Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 11.542
Filtrar
1.
Molecules ; 29(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731442

RESUMO

Two series, "a" and "b", each consisting of nine chemical compounds, with 2,3-disubstituted quinazolin-4(3H)-one scaffold, were synthesized and evaluated for their anticonvulsant activity. They were investigated as dual potential positive allosteric modulators of the GABAA receptor at the benzodiazepine binding site and inhibitors of carbonic anhydrase II. Quinazolin-4(3H)-one derivatives were evaluated in vivo (D1-3 = 50, 100, 150 mg/kg, administered intraperitoneally) using the pentylenetetrazole (PTZ)-induced seizure model in mice, with phenobarbital and diazepam, as reference anticonvulsant agents. The in silico studies suggested the compounds act as anticonvulsants by binding on the allosteric site of GABAA receptor and not by inhibiting the carbonic anhydrase II, because the ligands-carbonic anhydrase II predicted complexes were unstable in the molecular dynamics simulations. The mechanism targeting GABAA receptor was confirmed through the in vivo flumazenil antagonism assay. The pentylenetetrazole experimental anticonvulsant model indicated that the tested compounds, 1a-9a and 1b-9b, present a potential anticonvulsant activity. The evaluation, considering the percentage of protection against PTZ, latency until the onset of the first seizure, and reduction in the number of seizures, revealed more favorable results for the "b" series, particularly for compound 8b.


Assuntos
Anticonvulsivantes , Pentilenotetrazol , Receptores de GABA-A , Convulsões , Anticonvulsivantes/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Animais , Camundongos , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Receptores de GABA-A/metabolismo , Quinazolinonas/farmacologia , Quinazolinonas/química , Quinazolinonas/síntese química , Simulação de Acoplamento Molecular , Masculino , Relação Estrutura-Atividade , Simulação de Dinâmica Molecular , Simulação por Computador , Modelos Animais de Doenças , Estrutura Molecular , Sítio Alostérico
2.
Molecules ; 29(9)2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38731471

RESUMO

It has been several years since highly purified cannabidiol (CBD) was registered as a medication that can be used in children of at least 2 years of age to treat different types of seizures related to Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and more recently tuberous sclerosis complex (TSC). During this time, 39 randomized clinical trials (RCTs) and 13 meta-analyses on the efficacy and safety of CBD treatment have been published. Each of the meta-analyses had its own criteria for the RCTs' inclusion and, therefore, slightly different interpretations of the analyzed data. Each of them contributed in its own way to the understanding of CBD pharmacology, mechanisms of therapeutic action, development of adverse reactions, and drug-drug interactions. Hence, it seemed reasonable to gather the most relevant data in one article and present all the current knowledge on the use of CBD in epilepsy. The results of the 13 meta-analyses presented herein confirmed the effectiveness and safety of CBD in children and adolescents with DREs. In adults, reliable conclusions cannot be drawn due to insufficient data.


Assuntos
Anticonvulsivantes , Canabidiol , Epilepsia , Humanos , Canabidiol/uso terapêutico , Canabidiol/farmacologia , Epilepsia/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Síndrome de Lennox-Gastaut/tratamento farmacológico , Criança , Resultado do Tratamento , Epilepsias Mioclônicas/tratamento farmacológico
3.
Acta Neurobiol Exp (Wars) ; 84(1): 51-58, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38587324

RESUMO

Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8­hydroxy­2­deoxyguanosine (8­OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium­pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8­OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8­OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Piracetam , Masculino , Ratos , Animais , Levetiracetam/efeitos adversos , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/tratamento farmacológico , Piracetam/efeitos adversos , Antioxidantes/uso terapêutico , Dissulfeto de Glutationa/efeitos adversos , Peróxido de Hidrogênio/efeitos adversos , Ratos Wistar , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Glutationa/metabolismo , Oxirredução
4.
Neurologia (Engl Ed) ; 39(4): 329-339, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38616060

RESUMO

INTRODUCTION: In the present study, anticonvulsant effects of aqueous extract (AE), hydro-alcoholic crude extract (HE), and its fractions (F-CHCl3, F-EtOAc, F-MeOH) of Paeonia daurica subsp. macrophylla (P. daurica ssp. macrophylla) root examined by using a pentylenetetrazol-induced model (PTZ) on mice. METHODS: HE and its fractions as well as AE, in concentrations of (100, 200 and 400mg/kg), valproate (Val) (100 and 200mg/kg), and saline (negative control) (10mg/kg) were injected intraperitoneally (i.p.) 30min before PTZ (80mg/kg, i.p.). The time taken before the onset of myoclonic convulsions (MC), MC duration, time taken before the onset of generalized tonic-clonic seizures (GTCS), the duration of GTCS, and the percentage of GTCS and mortality protection recorded. The plant's anticonvulsant mechanisms were assessed using flumazenil (5mg/kg, i.p.) before AE (100, 200, and 400mg/kg, i.p.) injection. GraphPad Prism software was used to compare the differences between various treatment groups with one-way analysis of variance (ANOVA) followed by Tukey-Krammer multiple comparison tests. RESULTS: All the plant samples except F-EtOAc significantly delayed the onset and decreased the duration of PTZ-induced MCS and GTCS, and significantly reduced the GTCS and mortality rate. Pretreatment with flumazenil diminished the significant anticonvulsant effects of AE against PTZ-induced seizures. CONCLUSIONS: It can report that extract of P. daurica ssp. macrophylla might be a helpful guide for future studies in the treatment of epilepsy.


Assuntos
Anticonvulsivantes , Paeonia , Animais , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Pentilenotetrazol/toxicidade , Flumazenil , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
5.
J Biochem Mol Toxicol ; 38(4): e23706, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38591869

RESUMO

In this study, our goal was to synthesize novel aryl tacrine derivatives and assess their potential as anticancer, antibacterial agents, and enzyme inhibitors. We adopted a two-step approach, initiating with the synthesis of dibromotacrine derivatives 3 and 4 through the Friedlander reaction. These intermediates underwent further transformation into diarylated tacrine derivatives 3a-e and 4a-e using a Suzuki-Miyaura cross-coupling reaction. Thorough characterization of these novel diarylated tacrines was achieved using various spectroscopic techniques. Our findings highlighted the potent anticancer effects of these innovative compounds across a range of cancer cell lines, including lung, gynecologic, bone, colon, and breast cancers, while demonstrating low cytotoxicity against normal cells. Notably, these compounds surpassed the control drug, 5-Fluorouracil, in terms of antiproliferative activity in numerous cancer cell lines. Moreover, our investigation included an analysis of the inhibitory properties of these novel compounds against various microorganisms and cytosolic carbonic anhydrase enzymes. The results suggest their potential for further exploration as cancer-specific, enzyme inhibitory, and antibacterial therapeutic agents. Notably, four compounds, namely, 5,7-bis(4-(methylthio)phenyl)tacrine (3d), 5,7-bis(4-(trifluoromethoxy)phenyl)tacrine (3e), 2,4-bis(4-(trifluoromethoxy)phenyl)-7,8,9,10-tetrahydro-6H-cyclohepta[b]quinolin-11-amine (4e), and 6,8-dibromotacrine (3), emerged as the most promising candidates for preclinical studies.


Assuntos
Antineoplásicos , Neoplasias , Feminino , Humanos , Tacrina/farmacologia , Tacrina/química , Antifúngicos/farmacologia , Anticonvulsivantes/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Inibidores Enzimáticos/farmacologia , Antineoplásicos/química , Relação Estrutura-Atividade , Estrutura Molecular
6.
Epilepsy Res ; 202: 107364, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38640591

RESUMO

Focal cortical dysplasia (FCD) is an important etiology of focal epilepsy in children and adults. However, only a few preclinical models sufficiently reproduce the characteristic histopathologic features of FCD. To improve the success rate of clinical trials for antiseizure medications (ASMs) in patients with FCD, more human-relevant preclinical models are needed, and epileptic foci resected from patients are a powerful tool for this purpose. Here, we conducted ex vivo studies using epileptic foci resected from patients with FCD type II to evaluate the pharmacologic effects of the ASM candidate E2730, a selective uncompetitive inhibitor of γ-aminobutyric acid transporter 1. We used the same ex vivo assay system to assess carbamazepine (CBZ), an ASM often prescribed for focal epilepsy, as a reference. At the higher dose tested (200 µM), both E2730 and CBZ suppressed spontaneous epileptiform activities almost completely. At the lower dose (100 µM), CBZ reduced the area of brain tissue showing epileptiform activity, whereas E2730 significantly decreased the number of epileptiforms. These findings suggest that E2730-both as a single agent and in combination with CBZ-merits evaluation in clinical trials involving patients with FCD.


Assuntos
Anticonvulsivantes , Proteínas da Membrana Plasmática de Transporte de GABA , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Carbamazepina/farmacologia , Relação Dose-Resposta a Droga , Epilepsia/tratamento farmacológico , Displasia Cortical Focal/tratamento farmacológico , Inibidores da Captação de GABA/farmacologia , Malformações do Desenvolvimento Cortical/tratamento farmacológico , Malformações do Desenvolvimento Cortical do Grupo I/tratamento farmacológico , Técnicas In Vitro
7.
CNS Neurosci Ther ; 30(4): e14672, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38644561

RESUMO

AIMS: Motor abnormalities have been identified as one common symptom in patients with generalized tonic-clonic seizures (GTCS) inspiring us to explore the disease in a motor execution condition, which might provide novel insight into the pathomechanism. METHODS: Resting-state and motor-task fMRI data were collected from 50 patients with GTCS, including 18 patients newly diagnosed without antiepileptic drugs (ND_GTCS) and 32 patients receiving antiepileptic drugs (AEDs_GTCS). Motor activation and its association with head motion and cerebral gradients were assessed. Whole-brain network connectivity across resting and motor states was further calculated and compared between groups. RESULTS: All patients showed over-activation in the postcentral gyrus and the ND_GTCS showed decreased activation in putamen. Specifically, activation maps of ND_GTCS showed an abnormal correlation with head motion and cerebral gradient. Moreover, we detected altered functional network connectivity in patients within states and across resting and motor states by using repeated-measures analysis of variance. Patients did not show abnormal connectivity in the resting state, while distributed abnormal connectivity in the motor-task state. Decreased across-state network connectivity was also found in all patients. CONCLUSION: Convergent findings suggested the over-response of activation and connection of the brain to motor execution in GTCS, providing new clues to uncover motor susceptibility underlying the disease.


Assuntos
Encéfalo , Imageamento por Ressonância Magnética , Descanso , Convulsões , Humanos , Masculino , Feminino , Adulto , Encéfalo/fisiopatologia , Encéfalo/diagnóstico por imagem , Descanso/fisiologia , Adulto Jovem , Convulsões/fisiopatologia , Convulsões/diagnóstico por imagem , Pessoa de Meia-Idade , Mapeamento Encefálico , Vias Neurais/fisiopatologia , Vias Neurais/diagnóstico por imagem , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologia , Adolescente , Atividade Motora/fisiologia , Atividade Motora/efeitos dos fármacos
8.
J Mol Med (Berl) ; 102(6): 761-771, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38653825

RESUMO

Epilepsy is a neurological disorder characterized by spontaneous and recurring seizures. It poses significant therapeutic challenges due to diverse etiology, pathobiology, and pharmacotherapy-resistant variants. The anticonvulsive effects of herbal leads with biocompatibility and toxicity considerations have attracted much interest, inspiring mechanistic analysis with the view of their use for engagement of new targets and combination with antiseizure pharmacotherapies. This article presents a comprehensive overview of the key molecular players and putative action mechanisms of the most common antiepileptic herbals demonstrated in tissue culture and preclinical models. From the review of the literature, it emerges that their effects are mediated via five distinct mechanisms: (1) reduction of membrane excitability through inhibition of cation channels, (2) improvement of mitochondrial functions with antioxidant effects, (3) enhancement in synaptic transmission mediated by GABAA receptors, (4) improvement of immune response with anti-inflammatory action, and (5) suppression of protein synthesis and metabolism. While some of the primary targets and action mechanisms of herbal anticonvulsants (1, 3) are shared with antiseizure pharmacotherapies, herbal leads also engage with distinct mechanisms (2, 4, and 5), suggesting new drug targets and opportunities for their integration with antiseizure medications. Addressing outstanding questions through research and in silico modeling should facilitate the future use of herbals as auxiliary therapy in epilepsy and guide the development of treatment of pharmacoresistant seizures through rigorous trials and regulatory approval.


Assuntos
Anticonvulsivantes , Humanos , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologia , Animais , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/metabolismo , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo
9.
Neuroscience ; 546: 157-177, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38574797

RESUMO

Epilepsy is one of the most widespread and complex diseases in the central nervous system (CNS), affecting approximately 65 million people globally, an important factor resulting in neurological disability-adjusted life year (DALY) and progressive cognitive dysfunction. Medication is the most essential treatment. The currently used drugs have shown drug resistance in some patients and only control symptoms; the development of novel and more efficacious pharmacotherapy is imminent. Increasing evidence suggests neuroinflammation is involved in the occurrence and development of epilepsy, and high expression of NLRP3 inflammasome has been observed in the temporal lobe epilepsy (TLE) brain tissue of patients and animal models. The inflammasome is a crucial cause of neuroinflammation by activating IL-1ß and IL-18. Many preclinical studies have confirmed that regulating NLRP3 inflammasome pathway can prevent the development of epilepsy, reduce the severity of epilepsy, and play a neuroprotective role. Therefore, regulating NLRP3 inflammasome could be a potential target for epilepsy treatment. In summary, this review describes the priming and activation of inflammasome and its biological function in the progression of epilepsy. In addition, we reviewes the current pharmacological researches for epilepsy based on the regulation of NLRP3 inflammasome, aiming to provide a basis and reference for developing novel antiepileptic drugs.


Assuntos
Anticonvulsivantes , Epilepsia , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Animais , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Inflamassomos/metabolismo , Inflamassomos/efeitos dos fármacos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo
10.
Int J Mol Sci ; 25(8)2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38673747

RESUMO

Neuroinflammation and epilepsy are different pathologies, but, in some cases, they are so closely related that the activation of one of the pathologies leads to the development of the other. In this work, we discuss the three main cell types involved in neuroinflammation, namely (i) reactive astrocytes, (ii) activated microglia, and infiltration of (iii) peripheral immune cells in the central nervous system. Then, we discuss how neuroinflammation and epilepsy are interconnected and describe the use of different repurposing drugs with anti-inflammatory properties that have been shown to have a beneficial effect in different epilepsy models. This review reinforces the idea that compounds designed to alleviate seizures need to target not only the neuroinflammation caused by reactive astrocytes and microglia but also the interaction of these cells with infiltrated peripheral immune cells.


Assuntos
Astrócitos , Reposicionamento de Medicamentos , Epilepsia , Microglia , Doenças Neuroinflamatórias , Humanos , Epilepsia/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Doenças Neuroinflamatórias/tratamento farmacológico , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologia
11.
Behav Brain Res ; 466: 114981, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38580198

RESUMO

This study verified the effects of the natural compounds berberine and hesperidin on seizure development and cognitive impairment triggered by pentylenetetrazole (PTZ) in zebrafish. Adult animals were submitted to a training session in the inhibitory avoidance test and, after 10 minutes, they received an intraperitoneal injection of 25, 50, or 100 mg/kg berberine or 100 or 200 mg/kg hesperidin. After 30 minutes, the animals were exposed to 7.5 mM PTZ for 10 minutes. Animals were submitted to the test session 24 h after the training session to verify their cognitive performance. Zebrafish larvae were exposed to 100 µM or 500 µM berberine or 10 µM or 50 µM hesperidin for 30 minutes. After, larvae were exposed to PTZ and had the seizure development evaluated by latency to reach the seizure stages I, II, and III. Adult zebrafish pretreated with 50 mg/kg berberine showed a longer latency to reach stage III. Zebrafish larvae pretreated with 500 µM berberine showed a longer latency to reach stages II and III. Hesperidin did not show any effect on seizure development both in larvae and adult zebrafish. Berberine and hesperidin pretreatments prevented the memory consolidation impairment provoked by PTZ-induced seizures. There were no changes in the distance traveled in adult zebrafish pretreated with berberine or hesperidin. In larval stage, berberine caused no changes in the distance traveled; however, hesperidin increased the locomotion. Our results reinforce the need for investigating new therapeutic alternatives for epilepsy and its comorbidities.


Assuntos
Aprendizagem da Esquiva , Berberina , Hesperidina , Pentilenotetrazol , Convulsões , Peixe-Zebra , Animais , Pentilenotetrazol/farmacologia , Berberina/farmacologia , Berberina/administração & dosagem , Hesperidina/farmacologia , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Aprendizagem da Esquiva/efeitos dos fármacos , Consolidação da Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Masculino , Modelos Animais de Doenças , Convulsivantes/farmacologia , Larva/efeitos dos fármacos , Relação Dose-Resposta a Droga , Anticonvulsivantes/farmacologia
12.
ACS Chem Neurosci ; 15(9): 1937-1947, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38630556

RESUMO

The development of antiepileptic drugs is still a long process. In this study, heparin-modified superparamagnetic iron oxide nanoparticles (UFH-SPIONs) were prepared, and their antiepileptic effect and underlying mechanism were investigated. UFH-SPIONs are stable, homogeneous nanosystems with antioxidant enzyme activity that are able to cross the blood-brain barrier (BBB) and enriched in hippocampal epileptogenic foci. The pretreatment with UFH-SPIONs effectively prolonged the onset of seizures and reduced seizure severity after lithium/pilocarpine (LP)-induced seizures in rats. The pretreatment with UFH-SPIONs significantly decreased the expression of inflammatory factors in hippocampal tissues, including IL-6, IL-1ß, and TNF-α. LP-induced oxidative stress in hippocampal tissues was in turn reduced upon pretreatment with UFH-SPIONs, as evidenced by an increase in the levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and a decrease in the level of lipid peroxidation (MDA). Moreover, the LP-induced upregulation of apoptotic cells was decreased upon pretreatment with UFH-SPIONs. Together, these observations suggest that the pretreatment with UFH-SPIONs ameliorates LP-induced seizures and downregulates the inflammatory response and oxidative stress, which exerts neuronal protection during epilepsy.


Assuntos
Epilepsia do Lobo Temporal , Heparina , Inflamação , Cloreto de Lítio , Nanopartículas Magnéticas de Óxido de Ferro , Estresse Oxidativo , Pilocarpina , Animais , Estresse Oxidativo/efeitos dos fármacos , Ratos , Masculino , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/tratamento farmacológico , Cloreto de Lítio/farmacologia , Heparina/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/induzido quimicamente , Ratos Sprague-Dawley , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Anticonvulsivantes/farmacologia
13.
Neurochem Int ; 176: 105725, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38561151

RESUMO

Epilepsy constitutes a global health concern, affecting millions of individuals and approximately one-third of patients exhibit drug resistance. Recent investigations have revealed alterations in cerebral iron content in both epilepsy patients and animal models. However, the extant literature lacks a comprehensive exploration into the ramifications of modulating iron homeostasis as an intervention in epilepsy. This study investigated the impact of deferasirox, a iron ion chelator, on epilepsy. This study unequivocally substantiated the antiepileptic efficacy of deferasirox in a kainic acid-induced epilepsy model. Furthermore, deferasirox administration mitigated seizure susceptibility in a pentylenetetrazol-induced kindling model. Conversely, the augmentation of iron levels through supplementation has emerged as a potential exacerbating factor in the precipitating onset of epilepsy. Intriguingly, our investigation revealed a hitherto unreported discovery: ITPRIP was identified as a pivotal modulator of excitatory synaptic transmission, regulating seizures in response to deferasirox treatment. In summary, our findings indicate that deferasirox exerts its antiepileptic effects through the precise targeting of ITPRIP and amelioration of cerebral iron homeostasis, suggesting that deferasirox is a promising and novel therapeutic avenue for interventions in epilepsy.


Assuntos
Anticonvulsivantes , Encéfalo , Deferasirox , Epilepsia , Homeostase , Quelantes de Ferro , Ferro , Deferasirox/farmacologia , Ferro/metabolismo , Animais , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Masculino , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Quelantes de Ferro/farmacologia , Quelantes de Ferro/uso terapêutico , Camundongos , Excitação Neurológica/efeitos dos fármacos , Pentilenotetrazol/toxicidade , Ratos Sprague-Dawley
14.
Epilepsy Res ; 202: 107359, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38582072

RESUMO

PURPOSE: In developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), the thalamocortical network is suggested to play an important role in the pathophysiology of the progression from focal epilepsy to DEE-SWAS. Ethosuximide (ESM) exerts effects by blocking T-type calcium channels in thalamic neurons. With the thalamocortical network in mind, we studied the prediction of ESM effectiveness in DEE-SWAS treatment using phase-amplitude coupling (PAC) analysis. METHODS: We retrospectively enrolled children with DEE-SWAS who had an electroencephalogram (EEG) recorded between January 2009 and September 2022 and were prescribed ESM at Okayama University Hospital. Only patients whose EEG showed continuous spike-and-wave during sleep were included. We extracted 5-min non-rapid eye movement sleep stage N2 segments from EEG recorded before starting ESM. We calculated the modulation index (MI) as the measure of PAC in pair combination comprising one of two fast oscillation types (gamma, 40-80 Hz; ripples, 80-150 Hz) and one of five slow-wave bands (delta, 0.5-1, 1-2, 2-3, and 3-4 Hz; theta, 4-8 Hz), and compared it between ESM responders and non-responders. RESULTS: We identified 20 children with a diagnosis of DEE-SWAS who took ESM. Fifteen were ESM responders. Regarding gamma oscillations, significant differences were seen only in MI with 0.5-1 Hz slow waves in the frontal pole and occipital regions. Regarding ripples, ESM responders had significantly higher MI in coupling with all slow waves in the frontal pole region, 0.5-1, 3-4, and 4-8 Hz slow waves in the frontal region, 3-4 Hz slow waves in the parietal region, 0.5-1, 2-3, 3-4, and 4-8 Hz slow waves in the occipital region, and 3-4 Hz slow waves in the anterior-temporal region. SIGNIFICANCE: High MI in a wider area of the brain may represent the epileptic network mediated by the thalamus in DEE-SWAS and may be a predictor of ESM effectiveness.


Assuntos
Anticonvulsivantes , Eletroencefalografia , Etossuximida , Sono , Humanos , Etossuximida/uso terapêutico , Etossuximida/farmacologia , Masculino , Feminino , Eletroencefalografia/métodos , Estudos Retrospectivos , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologia , Pré-Escolar , Criança , Sono/efeitos dos fármacos , Sono/fisiologia , Lactente , Ondas Encefálicas/efeitos dos fármacos , Ondas Encefálicas/fisiologia , Tálamo/efeitos dos fármacos , Tálamo/fisiopatologia , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/fisiopatologia
15.
Molecules ; 29(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38542951

RESUMO

The fruits of Solanum torvum Swartz, a wild relative of eggplant, are consumed as a wild vegetable in tropical regions of Africa, Asia, and South America. In traditional Chinese medicine, it is believed to have anti-inflammatory and sedative effects. In the Philippines, water decoction is used to treat hyperactivity disorder. Twenty-two steroidal saponins were isolated and purified from the fruits grown in Yunnan, China, including six new compounds: torvosides U-Z (1-6). During drying and cooking, the saponins may undergo transformation, resulting in small amounts of sapogenins. These transformations can include dehydration of hydroxyl groups at position C22, formation of double bonds at position 20, 22 or 22, 23, and even formation of peroxide products. Saponin compounds torvoside X (4), torvoside Y (5), torvoside A (7), and (25S)-3-oxo-5α-spirostan-6α-yl-O-ß-d-xylopyranoside (20), which are glycosylated at C-6, showed certain anti-epileptic activity in a pentylenetetrazole-induced zebrafish seizure model. No antiproliferative activity was detected when tested on the cancer cell line HepG2, and no hepatotoxic effect was noted on normal liver cell line LO2.


Assuntos
Saponinas , Solanum melongena , Solanum , Animais , Solanum/química , Frutas/química , Peixe-Zebra , Pentilenotetrazol , China , Saponinas/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/análise , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico
16.
Neurosci Lett ; 828: 137750, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38548219

RESUMO

Azoles such as nafimidone, denzimol and loreclezole are known for their clinical efficacy against epilepsy, and loreclezole acts by potentiating γ-aminobutyric acid (GABA)-ergic currents. In the current study, we report a series of azole derivatives in alcohol ester and oxime ester structure showing promising anticonvulsant effects in 6 Hz and maximal electro shock (MES) models with minimal toxicity. The most promising of the series, 5f, was active in both 6 Hz and MES tests with a median effective dose (ED50) of 118.92 mg/kg in 6 Hz test and a median toxic dose (TD50) twice as high in mice. The compounds were predicted druglike and blood-brain barrier (BBB) penetrant in silico. Contrary to what was expected, the compounds showed no in vitro affinity to GABAA receptors (GABAARs) in radioligand binding assays; however, they were found structurally similar to peroxisome proliferator-activated receptors alpha (PPAR-α) agonists and predicted to show high affinity and agonist-like binding to PPAR-α in molecular docking studies. As a result, 5f emerged as a safe azole anticonvulsant with a wide therapeutic window and possible action through PPAR-α activation.


Assuntos
Anticonvulsivantes , Azóis , Camundongos , Animais , Anticonvulsivantes/farmacologia , Convulsões/tratamento farmacológico , Simulação de Acoplamento Molecular , PPAR alfa , Ácido gama-Aminobutírico , Ésteres , Relação Estrutura-Atividade
17.
Epilepsy Res ; 201: 107318, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38430668

RESUMO

BACKGROUND: Many anti-seizure medications (ASMs) trigger neuronal cell death when administered during a confined period of early life in rodents. Prototypical ASMs used to treat early-life seizures such as phenobarbital induce this effect, whereas levetiracetam does not. However, most prior studies have examined the effect of ASMs in naïve animals, and the degree to which underlying brain injury interacts with these drugs to modify cell death is poorly studied. Moreover, the degree to which drug-induced neuronal cell death differs as a function of sex is unknown. METHODS: We treated postnatal day 7 Sprague Dawley rat pups with vehicle, phenobarbital (75 mg/kg) or levetiracetam (200 mg/kg). Separate groups of pups were pre-exposed to either normoxia or graded global hypoxia. Separate groups of males and females were used. Twenty-four hours after drug treatment, brains were collected and processed for markers of cell death. RESULTS: Consistent with prior studies, phenobarbital, but not levetiracetam, increased cell death in cortical regions, basal ganglia, hippocampus, septum, and lateral thalamus. Hypoxia did not modify basal levels of cell death. Females - collapsed across treatment and hypoxia status, displayed a small but significant increase in cell death as compared to males in the cingulate cortex, somatosensory cortex, and the CA1 and CA3 hippocampus; these effects were not modulated by hypoxia or drug treatment. CONCLUSION: We found that a history of graded global hypoxia does not alter the neurotoxic profile of phenobarbital. Levetiracetam, which does not induce cell death in normal developing animals, maintained a benign profile on the background of neonatal hypoxia. We found a sex-based difference, as female animals showed elevated levels of cell death across all treatment conditions. Together, these data address several long-standing gaps in our understanding of the neurotoxic profile of antiseizure medications during early postnatal development.


Assuntos
Anticonvulsivantes , Fenobarbital , Masculino , Animais , Ratos , Feminino , Anticonvulsivantes/farmacologia , Animais Recém-Nascidos , Levetiracetam/farmacologia , Ratos Sprague-Dawley , Fenobarbital/farmacologia , Morte Celular , Hipóxia/tratamento farmacológico
18.
Chem Biodivers ; 21(5): e202400255, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38533537

RESUMO

Epilepsy originates from unusual electrical rhythm within brain cells, causes seizures. Calotropis species have been utilized to treat a wide spectrum of ailments since antiquity. Despite chemical and biological investigations, there have been minimal studies on their anticonvulsant activity, and the molecular targets of this plant constituents are unexplored. This study aimed to investigate the plausible epileptic targets of Calotropis phytoconstituents through network pharmacology, and to evaluate their binding strength and stability with the identified targets. In detail, 125 phytoconstituents of the Calotropis plant (C. procera and C. gigantea) were assessed for their drug-likeness (DL), blood-brain-barrier (BBB) permeability and oral bioavailability (OB). Network analysis revealed that targets PTGS2 and PPAR-γ were ranked first and fourth, respectively, among the top ten hub genes significantly linked with antiepileptic drug targets. Additionally, docking, molecular dynamic (MD) simulation, and Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) were employed to validate the compound-gene interactions. Docking studies suggested ergost-5-en-3-ol, stigmasterol and ß-sitosterol exhibit stronger binding affinity and favorable interactions than co-crystallized ligands with both the targets. Furthermore, both MD simulations and MM-PBSA calculations substantiated the docking results. Combined data revealed that Calotropis phytoconstituents ergost-5-en-3-ol, stigmasterol, and ß-sitosterol might be the best inhibitors of both PTGS2 and PPAR-γ.


Assuntos
Anticonvulsivantes , Calotropis , Ciclo-Oxigenase 2 , Epilepsia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Farmacologia em Rede , PPAR gama , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Calotropis/química , Ciclo-Oxigenase 2/metabolismo , PPAR gama/metabolismo , Humanos , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos
19.
Br J Pharmacol ; 181(12): 1886-1894, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38529699

RESUMO

BACKGROUND AND PURPOSE: GRIN-related disorders are neurodevelopmental disorders caused by mutations in N-methyl-D-aspartate receptor (NMDAR) subunit genes. A large fraction of these mutations lead to a 'gain of function' (GoF) of the NMDAR. Patients present with a range of symptoms including epilepsy, intellectual disability, behavioural and motor. Controlling seizures is a significant unmet medical need in most patients with GRIN-related disorders. Although several hundred GRIN mutations have been identified in humans, until recently none of the mouse models carrying Grin mutations/deletions showed an epileptic phenotype. The two recent exceptions both carry mutations of GluN2A. The aim of this study was to assess the efficacy of radiprodil, a selective negative allosteric modulator of GluN2B-containing NMDARs, in counteracting audiogenic seizures (AGS) in a murine model carrying the GluN2A(N615S) homozygous mutation (Grin2aS/S mice). EXPERIMENTAL APPROACH: Grin2aS/S mice were acutely treated with radiprodil at different doses before the presentation of a high-frequency acoustic stimulus commonly used for AGS induction. KEY RESULTS: Radiprodil significantly and dose-dependently reduced the onset and severity of AGS in Grin2aS/S mice. Surprisingly, the results revealed a sex-dependent difference in AGS susceptibility and in the dose-dependent protection of radiprodil in the two genders. Specifically, radiprodil was more effective in female versus male mice. CONCLUSION AND IMPLICATIONS: Overall, our data clearly show that radiprodil, a GluN2B selective negative allosteric modulator, may have the potential to control seizures in patients with GRIN2A GoF mutations. Further studies are warranted to better understand the sex-dependent effects observed in this study.


Assuntos
Mutação , Receptores de N-Metil-D-Aspartato , Animais , Receptores de N-Metil-D-Aspartato/genética , Masculino , Feminino , Camundongos , Piperidinas/farmacologia , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Epilepsia Reflexa/genética , Epilepsia Reflexa/tratamento farmacológico , Regulação Alostérica/efeitos dos fármacos , Convulsões/tratamento farmacológico , Convulsões/genética , Camundongos Endogâmicos C57BL , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/administração & dosagem , Relação Dose-Resposta a Droga
20.
Chem Biodivers ; 21(5): e202400056, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38472742

RESUMO

N-Arylenaminones are highly versatile compounds which can be synthesized in relatively simple ways. In this work we explored the synthesis of the four monosubstituted N-(4-R-phenyl)enaminones 3 a (R=NO2), 3 b (R=F), 3 c (R=H), and 3 d (R=OMe) with the goal of determining the influence of the substituents' electronic effects on tautomer stability and biological activity. These compounds were analyzed by means of Density Functional Theory calculations (DFT), to evaluate the relative stability of the possible tautomers. We found that the enaminone structure is the most stable with respect to the ketoimine and iminoenol forms. In addition, all four compounds display anticonvulsant activity, with 3 d being the one that mostly increased latency and mostly decreased the number of convulsions with respect to the control group. The suggested mechanism of action involves blockage of the voltage-dependent Na+ channels, considering that these molecules meet the structural characteristics needed to block the receptor, as is the case of the positive control molecules phenytoin (PHT) and valproic acid (VPA).


Assuntos
Anticonvulsivantes , Teoria da Densidade Funcional , Anticonvulsivantes/farmacologia , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Animais , Convulsões/tratamento farmacológico , Relação Estrutura-Atividade , Camundongos , Estrutura Molecular
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...