-4, IL-7, TNF-α, etc. (multiplex analysis) were studied. In the present work, ultrastructural and immunohistochemical apoptotic signs were found in neurons and oligodendrocytes in the temporal lobe of DRE patients. Levels of proinflammatory cytokines that play a role in apoptosis (TNF-α, FAS, NF-kB) were increased. The blood concentration of IL-4, IL-7, TNF-α is increased and IL-2 is reduced. Oligodendroglial apoptosis has been shown to play an important role in DRE pathogenesis and to explain demyelination. Thus, a comprehensive analysis of revealed changes in the blood and brain in DRE patients showed the neuroinflammation in the epileptic focus, which was combined with the development of apoptosis of glial cells and neurons. This creates conditions for the development of drug resistance and the epilepsy progression. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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16 pages, 3606 KiB

Open AccessArticle

Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy

by Chen-Ling Gan, Yulian Zou, Dongmei Chen, Xindong Shui, Li Hu, Ruomeng Li, Tao Zhang, Junhao Wang, Yingxue Mei, Long Wang, Mi Zhang, Yuan Tian, Xi Gu and Tae Ho Lee

Int. J. Mol. Sci. 2022, 23(12), 6370; https://doi.org/10.3390/ijms23126370 - 07 Jun 2022

Cited by 4 | Viewed by 1973

Abstract

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not [...] Read more.

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not been determined. We assessed multiple electroencephalograms and seizure grades and performed biochemical and cell death analyses with cellular and animal models. We applied small molecules and peptides and knocked out and mutated genes to evaluate the therapeutic efficacy of kainic acid (KA), an analog of glutamate-induced neuronal damage. KA administration increased DAPK1 activity by promoting its phosphorylation by activated extracellular signal-regulated kinase (ERK). DAPK1 activation increased seizure severity and neuronal cell death in mice. Selective ERK antagonist treatment, DAPK1 gene ablation, and uncoupling of DAPK1 and ERK peptides led to potent anti-seizure and anti-apoptotic effects in vitro and in vivo. Moreover, a DAPK1 phosphorylation-deficient mutant alleviated glutamate-induced neuronal apoptosis. These results provide novel insight into the pathogenesis of epilepsy and indicate that targeting DAPK1 may be a potential therapeutic strategy for treating epilepsy. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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11 pages, 3251 KiB

Open AccessArticle

Spectroscopic Evaluation of the Potential Neurotoxic Effects of a New Candidate for Anti-Seizure Medication—TP-315 during Chronic Administration (In Vivo)

by Mikolaj Krysa, Anna Makuch-Kocka, Katarzyna Susniak, Tomasz Plech, Marta Andres-Mach, Mirosław Zagaja and Anna Sroka-Bartnicka

Int. J. Mol. Sci. 2022, 23(9), 4607; https://doi.org/10.3390/ijms23094607 - 21 Apr 2022

Viewed by 1485

Abstract

The aim of this study was to investigate the potential neurotoxic effect of the new anti-seizure medication candidate—5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP-315), after chronic administration to mice. TP-315 was administered to mice intraperitoneally for 14 days. At 24 h post the last injection, animals [...] Read more.

The aim of this study was to investigate the potential neurotoxic effect of the new anti-seizure medication candidate—5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP-315), after chronic administration to mice. TP-315 was administered to mice intraperitoneally for 14 days. At 24 h post the last injection, animals were decapitated, their brains were acquired, flash-frozen in liquid nitrogen and cut into 10 µm slices. The FT-IR chemical imaging technique was used for the investigation of the potential neurotoxic effect in the cerebral cortex and hippocampus. The effect on the lipidomic and proteomic profile and on oxidative stress was investigated. The results showed no statistically significant changes in the above-mentioned parameters. TP-315 seems to pose no neurotoxic effect on the mouse brain after chronic use, therefore, its use should be safe. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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20 pages, 2792 KiB

Open AccessReview

Identification of New Antiseizure Medication Candidates in Preclinical Animal Studies

by Chih-Sheng Yang, Man-Chun Wu, Ming-Chi Lai, Sheng-Nan Wu and Chin-Wei Huang

Int. J. Mol. Sci. 2023, 24(17), 13143; https://doi.org/10.3390/ijms241713143 - 24 Aug 2023

Cited by 1 | Viewed by 1078

Abstract

Epilepsy is a multifactorial neurologic disease that often leads to many devastating disabilities and an enormous burden on the healthcare system. Until now, drug-resistant epilepsy has presented a major challenge for approximately 30% of the epileptic population. The present article summarizes the validated [...] Read more.

Epilepsy is a multifactorial neurologic disease that often leads to many devastating disabilities and an enormous burden on the healthcare system. Until now, drug-resistant epilepsy has presented a major challenge for approximately 30% of the epileptic population. The present article summarizes the validated rodent models of seizures employed in pharmacological researches and comprehensively reviews updated advances of novel antiseizure candidates in the preclinical phase. Newly discovered compounds that demonstrate antiseizure efficacy in preclinical trials will be discussed in the review. It is inspiring that several candidates exert promising antiseizure activities in drug-resistant seizure models. The representative compounds consist of derivatives of hybrid compounds that integrate multiple approved antiseizure medications, novel positive allosteric modulators targeting subtype-selective γ-Aminobutyric acid type A receptors, and a derivative of cinnamamide. Although the precise molecular mechanism, pharmacokinetic properties, and safety are not yet fully clear in every novel antiseizure candidate, the adapted approaches to design novel antiseizure medications provide new insights to overcome drug-resistant epilepsy. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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16 pages, 1145 KiB

Open AccessReview

N-Type Ca Channel in Epileptic Syndromes and Epilepsy: A Systematic Review of Its Genetic Variants

by Sonia Mayo, Irene Gómez-Manjón, Ana Victoria Marco-Hernández, Francisco Javier Fernández-Martínez, Ana Camacho and Francisco Martínez

Int. J. Mol. Sci. 2023, 24(7), 6100; https://doi.org/10.3390/ijms24076100 - 23 Mar 2023

Viewed by 1583

Abstract

N-type voltage-gated calcium channel controls the release of neurotransmitters from neurons. The association of other voltage-gated calcium channels with epilepsy is well-known. The association of N-type voltage-gated calcium channels and pain has also been established. However, the relationship between this type of calcium [...] Read more.

N-type voltage-gated calcium channel controls the release of neurotransmitters from neurons. The association of other voltage-gated calcium channels with epilepsy is well-known. The association of N-type voltage-gated calcium channels and pain has also been established. However, the relationship between this type of calcium channel and epilepsy has not been specifically reviewed. Therefore, the present review systematically summarizes existing publications regarding the genetic associations between N-type voltage-dependent calcium channel and epilepsy. Full article

(This article belongs to the Special Issue Epilepsy Research and Antiepileptic Drugs)

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