Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.567
Filtrar
1.
Lancet Neurol ; 19(9): 784-796, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32822636

RESUMO

Trigeminal neuralgia is a very painful neurological condition with severe, stimulus-evoked, short-lasting stabbing pain attacks in the face. The past decade has offered new insights into trigeminal neuralgia symptomatology, pathophysiology, and treatment, leading to a change in the classification of the condition. An accurate diagnosis is crucial because neuroimaging interpretation and clinical management differ among the various forms of facial pain. MRI using specific sequences should be a part of the diagnostic workup to detect a possible neurovascular contact and exclude secondary causes. Demonstration of a neurovascular contact should not be used to confirm a diagnosis but rather to facilitate surgical decision making. Carbamazepine and oxcarbazepine are drugs of first choice for long-term treatment, whereas microvascular decompression is the first-line surgery in medically refractory patients. Advances in neuroimaging techniques and animal models will provide further insight into the causes of trigeminal neuralgia and its pathophysiology. Development of more efficacious treatment options is highly warranted.


Assuntos
Gerenciamento Clínico , Neuralgia do Trigêmeo/diagnóstico por imagem , Neuralgia do Trigêmeo/fisiopatologia , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Carbamazepina/farmacologia , Carbamazepina/uso terapêutico , Descompressão Cirúrgica/métodos , Humanos , Neuroimagem/métodos , Oxcarbazepina/farmacologia , Oxcarbazepina/uso terapêutico , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Neuralgia do Trigêmeo/classificação , Neuralgia do Trigêmeo/terapia
2.
S Afr Med J ; 110(2): 102-105, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-32657678

RESUMO

The compounds present in cannabis have been in use for both recreational and medicinal purposes for many centuries. Changes in the legislation in South Africa have led to an increase in the number of people interested in using these compounds for self-medication. Many of them may approach their general practitioner as the first source of information about possible therapeutic effects. It is important that medical professionals are able to give patients the correct information. Cannabidiol (CBD) is one of the main compounds in cannabis plants, and there is evidence that it can successfully treat certain patients with epilepsy. This review looks at the most recent evidence on the use of CBD in the treatment of epilepsy and explores the mechanisms behind these beneficial effects.


Assuntos
Canabidiol/farmacologia , Cannabis/química , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/isolamento & purificação , Anticonvulsivantes/farmacologia , Canabidiol/isolamento & purificação , Epilepsia/fisiopatologia , Humanos , África do Sul
3.
Life Sci ; 257: 118081, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663576

RESUMO

Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures, and currently available drugs may fail to provide a thorough treatment of the patients. The present study demonstrates the utility of glucose-coated gold nanoparticles (GNPs) as selective carriers of an antiepileptic drug, lacosamide (LCM), in developing a strategy to cross the blood-brain barrier to overcome drug resistance. Intravenous administration of LCM-loaded GNPs to epileptic animals yielded significantly higher nanoparticle levels in the hippocampus compared to the nanoparticle administration to intact animals. The amplitude and frequency of EEG-waves in both ictal and interictal stages decreased significantly after LCM-GNP administration to animals with TLE, while a decrease in the number of seizures was also observed though statistically insignificant. In these animals, malondialdehyde was unaffected, and glutathione levels were lower in the hippocampus compared to sham. Ultrastructurally, LCM-GNPs were observed in the brain parenchyma after intravenous injection to animals with TLE. We conclude that glucose-coated GNPs can be efficient in transferring effective doses of LCM into the brain enabling elimination of the need to administer high doses of the drug, and hence, may represent a new approach in the treatment of drug-resistant TLE.


Assuntos
Anticonvulsivantes/administração & dosagem , Sistemas de Liberação de Medicamentos , Epilepsia do Lobo Temporal/tratamento farmacológico , Lacosamida/administração & dosagem , Nanopartículas Metálicas , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Eletroencefalografia , Ouro/química , Hipocampo/metabolismo , Injeções Intravenosas , Lacosamida/farmacocinética , Lacosamida/farmacologia , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual
4.
Life Sci ; 257: 118066, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652135

RESUMO

AIMS: Understanding the underlying molecular mechanisms involved in epileptogenesis is necessary to target the best therapeutic interventions in epilepsy. Recently, it has been postulated that metformin, an old antidiabetic oral drug, has anti-seizure properties mostly due to its antioxidant activities. This study was designed to evaluate the ameliorative effects of metformin on the progression of epilepsy in the temporal lobe epilepsy model in rats. MAIN METHODS: Temporal lobe Epilepsy was induced by intracerebroventricular microinjection of kainic acid. Metformin was orally administered for two weeks before induction of epilepsy. Anti-epileptogenic activity of metformin was evaluated by intracranial electroencepholography (IEEG) recording to detect spontaneous seizures, mossy fiber sprouting by Timm staining, neurogenesis by BrdU staining. KEY FINDINGS: Oral administration of metformin prior to kainite-induced status epilepticus blocked the variant characterizations of epileptogenesis like neuronal cell death, aberrant neurogenesis, mossy fiber sprouting, and spontaneous seizures. SIGNIFICANCE: These findings indicate that metformin has potential anti-epileptogenic properties in temporal lobe epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Metformina/farmacologia , Administração Oral , Animais , Anticonvulsivantes/administração & dosagem , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia do Lobo Temporal/fisiopatologia , Ácido Caínico/toxicidade , Masculino , Metformina/administração & dosagem , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar
5.
Life Sci ; 258: 118140, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730838

RESUMO

AIMS: This study was performed to investigate the expression profile of cytochrome P450 (CYP) isoforms and effects of polycyclic aromatic hydrocarbons (PAHs) and antiepileptic drugs on CYP1 expression in human astrocytoma MOG-G-CCM cells. MAIN METHODS: CYP1A1 and CYP1B1 expression were determined by quantitative real-time polymerase chain reaction, Western blotting, and immunocytochemistry. KEY FINDINGS: MOG-G-CCM cells expressed various CYP isoforms. Among the CYP isoforms analyzed, CYP1B1 showed the highest expression level, followed by CYP1A1. Furthermore, CYP1B1 was localized in both the endoplasmic reticulum and mitochondria. 3-Methylcholanthrene (3-MC), benz[a]anthracene (B[a]A), benzo[a]pyrene (B[a]P), and valproic acid (VPA) increased the expression of CYP1B1 and CYP1A1. The potent aryl hydrocarbon receptor antagonist GNF351 significantly suppressed the 3-MC- and VPA-mediated upregulation of CYP1B1 and CYP1A1. In addition, VPA potentiated the induction of CYP1B1 and CYP1A1 by 3-MC, B[a]A, and B[a]P, although the augmentation of CYP1A1 was more remarkable than that of CYP1B1. In contrast, other antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, phenytoin) did not affect the 3-MC-mediated upregulation of CYP1B1 and CYP1A1. VPA is known to act as a histone deacetylase (HDAC) inhibitor. Therefore, the effects of trichostatin A, a representative HDAC inhibitor, on CYP1 induction by 3-MC were examined. Trichostatin A enhanced the 3-MC-mediated upregulation of CYP1A1 but not CYP1B1. SIGNIFICANCE: These results partially indicated that VPA may augment the PAH-mediated induction of CYP1B1 and CYP1A1 through the activation of transcription by HDAC inhibition.


Assuntos
Anticonvulsivantes/farmacologia , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1B1/genética , Hidrocarbonetos Policíclicos Aromáticos/farmacologia , Regulação para Cima/efeitos dos fármacos , Ácido Valproico/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Linhagem Celular Tumoral , Humanos , Transcriptoma/efeitos dos fármacos
6.
Pharmacol Rev ; 72(3): 606-638, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32540959

RESUMO

Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic treatment of epileptic seizures, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Patients with such drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life, so development of more effective therapies is an urgent clinical need. However, the various types of epilepsy and seizures and the complex temporal patterns of refractoriness complicate the issue. Furthermore, the underlying mechanisms of DRE are not fully understood, though recent work has begun to shape our understanding more clearly. Experimental models of DRE offer opportunities to discover, characterize, and challenge putative mechanisms of drug resistance. Furthermore, such preclinical models are important in developing therapies that may overcome drug resistance. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of ASD resistance and discuss how to overcome this problem. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning epilepsies and drug resistance by concerted preclinical and clinical efforts have recently enabled a revised approach to the development of more promising therapies, including numerous potential etiology-specific drugs ("precision medicine") for severe pediatric (monogenetic) epilepsies and novel multitargeted ASDs for acquired partial epilepsies, suggesting that the long hoped-for breakthrough in therapy for as-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Resistência a Medicamentos , Epilepsia/genética , Epilepsia/metabolismo , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
7.
Ann Agric Environ Med ; 27(2): 279-283, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32588606

RESUMO

INTRODUCTION: Schizencephaly is one of the rare congenital defects of the central nervous system (CNS), known as neuronal migration disorders. The etiology of schizencecephaly is unequivocal. Established etiologies include in-utero infections (cytomegalovirus and herpes simplex virus, HSV type I), toxic abuse (cocaine, alcohol), as well as drug use (warfarin). OBJECTIVES: he aim of the study was to analyze the clinical presentation of schizencephaly with particular consideration of the course of epilepsy in paediatric patients. MATERIAL AND METHODS: The study group consisted of 38 children with schizencephaly (20 of them had seizure) and was retrospectively assessed. Data were analyzed using SAS version 9.4. U Mann-Whitney and χ 2 tests and logistic regression analysis were used in statistical analyses. RESULTS: Epilepsy was the most frequent in bilateral type II schizencephaly (p=0.033). In logistic regression analysis, the presence of bilateral open schizencephaly significantly increased the risk of seizures (OR=11.67; 95%CI 2.44-55.83; p=0.002). Drug-resistant epilepsy was observed in 9 children (45% of the children with epilepsy). Prevalence of both epilepsy and drug-resistant epilepsy in schizencephaly did not significantly depend on gender, stage of development, type or localization of schizencephaly, and other coexisting CNS defects or clinical presentation of schizencephaly at follow-up in the study group of patients. CONCLUSIONS: The bilateral type of schizencephaly was identified as an independent risk factor for epilepsy in the analyzed children.


Assuntos
Anticonvulsivantes/farmacologia , Epilepsia Resistente a Medicamentos/epidemiologia , Esquizencefalia/epidemiologia , Convulsões/epidemiologia , Adolescente , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/etiologia , Feminino , Humanos , Lactente , Masculino , Polônia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Esquizencefalia/etiologia , Convulsões/etiologia
8.
Toxicol Appl Pharmacol ; 399: 115033, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32387339

RESUMO

N-(2-hydroxyphenyl)-2-propylpentamide (HO-AAVPA) is a novel arylamide derivative of valproic acid (VPA) designed in silico, with better antioxidant and antiproliferative effect on cancer cell lines than VPA. This study was aimed to evaluate the anticonvulsant activity, the toxicity and teratogenicity produced in HO-AAVPA-treated CD1 mice using VPA as positive control. With the maximal electroshock (MES)- and pentylenetetrazole (PTZ)-induced seizure models, HO-AAVPA reduced the time of hind limb extension, stupor and recovery, the number of clonic and tonic seizures and the mortality rate in a dose-dependent manner, obtaining an ED50 of 370 and 348 mg/kg for MES and PTZ, respectively. On the rotarod test, mice administered with 600 mg/kg HO-AAVPA manifested reduced locomotor activity (2.78%); while HO-AAVPA at 300 mg/kg and VPA at 500 mg/kg gave a similar outcome (∼60%). The LD50 of 936.80 mg/kg herein found for HO-AAVPA reflects moderate toxicity. Concerning teratogenicity, the administration of HO-AAVPA to pregnant females at 300 and 600 mg/kg on gestation day (GD) 8.5 generated less visceral and skeletal alterations in the fetuses, as well as, minor rate of modifications in the expression pattern of the neuronal marker Tuj1 and endothelial marker PECAM1 in embryos, that those induced by VPA administration. Altered embryonic development occurred with less frequency and severity with HO-AAVPA at 600 mg/kg than VPA at 500 mg/kg. In conclusion, the protective effect against convulsions provided by HO-AAVPA was comparable to that of VPA in the MES and PZT seizure models, showed lower toxicity and less damage to embryonic and fetal development.


Assuntos
Amidas/efeitos adversos , Amidas/farmacologia , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacologia , Pentanos/efeitos adversos , Pentanos/farmacologia , Ácido Valproico/efeitos adversos , Ácido Valproico/farmacologia , Animais , Antioxidantes/efeitos adversos , Antioxidantes/farmacologia , Biomarcadores/metabolismo , Eletrochoque/métodos , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Feminino , Dose Letal Mediana , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Pentilenotetrazol/efeitos adversos , Pentilenotetrazol/farmacologia , Gravidez , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/metabolismo
9.
Proc Natl Acad Sci U S A ; 117(20): 11118-11125, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32358198

RESUMO

Cortical network functioning critically depends on finely tuned interactions to afford neuronal activity propagation over long distances while avoiding runaway excitation. This importance is highlighted by the pathological consequences and impaired performance resulting from aberrant network excitability in psychiatric and neurological diseases, such as epilepsy. Theory and experiment suggest that the control of activity propagation by network interactions can be adequately described by a branching process. This hypothesis is partially supported by strong evidence for balanced spatiotemporal dynamics observed in the cerebral cortex; however, evidence of a causal relationship between network interactions and cortex activity, as predicted by a branching process, is missing in humans. Here this cause-effect relationship is tested by monitoring cortex activity under systematic pharmacological reduction of cortical network interactions with antiepileptic drugs. This study reports that cortical activity cascades, presented by the propagating patterns of epileptic spikes, as well as temporal correlations decline precisely as predicted for a branching process. The results provide a missing link to the branching process theory of cortical network function with implications for understanding the foundations of cortical excitability and its monitoring in conditions like epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Eletrocorticografia , Epilepsia , Humanos , Redes Neurais de Computação , Neurônios/fisiologia
10.
Adv Exp Med Biol ; 1195: 189-198, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468477

RESUMO

In the present work, new indole derivatives, i.e., 5-[N,N-di alkyl amino alkoxy] azaindole 2,3- di-one derivatives, are synthesized and characterized. These compounds were subjected to acute toxicity and then screened for antiepileptic activity on maximal electroshock seizure (MES) model in albino Wistar rats. In that study 5-[2-dimethyl amino ethoxy] Azaindole-3-hydrazone,2-one and 5-[2- dimethyl amino ethoxy] Azaindole 2-one,3-thiothiosemicarbazone(IIIa) showed good antiepileptic activity and less neurotoxicity compared to phenytoin. The purpose of the present study is to investigate the effect of 5-[2-dimethyl amino ethoxy] Indole 2,3- di one and 5-[2-dimethyl amino ethoxy] Azaindole 2-one,3-thiosemicarbazone(IIIa) derivatives on biogenic amines concentrations in rat brain after induction of seizures by MES method. The aim of study was relationship between seizure activities and altered the monoamines such as Noradrenaline (NA), Dopamine (DA), Serotonin (5-HT) in forebrain of rats in MES seizure models. In MES model, study of 5-[2-dimethyl amino ethoxy] Azaindole 3-hydrazone,2-one(Va) and 5-[2-dimethyl amino ethoxy]Azaindole 2-one,3-thiosemicarbazone(IIIa) (100 mg/kg) showed significant restoration of the decreased levels of brain monoamines such as noradrenaline, dopamine, and 5-hydroxytryptamine. Thus, this study suggests that 5-[2-Dimethyl amino ethoxy] Azaindole 3-hydrazone,2-one (V) and 5-[2-dimethyl amino ethoxy] Azaindole 2-one,3-thiosemicarbazone (IIIa) increased the monoamines on rat brain, which may decrease the susceptibility to MES-induced seizure in rats.


Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/uso terapêutico , Indóis/síntese química , Indóis/uso terapêutico , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/uso terapêutico , Álcoois/síntese química , Álcoois/química , Álcoois/farmacologia , Álcoois/uso terapêutico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Modelos Animais de Doenças , Hidrazonas/síntese química , Hidrazonas/química , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Indóis/química , Indóis/farmacologia , Ratos , Ratos Wistar , Convulsões/tratamento farmacológico , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
11.
Adv Exp Med Biol ; 1260: 283-296, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32304038

RESUMO

In our society, anxiety and depression are serious health issues that affect a large proportion of the population. Unfortunately, drug therapies are not always effective and can lead to drug abuse, delay of therapeutic effect, dependence, and tolerance. Traditionally, aromatherapy has also been used for anxiety relief and mood improvement. The use of essential oils, in relieving anxiety and depression, does not have the disadvantages associated with currently used drug therapies. In-vivo studies on animal models have verified the anxiolytic effects of these essential oils and the interactions of their major components with central nervous system receptors. Therefore, it seems reasonable to argue that the modulation of glutamate and GABA neurotransmitter systems are likely to be the critical mechanisms responsible for the sedative, anxiolytic, and anticonvulsant proprieties of linalool and essential oils containing linalool in significant proportions. Popular anxiolytic essential oils are generally rich in terpenoid alcohols like linalool, geraniol and citronellol, and the monoterpene limonene (or citral). Therefore, other essential oils or formulations that contain these terpenoids as major components may serve as important aromatherapeutics for relief of anxiety.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Aromaterapia , Depressão/tratamento farmacológico , Óleos Voláteis/uso terapêutico , Terpenos/uso terapêutico , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Hipnóticos e Sedativos/uso terapêutico , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Terpenos/química , Terpenos/farmacologia
12.
World Neurosurg ; 137: e437-e446, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32045726

RESUMO

OBJECTIVE: 5-aminolevulinic acid (5-ALA) has been increasingly used in recent years to identify anaplastic foci in primarily suspected low-grade gliomas (LGGs). However, 5-ALA fails to visualize a subgroup of focally anaplastic gliomas. Recently, 2 in vitro studies and 1 in vivo study assumed that antiepileptic drugs (AEDs) and dexamethasone have an influence on the 5-ALA metabolism/visible fluorescence in gliomas. The aim of this study was to analyze for the first time the influence of different AEDs and dexamethasone on visible 5-ALA fluorescence in a large cohort of suspected LGG. METHODS: We retrospectively analyzed adult patients with resection of radiologically suspected diffusely infiltrating LGG after 5-ALA administration at 2 specialized centers. Clinical data on the intraoperative 5-ALA fluorescence status, preoperative treatment with AED/dexamethasone, and the total daily dose in cases of levetiracetam and dexamethasone intake were noted. RESULTS: Altogether, 110 patients with suspected LGG were included. A significantly higher percentage of visible fluorescence was present in World Health Organization grade III/IV (73%) compared with World Health Organization grade II gliomas (11%; P < 0.001). In the multivariate analysis, we did not find an independent correlation between the visible fluorescence status and intake of dexamethasone/AED. Furthermore, the median daily dose of dexamethasone and levetiracetam did not differ significantly between fluorescing and nonfluorescing gliomas. CONCLUSIONS: In the largest series to date, we did not find a drug-related influence of either dexamethasone or different AED on visible 5-ALA fluorescence in suspected LGG. According to our preliminary data, preoperative treatment with these common drugs in neurosurgery can be performed safely before 5-ALA-assisted surgery of suspected LGG.


Assuntos
Corticosteroides/farmacologia , Anticonvulsivantes/farmacologia , Neoplasias Encefálicas/cirurgia , Glioma/cirurgia , Convulsões/tratamento farmacológico , Corticosteroides/uso terapêutico , Adulto , Idoso , Ácido Aminolevulínico , Anticonvulsivantes/uso terapêutico , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/metabolismo , Feminino , Fluorescência , Glioma/complicações , Glioma/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Estudos Retrospectivos , Convulsões/metabolismo , Adulto Jovem
13.
Invest Ophthalmol Vis Sci ; 61(2): 17, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32053727

RESUMO

Purpose: Vigabatrin (VGB) is an effective antiepileptic that increases concentrations of inhibitory γ-aminobutyric acid (GABA) by inhibiting GABA transaminase. Reports of VGB-associated visual field loss limit its clinical usefulness, and retinal toxicity studies in laboratory animals have yielded conflicting results. Methods: We examined the functional and morphologic effects of VGB in C57BL/6J mice that received either VGB or saline IP from 10 to 18 weeks of age. Retinal structure and function were assessed in vivo by optical coherence tomography (OCT), ERG, and optomotor response. After euthanasia, retinas were processed for immunohistochemistry, and retinal GABA, and VGB quantified by mass spectrometry. Results: No significant differences in visual acuity or total retinal thickness were identified between groups by optomotor response or optical coherence tomography, respectively. After 4 weeks of VGB treatment, ERG b-wave amplitude was enhanced, and amplitudes of oscillatory potentials were reduced. Dramatic rod and cone bipolar and horizontal cell remodeling, with extension of dendrites into the outer nuclear layer, was observed in retinas of VGB-treated mice. VGB treatment resulted in a mean 3.3-fold increase in retinal GABA concentration relative to controls and retinal VGB concentrations that were 20-fold greater than brain. Conclusions: No evidence of significant retinal thinning or ERG a- or b-wave deficits were apparent, although we describe significant alterations in ERG b-wave and oscillatory potentials and in retinal cell morphology in VGB-treated C57BL/6J mice. The dramatic concentration of VGB in retina relative to the target tissue (brain), with a corresponding increase in retinal GABA, offers insight into the pathophysiology of VGB-associated visual field loss.


Assuntos
Anticonvulsivantes/farmacologia , GABAérgicos/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Retina/efeitos dos fármacos , Vigabatrina/farmacologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Músculos Oculomotores/efeitos dos fármacos , Distribuição Aleatória , Retina/fisiopatologia , Doenças Retinianas/tratamento farmacológico , Doenças Retinianas/fisiopatologia , Tomografia de Coerência Óptica , Campos Visuais/fisiologia
14.
Epilepsia ; 61(3): 549-560, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32096222

RESUMO

OBJECTIVE: To pinpoint the earliest cellular defects underlying seizure onset (epileptogenic period) during perinatal brain development in a new zebrafish model of Dravet syndrome (DS) and to investigate potential disease-modifying activity of the 5HT2 receptor agonist fenfluramine. METHODS: We used CRISPR/Cas9 mutagenesis to introduce a missense mutation, designed to perturb ion transport function in all channel isoforms, into scn1lab, the zebrafish orthologue of SCN1A (encoding voltage-gated sodium channel alpha subunit 1). We performed behavioral analysis and electroencephalographic recordings to measure convulsions and epileptiform discharges, followed by single-cell RNA-Seq, morphometric analysis of transgenic reporter-labeled γ-aminobutyric acidergic (GABAergic) neurons, and pharmacological profiling of mutant larvae. RESULTS: Homozygous mutant (scn1labmut/mut ) larvae displayed spontaneous seizures with interictal, preictal, and ictal discharges (mean = 7.5 per 20-minute recording; P < .0001; one-way analysis of variance). Drop-Seq analysis revealed a 2:1 shift in the ratio of glutamatergic to GABAergic neurons in scn1labmut/mut larval brains versus wild type (WT), with dynamic changes in neuronal, glial, and progenitor cell populations. To explore disease pathophysiology further, we quantified dendritic arborization in GABAergic neurons and observed a 40% reduction in arbor number compared to WT (P < .001; n = 15 mutant, n = 16 WT). We postulate that the significant reduction in inhibitory arbors causes an inhibitory to excitatory neurotransmitter imbalance that contributes to seizures and enhanced electrical brain activity in scn1labmut/mut larvae (high-frequency range), with subsequent GABAergic neuronal loss and astrogliosis. Chronic fenfluramine administration completely restored dendritic arbor numbers to normal in scn1labmut/mut larvae, whereas similar treatment with the benzodiazepine diazepam attenuated seizures, but was ineffective in restoring neuronal cytoarchitecture. BrdU labeling revealed cell overproliferation in scn1labmut/mut larval brains that were rescued by fenfluramine but not diazepam. SIGNIFICANCE: Our findings provide novel insights into early mechanisms of DS pathogenesis, describe dynamic cell population changes in the scn1labmut/mut brain, and present first-time evidence for potential disease modification by fenfluramine.


Assuntos
Encéfalo/fisiopatologia , Epilepsias Mioclônicas/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Plasticidade Neuronal/genética , Proteínas de Peixe-Zebra/genética , Animais , Anticonvulsivantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Sistemas CRISPR-Cas , Proliferação de Células/efeitos dos fármacos , Diazepam/farmacologia , Modelos Animais de Doenças , Eletroencefalografia , Epilepsias Mioclônicas/metabolismo , Epilepsias Mioclônicas/patologia , Epilepsias Mioclônicas/fisiopatologia , Fenfluramina/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Perfilação da Expressão Gênica , Gliose/genética , Gliose/patologia , Locomoção/efeitos dos fármacos , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.1/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Análise de Célula Única , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-32007745

RESUMO

Prostaglandin E2 (PGE2), a physiologically active lipid compound, is increased in several diseases characterized by chronic inflammation. To determine its significance in epilepsy-associated inflammation and response to antiepileptic drug (AED), we evaluated the plasma PGE2 (median, pg/ml) levels in drug-free patients with epilepsy (N = 34) and patients receiving AED monotherapy (N = 55) in addition to that in healthy controls (N = 34). When compared to controls, plasma PGE2 levels were significantly elevated in all drug-free patients independent of the type of epilepsy (137.2 versus 475.7 pg/ml, p < 0.0001). Among the patients receiving AED monotherapy, only valproate responders showed a significant decrease compared to both drug-free patients (232.1 versus 475.7 pg/ml, p < 0.01) as well as valproate non-responders (232.1 versus 611.9 pg/ml, p < 0.0001). Both responders and non-responders on phenytoin or carbamazepine monotherapy had elevated PGE2 levels similar to drug-free patients. In addition, no difference was observed in plasma profiles of PGE2 precursor, arachidonic acid among the groups. Our work presents the clinical evidence of the association between plasma PGE2 levels and valproate efficacy in patients with epilepsy.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia/tratamento farmacológico , Prostaglandinas E/sangue , Adolescente , Adulto , Anticonvulsivantes/farmacologia , Carbamazepina/administração & dosagem , Carbamazepina/farmacologia , Estudos de Casos e Controles , Epilepsia/metabolismo , Feminino , Humanos , Masculino , Fenitoína/administração & dosagem , Fenitoína/farmacologia , Resultado do Tratamento , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacologia , Adulto Jovem
16.
Paediatr Drugs ; 22(1): 73-84, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31912454

RESUMO

Tuberous sclerosis complex (TSC) is a genetic neurocutaneous disorder with epilepsy as a common and early presenting symptom. The neurological phenotype, however, is variable and unpredictable. Early and refractory seizures, infantile spasms in particular, are associated with a poor neurological outcome. Preliminary data suggests early and aggressive seizure control may mitigate the detrimental neurodevelopmental effects of epilepsy. For infantile spasms, vigabatrin is the first line of treatment, and steroids and classic antiepileptic drugs (AEDs) are suitable for second line. Based on retrospective data, vigabatrin should be considered for other indications, especially in infants with focal seizures, as this may prevent infantile spasms, but also in children and adults with epileptic spasms and tonic seizures. Otherwise, for most seizure types, treatment is similar to that for patients without TSC, including the use of novel AEDs, although limited data are available. Three major developments are changing the field of epilepsy management in TSC. First, final recommendations on preventive treatment with vigabatrin will result from two multicenter trials in the US (PREVeNT, clinicaltrials.gov #NCT02849457) and Europe (EPISTOP, clinicaltrials.gov #NCT02098759). Second, treatment with everolimus, an inhibitor of the mechanistic target of rapamycin (mTOR), reduced seizures when compared to placebo. Further, mTOR inhibitors may have an overall disease-modifying effect. Third, the role of cannabidiol in the treatment of refractory seizures in TSC is yet to be established. With treatment recommendations in TSC, we keep an eye on the prize for the broader field of pediatric epilepsy: the lessons learned from TSC are likely applicable to other epileptic encephalopathies.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Esclerose Tuberosa/tratamento farmacológico , Adulto , Anticonvulsivantes/farmacologia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Esclerose Tuberosa/complicações , Adulto Jovem
17.
J Clin Neurophysiol ; 37(1): 15-27, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895186

RESUMO

Cannabinoids are compounds that are structurally and/or functionally related to the primary psychoactive constituent of Cannabis sativa, [INCREMENT]-tetrahydrocannabinol (THC). Cannabinoids can be divided into three broad categories: endogenous cannabinoids, plant-derived cannabinoids, and synthetic cannabinoids (SCs). Recently, there has been an unprecedented surge of interest into the pharmacological and medicinal properties of cannabinoids for the treatment of epilepsies. This surge has been stimulated by an ongoing shift in societal opinions about cannabinoid-based medicines and evidence that cannabidiol, a nonintoxicating plant cannabinoid, has demonstrable anticonvulsant activity in children with treatment-refractory epilepsy. The major receptors of the endogenous cannabinoid system (ECS)-the type 1 and 2 cannabinoid receptors (CB1R, CB2R)-have critical roles in the modulation of neurotransmitter release and inflammation, respectively; so, it is not surprising therefore that the ECS is being considered as a target for the treatment of epilepsy. SCs were developed as potential new drug candidates and tool compounds for studying the ECS. Beyond the plant cannabinoids, an extensive research effort is underway to determine whether SCs that directly target CB1R, CB2R, or the enzymes that breakdown endogenous cannabinoids have anticonvulsant effects in preclinical rodent models of epilepsy and seizure. This research demonstrates that many SCs do reduce seizure severity in rodent models and may have both positive and negative pharmacodynamic and pharmacokinetic interactions with clinically used antiepilepsy drugs. Here, we provide a comprehensive review of the preclinical evidence for and against SC modulation of seizure and discuss the important questions that need to be addressed in future studies.


Assuntos
Anticonvulsivantes/farmacologia , Canabinoides/farmacologia , Epilepsia , Receptores de Canabinoides/efeitos dos fármacos , Convulsões , Animais , Modelos Animais de Doenças , Endocanabinoides/fisiologia , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Receptores de Canabinoides/metabolismo , Convulsões/metabolismo , Convulsões/fisiopatologia
18.
FASEB J ; 34(1): 676-690, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914696

RESUMO

Sodium valproate (VPA), an antiepileptic drug, may cause dose- and time-dependent hepatotoxicity. However, its iatrogenic molecular mechanism and the rescue therapy are disregarded. Recently, it has been demonstrated that sodium butyrate (NaB) reduces hepatic steatosis, improving respiratory capacity and mitochondrial dysfunction in obese mice. Here, we investigated the protective effect of NaB in counteracting VPA-induced hepatotoxicity using in vitro and in vivo models. Human HepG2 cells and primary rat hepatocytes were exposed to high VPA concentration and treated with NaB. Mitochondrial function, lipid metabolism, and oxidative stress were evaluated, using Seahorse analyzer, spectrophotometric, and biochemical determinations. Liver protection by NaB was also evaluated in VPA-treated epileptic WAG/Rij rats, receiving NaB for 6 months. NaB prevented VPA toxicity, limiting cell oxidative and mitochondrial damage (ROS, malondialdehyde, SOD activity, mitochondrial bioenergetics), and restoring fatty acid oxidation (peroxisome proliferator-activated receptor α expression and carnitine palmitoyl-transferase activity) in HepG2 cells, primary hepatocytes, and isolated mitochondria. In vivo, NaB confirmed its activity normalizing hepatic biomarkers, fatty acid metabolism, and reducing inflammation and fibrosis induced by VPA. These data support the protective potential of NaB on VPA-induced liver injury, indicating it as valid therapeutic approach in counteracting this common side effect due to VPA chronic treatment.


Assuntos
Ácido Butírico/farmacologia , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Anticonvulsivantes/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Crônica Induzida por Substâncias e Drogas/prevenção & controle , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Valproico/farmacologia
19.
Epilepsia ; 61(1): 149-156, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31957880

RESUMO

OBJECTIVES: To advance the development of (2S,3S)-sec-butylpropylacetamide (SPD) as a new treatment for acute repetitive seizures (ARS), by studying its pharmacokinetics (PK) in pigs and its PK-pharmacodynamic (PK-PD) correlation in rats. METHODS: Two (2S,3S)-SPD intramuscular formulations (FA and FB ) were administered to pigs and rats and blood samples were withdrawn at different times after dosing. Major PK parameters were estimated in both species. PD analysis was conducted in rats utilizing the maximal-electroshock seizure threshold (MEST) test. Because ARS treatment requires a rapid action, the MEST test allows comparative evaluation of (2S,3S)-SPD intramuscular injection on rat susceptibility to electroconvulsive shock at various times after dosing. RESULTS: In rats, (2S,3S)-SPD plasma exposure increased proportionally following intramuscular dosing (20, 25 and 40 mg/kg) of FA and FB . Peak plasma concentration (Cmax ) was obtained at 1-2 hours after dosing and ranged between 6.8 and 9.4 mg/L. (2S,3S)-SPD plasma concentration at 10 minutes after dosing (C10 ) ranged between 2.1 and 3.5 mg/mL, and its half-life ranged between 0.9 and 2.3 hours. The highest C10 value, which may indicate rapid activity onset, and the highest Cmax were observed following administration of FA (40 mg/kg): C10  = 3.5 mg/L and Cmax  = 9.5 mg/L. In the MEST test, (2S,3S)-SPD (20 and 60 mg/kg) significantly raised the tonic seizure threshold compared to vehicle at 4, 7, 10, and 20 minutes after dosing, with a 1.6-fold increase at 20 minutes, which coincided with (2S,3S)-SPD brain Cmax . Following intramuscular dosing of (2S,3S)-SPD (12 mg/kg) to pigs of FA and FB , a Cmax value of 0.9 mg/L was obtained 0.42 and 0.75 hours after dosing, respectively. (2S,3S)-SPD C10 was 0.27 mg/L (FA ) and 0.49 mg/L (FB ). (2S,3S)-SPD clearance, volume of distribution, and half-life were 2 L/h/kg, 18-28 L/kg, and 6.1-9.7 hours, respectively. SIGNIFICANCE: (2S,3S)-SPD demonstrated a good PK-PD correlation in the rat MEST test, with a rapid onset. (2S,3S)-SPD first PK study in pigs showed that doses >12 mg/kg are required to achieve in pigs the plasma concentrations associated with activity at the rat MEST test.


Assuntos
Amidas/farmacologia , Anticonvulsivantes/farmacologia , Convulsões , Ácido Valproico/análogos & derivados , Animais , Encéfalo/efeitos dos fármacos , Feminino , Masculino , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Suínos , Ácido Valproico/farmacologia
20.
Ir J Med Sci ; 189(1): 305-313, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31187336

RESUMO

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common comorbidity of childhood epilepsy. ADHD symptoms in children with epilepsy have been studied since 1970s in western countries. However, relative studies are still rather limited in China. AIMS: To study the incidence rate of ADHD in children with epilepsy, and further analyze the relationship of epilepsy and ADHD in China. MATERIALS AND METHODS: 206 children (age 6-16) with epilepsy and 58 healthy controls underwent assessment instruments (DSM-IV ADHD, ADHD Rating Scale-IV, and SNAP-IV Rating Scale). RESULTS: The prevalence of comorbid ADHD was significantly higher in children with epilepsy (24.76%) than that in controls (5.17%), and inattentive subtype (ADHD-I, 14.1%) was the most prevalent. ADHD in childhood epilepsy was associated with younger age, early first onset age, and high frequency of epileptic seizures. There was no significant difference of ADHD incidence rate regarding the seizure type and abnormal electroencephalogram (EEG) discharges. The ADHD comorbidity rate in children treated with antiepileptic drugs (AEDs) (27.6%) was higher than that without AEDs therapy (14.0%); multiple AEDs were associated with a higher rate of ADHD comorbidity as compared with single AEDs. The incidence of comorbid ADHD in epileptic children treated with traditional single AEDs was significantly higher than those treated with novel single AEDs. CONCLUSION: Children with epilepsy have more attention problems as compared with healthy controls. ADHD in childhood epilepsy is associated with male sex, younger age, early first onset age, high frequency of epileptic seizures, and multiple AEDs.


Assuntos
Anticonvulsivantes/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Epilepsia/complicações , Adolescente , Anticonvulsivantes/farmacologia , Criança , Comorbidade , Feminino , Humanos , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA