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1.
Acta Pharm ; 73(1): 59-74, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36692466

RESUMO

Nitric oxide (NO) participates in processes such as endothelium-dependent vasodilation and neurotransmission/neuromodulation. The role of NO in epilepsy is controversial, attributing it to anticonvulsant but also proconvulsant properties. Clarification of this dual effect of NO might lead to the development of new antiepileptic drugs. Previous results in our laboratory indicated that this contradictory role of NO in seizures could depend on the nitric oxide synthase (NOS) isoform involved, which could play opposite roles in epileptogenesis, one of them being proconvulsant but the other anticonvulsant. The effect of convulsant drugs on neuronal NO (nNO) and endothelial NO (eNO) levels was investigated. Considering the distribution of neuronal and endothelial NOS in neurons and astrocytes, resp., primary cultures of neurons and astrocytes were used as a study model. The effects of convulsant drugs pentylenetetrazole, thiosemicarbazide, 4-aminopyridine and bicuculline on NO levels were studied, using a spectrophotometric method. Their effects on NO levels in neurons and astrocytes depend on the concentration and time of treatment. These convulsant drugs caused an increase in nNO, but a decrease in eNO was proportional to the duration of treatment in both cases. Apparently, nNO possesses convulsant properties mediated by its effect on the glutamatergic and GABAergic systems, probably through GABAA receptors. Anticonvulsant properties of eNO may be the consequence of its effect on endothelial vasodilation and its capability to induce angiogenesis. Described effects last as seizures do. Considering the limitations of these kinds of studies and the unexplored influence of inducible NO, further investigations are required.


Assuntos
Convulsivantes , Óxido Nítrico , Humanos , Convulsivantes/efeitos adversos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Óxido Nítrico Sintase Tipo III , Inibidores Enzimáticos/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Pentilenotetrazol/farmacologia , Neurônios
2.
Exp Neurol ; 359: 114237, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36206806

RESUMO

Novel and effective antiseizure medications are needed to treat refractory and rare forms of epilepsy. Cannabinoids, which are obtained from the cannabis plant, have a long history of medical use, including for neurologic conditions. In 2018, the US Food and Drug Administration approved the first phytocannabinoid, cannabidiol (CBD, Epidiolex), which is now indicated for severe seizures associated with three rare forms of developmental and epileptic encephalopathy: Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex. Compelling evidence supports the efficacy of CBD in experimental models and patients with epilepsy. In randomized clinical trials, highly-purified CBD has demonstrated efficacy with an acceptable safety profile in children and adults with difficult-to-treat seizures. Although the underlying antiseizure mechanisms of CBD in humans have not yet been elucidated, the identification of novel antiseizure targets of CBD preclinically indicates multimodal mechanisms that include non-cannabinoid pathways. In addition to antiseizure effects, CBD possesses strong anti-inflammatory and neuroprotective activities, which might contribute to protective effects in epilepsy and other conditions. This article provides a succinct overview of therapeutic approaches and clinical foundations of CBD, emphasizing the clinical utility of CBD for the treatment of seizures associated with refractory and rare epilepsies. CBD has shown to be a safe and effective antiseizure medicine, demonstrating a broad spectrum of efficacy across multiple seizure types, including those associated with severe epilepsies with childhood onset. Despite such promise, there are many perils with CBD that hampers its widespread use, including limited understanding of pharmacodynamics, limited exposure-response relationship, limited information for seizure freedom with continued use, complex pharmacokinetics with drug interactions, risk of adverse effects, and lack of expert therapeutic guidelines. These scientific issues need to be resolved by further investigations, which would decide the unique role of CBD in the management of refractory epilepsy.


Assuntos
Canabidiol , Canabinoides , Epilepsia Resistente a Medicamentos , Epilepsias Mioclônicas , Epilepsia , Síndrome de Lennox-Gastaut , Criança , Adulto , Humanos , Canabidiol/uso terapêutico , Canabidiol/farmacologia , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologia , Síndrome de Lennox-Gastaut/tratamento farmacológico , Convulsões/tratamento farmacológico , Convulsões/induzido quimicamente , Epilepsias Mioclônicas/tratamento farmacológico , Epilepsia/tratamento farmacológico , Epilepsia/induzido quimicamente , Canabinoides/farmacologia
3.
Exp Neurol ; 359: 114240, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36216124

RESUMO

Presently there is no drug therapy for curing epilepsy. Despite many advancements in epilepsy research, nearly 30% of people with epilepsy remain refractory to current antiseizure medications (ASM). Cannabidiol (CBD) has recently been approved as an ASM for pediatric refractory seizures, but it has not been widely tested for adult epileptogenesis and focal onset seizures. In this study, we investigated the efficacy of the FDA-approved CBD in controlling epileptogenesis and complex focal onset seizures using the mouse kindling model of human temporal lobe epilepsy. We also tested combination regimens of CBD with other ASMs. The two primary outcome measures were disease modification and suppression of generalized seizures. In the epileptogenesis study, CBD had a striking effect in attenuating kindling development, with a dose-dependent decrease in behavioral and electrographic seizure activity. In the retention study, mice previously treated with CBD had significantly reduced overall seizure burden, suggesting disease modification. In a fully-kindled seizure study, CBD produced rapid and atypical U-shaped dose-dependent protection against generalized seizures (ED50, 52 mg/kg, i.p.). In a time-course study, CBD showed a maximal protective effect within 1 h of injection, and it declined within 4 h with a biphasic response. In the combination study, CBD produced synergistic/ additive protection when given with midazolam and ganaxolone but not with tiagabine, indicating its strong potential as an adjunct ASM. Finally, the protective effects of CBD were not associated with motor and functional impairments. These preclinical findings demonstrate the potential of adjunct CBD for controlling adult complex focal onset seizure conditions.


Assuntos
Canabidiol , Epilepsia do Lobo Temporal , Epilepsia , Humanos , Criança , Camundongos , Animais , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Convulsões/tratamento farmacológico , Epilepsia/tratamento farmacológico , Modelos Animais de Doenças
4.
Drug Deliv ; 30(1): 2163321, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36579655

RESUMO

Lamotrigine. (LMT) is a triazine drug has an antiepileptic effect but with low water solubility, dissolution rate and thus therapeutic effect. Spanlastics are nano-vesicular carriers' act as site-specific drug delivery system. Intranasal route could direct the drug from nose to brain and provide a faster and more specific therapeutic effect. Therefore, this study aimed to upload lamotrigine onto nano-vesicles using spanlastic nasal insert delivery for effective epilepsy treatment via overcoming lamotrigine's low solubility and improving its bioavailability. Lamtrigine-loaded nano-spanlastic vesicles were prepared by ethanol injection method. To study different formulation factor's effect on formulations characters; particle size (PS), Zeta potential (ZP), polydispersity index (PDI), entrapment efficiency percentage (EE%) and LMT released amount after 6 h (Q6h); 2^1 and 3^1 full factorial designs were employed. Optimized formula was loaded in lyophilized nasal inserts formulation which were characterized for LMT release and mucoadhesion. Pharmacokinetics studies in plasma and brain were performed on rats to investigate drug targeting efficiency. The optimal nano-spanlastic formulation (F4; containing equal Span 60 amount (100 mg) and edge activator; Tween 80) exhibited nano PS (174.2 nm), high EE% (92.75%), and Q6h > 80%. The prepared nasal inserts (S4) containing 100 mg HPMC has a higher mucoadhesive force (9319.5 dyne/cm2) and dissolution rate (> 80% within 10 min) for rapid in vivo bio-distribution. In vivo studies showed considerable improvement brain and plasma's rate and extent absorption after intranasal administration indicating a high brain targeting efficiency. The results achieved indicate that nano-spanlastic nasal-inserts offer a promising LMT brain targeting in order to maximize its antiepileptic effect.


Assuntos
Anticonvulsivantes , Epilepsia , Ratos , Animais , Lamotrigina/farmacologia , Anticonvulsivantes/farmacologia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos/métodos , Encéfalo , Administração Intranasal , Epilepsia/tratamento farmacológico , Tamanho da Partícula
5.
Pharm Biol ; 61(1): 100-110, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36548216

RESUMO

CONTEXT: Tanshinone IIA is an extract of Salvia miltiorrhiza Bunge (Labiatae) used to treat cardiovascular disorders. It shows potential anticonvulsant and cognition-protective properties. OBJECTIVE: We investigated the mechanism of tanshinone IIA on antiepileptic and cognition-protective effects in the model of epileptic rats. MATERIALS AND METHODS: Lithium chloride (LiCl)-pilocarpine-induced epileptic Wistar rats were randomly assigned to the following groups (n = 12): control (blank), model, sodium valproate (VPA, 189 mg/kg/d, positive control), tanshinone IIA low dose (TS IIA-L, 10 mg/kg/d), medium dose (TS IIA-M, 20 mg/kg/d) and high dose (TS IIA-H, 30 mg/kg/d). Then, epileptic behavioural observations, Morris water maze test, Timm staining, transmission electron microscopy, immunofluorescence staining, western blotting and RT-qPCR were measured. RESULTS: Compared with the model group, tanshinone IIA reduced the frequency and severity of seizures, improved cognitive impairment, and inhibited hippocampal mossy fibre sprouting score (TS IIA-M 1.50 ± 0.22, TS IIA-H 1.17 ± 0.31 vs. model 2.83 ± 0.31), as well as improved the ultrastructural disorder. Tanshinone IIA increased levels of synapse-associated proteins synaptophysin (SYN) and postsynaptic dense substance 95 (PSD-95) (SYN: TS IIA 28.82 ± 2.51, 33.18 ± 2.89, 37.29 ± 1.69 vs. model 20.23 ± 3.96; PSD-95: TS IIA 23.10 ± 0.91, 26.82 ± 1.41, 27.00 ± 0.80 vs. model 18.28 ± 1.01). DISCUSSION AND CONCLUSIONS: Tanshinone IIA shows antiepileptic and cognitive function-improving effects, primarily via regulating synaptic plasticity. This research generates a theoretical foundation for future research on potential clinical applications for tanshinone IIA.


Assuntos
Anticonvulsivantes , Epilepsia , Ratos , Animais , Anticonvulsivantes/farmacologia , Ratos Wistar , Cognição , Epilepsia/tratamento farmacológico , Plasticidade Neuronal
6.
Physiol Behav ; 259: 114054, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36502893

RESUMO

Nocturnal epilepsy is a neurological disease that has a significant effect on sleep. Various treatments have been implemented to help mitigate these effects and improve patients' quality of life. The use of experimental animal models for epilepsy has facilitated efficacy assessment and the development of different medications to treat the symptoms of this disease. The objective of this study was to evaluate the effect of valproate on sleep patterns altered by epilepsy. Chronically implanted Wistar rats were used to study sleep patterns over three consecutive days under different experimental conditions. The animals were separated into two groups. The first day was considered the control recording; on the second day, one group received pentylenetetrazol (PTZ) alone, and the other group received valproate prior to induction of convulsive seizures with PTZ administration. The results show that in addition to its antiepileptic effect, valproate has hypnotic properties. It is considered to facilitate the action of GABAergic mechanisms to mitigate the effect of convulsive seizures and increase the occurrence of sleep.


Assuntos
Epilepsia , Ácido Valproico , Ratos , Animais , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêutico , Qualidade de Vida , Ratos Wistar , Epilepsia/induzido quimicamente , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Pentilenotetrazol/toxicidade , Sono , Modelos Animais de Doenças
7.
Neuroreport ; 34(1): 61-66, 2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36484279

RESUMO

OBJECTIVES: The anticonvulsant and antioxidant effects of lamotrigine on status epilepticus (SE) are incompletely understood. We assessed these effects of lamotrigine on pilocarpine (Pilo)-induced SE in mice. METHODS: Male C57BL/J6 mice were assigned to three groups: the control group, Pilo (400 mg/kg, s.c.)-induced SE (Pilo group) and lamotrigine (20 mg/kg, i.p.) treated (Pilo/lamotrigine group). The latency to SE of Racine's stage 3 or higher, the mortality rate within 2 h of Pilo administration, and the duration of SE until sacrifice were examined. Nitric oxide (NO), malondialdehyde and glutathione of oxidative stress biomarkers were detected in the hippocampus of the sacrificed animals in the above groups. NO was also detected in the cultured rat hippocampal neurons treated with 4 µM Pilo, Pilo+100 µM lamotrigine (Pilo/lamotrigine) and Pilo/lamotrigine+ N-methyl-D-aspartic acid (NMDA) receptor antagonist (10 µM MK-801, 3 µM ifenprodil) to examine the antioxidant effects of lamotrigine via non-NMDA-related pathways. RESULTS: lamotrigine prolonged the latency to SE, the SE duration until sacrifice, and decreased the mortality rate in mice with Pilo-induced SE. Lamotrigine also decreased hippocampal concentrations of NO and malondialdehyde and increased the concentrations of glutathione in the SE model. Furthermore, there were significant differences in NO concentrations between groups of cultured rat hippocampal neurons treated with Pilo and Pilo/lamotrigine, and with Pilo/lamotrigine and Pilo/lamotrigine+MK-801. CONCLUSION: Our findings suggest that lamotrigine exerts anticonvulsant and antioxidant effects on SE, but its antioxidant activity may not be fully exerted via NMDA-related pathways.


Assuntos
Pilocarpina , Estado Epiléptico , Animais , Masculino , Camundongos , Ratos , Pilocarpina/toxicidade , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Lamotrigina/efeitos adversos , Maleato de Dizocilpina , Camundongos Endogâmicos C57BL , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/metabolismo , Hipocampo/metabolismo , Glutationa/metabolismo
8.
Brain Dev ; 44(2): 148-152, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34579981

RESUMO

INTRODUCTION: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by mutations in TCF4. Seizures have been found to vary among patients with PTHS. We report the case of a PTHS patient with a novel missense mutation in the gene TCF4, presenting with two types of early epileptic encephalopathy. CASE REPORT: The patient was a Japanese boy. His first seizure was reported at 17 days of age, with twitching of the left eyelid and tonic-clonic seizures on either side of his body. An ictal electroencephalogram (EEG) showed epileptic discharges arising independently from both hemispheres, occasionally resembling migrating partial seizures of infancy (MPSI) that migrated from one side to the other. Brain magnetic resonance imaging revealed agenesis of the corpus callosum. His facial characteristics included a distinctive upper lip and thickened helices. His seizures were refractory, and psychomotor development was severely delayed. At the age of 10 months, he developed West syndrome with spasms and hypsarrhythmia. After being prescribed topiramate (TPM), his seizures and EEG abnormalities dramatically improved. Also, psychomotor development progressed. Whole-exome sequencing revealed a novel de novo missense mutation in exon 18 (NM_001083962.2:c.1718A > T, p.(Asn573Ile)), corresponding to the basic region of the basic helix-loop-helix domain, which may be a causative gene for epileptic encephalopathy. CONCLUSIONS: To our knowledge, this is the first report of a patient with PTHS treated with TPM, who presented with both MPSI as well as West syndrome. This may help provide new insights regarding the phenotypes caused by mutations in TCF4.


Assuntos
Facies , Hiperventilação , Deficiência Intelectual , Espasmos Infantis , Fator de Transcrição 4/genética , Anticonvulsivantes/farmacologia , Humanos , Hiperventilação/diagnóstico , Hiperventilação/tratamento farmacológico , Hiperventilação/genética , Hiperventilação/fisiopatologia , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Deficiência Intelectual/fisiopatologia , Masculino , Mutação de Sentido Incorreto , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Topiramato/farmacologia
9.
Eur Rev Med Pharmacol Sci ; 26(22): 8534-8538, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36459034

RESUMO

INTRODUCTION: The limitations imposed by the blood-brain barrier (BBB) on the sufficient accumulation of antiepileptic drugs (AEDs) in the epileptogenic focus is considered the major cause of the high percentage of morbidity and mortality cases among epilepsy patients. This study aimed at examining the potential effect of insulin on the anticonvulsant action of phenytoin (PHT) in the mouse maximal electroshock-induced seizure model. SUBJECTS AND METHODS: PHT was administered orally in single doses either alone or in combination with insulin given as single intraperitoneal injections. To assess the anticonvulsant activity of PHT, the ED50 values were calculated. The current strength (CS50) threshold for insulin was also estimated. The animals were sacrificed, and the brains were removed to measure their PHT concentrations in the brain. RESULTS: It has been demonstrated that insulin (in all used doses) has no effect on the CS50 but can cause a significant increase in concentrations of PHT in the brain and potentiate the antiepileptic efficiency of this drug in electroshock-induced models of epilepsy in mice. CONCLUSIONS: The combination of insulin with PHT may be of great importance for developing new treatment possibilities following further investigations with other animal models of epilepsy and preclinical studies. Further research is also needed to explore the concentrations of PHT in the brain and the anticonvulsant activity of this drug against maximal electroshock seizures in diabetic mice.


Assuntos
Diabetes Mellitus Experimental , Insulina , Animais , Camundongos , Fenitoína/farmacologia , Eletrochoque , Anticonvulsivantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Convulsões/tratamento farmacológico , Convulsões/etiologia , Modelos Animais de Doenças
10.
Arq Neuropsiquiatr ; 80(12): 1220-1226, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36580959

RESUMO

BACKGROUND: The fact that inflammation triggers epileptic seizures brings to mind the antiepileptic properties of anti-inflammatory drugs. OBJECTIVE: To investigate the electrophysiological and anti-inflammatory effects of fingolimod on an experimental penicillin-induced acute epileptic seizure model in rats. METHODS: Thirty-two male Wistar rats were divided into four groups: control (penicillin), positive control (penicillin + diazepam [5 mg/kg]), drug (penicillin + fingolimod [0.3 mg/kg]) and synergy group (penicillin + diazepam + fingolimod). The animals were anesthetized with urethane, and epileptiform activity was induced by intracortical injection of penicillin (500,000 IU). After electrophysiological recording for 125 minutes, IL-1ß, TNF-α, and IL-6 were evaluated by ELISA in the serum of sacrificed animals. RESULTS: During the experiment, animal deaths occurred in the synergy group due to the synergistic negative chronotropic effect of diazepam and fingolimod. Although not statistically significant, fingolimod caused a slight decrease in spike-wave activity and spike amplitudes in the acute seizure model induced by penicillin (p > 0.05). Fingolimod decreased serum IL-1ß (p < 0.05); fingolimod and diazepam together reduced IL-6 (p < 0.05), but no change was observed in serum TNF-α values. CONCLUSION: Even in acute use, the spike-wave and amplitude values of fingolimod decrease with diazepam, anticonvulsant and anti-inflammatory effects of fingolimod will be more prominent in chronic applications and central tissue evaluations. In addition, concomitant use of fingolimod and diazepam is considered to be contraindicated due to the synergistic negative inotropic effect.


ANTECEDENTES: O fato de a inflamação desencadear crises epilépticas traz à mente as propriedades antiepilépticas dos anti-inflamatórios. OBJETIVO: Investigar os efeitos eletrofisiológicos e anti-inflamatórios do fingolimode em um modelo experimental de crise epiléptica aguda induzida por penicilina em ratos. MéTODOS: Trinta e dois ratos Wistar machos foram divididos em quatro grupos: controle (penicilina), controle positivo (penicilina + diazepam [5 mg/kg]), droga (penicilina + fingolimode [0,3 mg/kg]) e grupo sinergia (penicilina + diazepam + fingolimode). Os animais foram anestesiados com uretano, e a atividade epileptiforme foi induzida por injeção intracortical de penicilina (500.000 UI). Após registro eletrofisiológico por 125 minutos, IL-1ß, TNF-α e IL-6 foram avaliados por ELISA no soro dos animais sacrificados. RESULTADOS: Durante o experimento, ocorreram mortes de animais no grupo sinérgico devido ao efeito cronotrópico negativo sinérgico do diazepam e do fingolimode. Embora não seja estatisticamente significativo, o fingolimode causou uma ligeira diminuição na atividade pico-onda e nas amplitudes pico no modelo de convulsão aguda induzida pela penicilina (p > 0,05). O fingolimode diminuiu a IL-1ß sérica (p < 0,05); fingolimode e diazepam juntos reduziram a IL-6 (p < 0,05), mas não foi observada alteração nos valores séricos de TNF-α. CONCLUSãO: Pensa-se que o efeito anticonvulsivante leve de uma dose única de fingolimode será mais proeminente em aplicações crônicas e em avaliações de tecidos centrais. Além disso, o uso concomitante de fingolimode e diazepam é considerado contraindicado devido ao efeito inotrópico negativo sinérgico.


Assuntos
Cloridrato de Fingolimode , Penicilinas , Convulsões , Animais , Masculino , Ratos , Anti-Inflamatórios/farmacologia , Anticonvulsivantes/farmacologia , Diazepam/farmacologia , Modelos Animais de Doenças , Eletroencefalografia , Cloridrato de Fingolimode/farmacologia , Interleucina-6 , Penicilinas/efeitos adversos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Fator de Necrose Tumoral alfa , Contraindicações de Medicamentos
11.
Molecules ; 27(23)2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36500408

RESUMO

Bombyx batryticatus (BB) is an anticonvulsant animal medicine in traditional Chinese medicine (TCM) and acts on the central nervous system. This research aimed to study the anticonvulsant effects of different polarity fractions of extracts from BB and to explore the components conferring anticonvulsant activity. Materials and methods: Crude extracts of BB at 20 g/kg were divided into different polarity fractions (petroleum ether, chloroform, ethyl acetate, water) and were administered to groups of mice before injecting pentylenetetrazol (PTZ) to induce convulsions. The animals were placed in chambers, and their behaviors were recorded for 30 min following the injection. Latency time, percent of protection, convulsion, convulsion rate, and convulsion score were determined for these mice. The compounds present in the different fractions were analyzed, and those from the fraction that conferred anticonvulsant activity were identified by high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF MS) and molecular networking (MN). The chloroform extract fractions (B-C) clearly increased the seizure latency time and protection percentage and decreased the convulsion percentage compared to the control group. The anticonvulsant effect of other extract fractions was not significant. Our study shows that the chloroform extract fractions (B-C) of BB have a significant anticonvulsant effect. We also identified 17 compounds including lumichrome, pheophorbide A, and episyringaresinol 4'-O-beta-d-glucopyranose that were found for the first time. The results of this study may lay the groundwork for studying compounds derived from Bombyx batryticatus and their anticonvulsant effect.


Assuntos
Anticonvulsivantes , Bombyx , Camundongos , Animais , Anticonvulsivantes/farmacologia , Espectrometria de Massas em Tandem , Bombyx/química , Pentilenotetrazol , Cromatografia Líquida de Alta Pressão/métodos , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/química
12.
Molecules ; 27(24)2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36558088

RESUMO

Ranolazine, an antianginal and antiarrhythmic drug blocking slow inactivating persistent sodium currents, is described as a compound with anticonvulsant potential. Since arrhythmia often accompanies seizures, patients suffering from epilepsy are frequently co-treated with antiepileptic and antiarrhythmic drugs. The aim of this study was to evaluate the effect of ranolazine on maximal-electroshock (MES)-induced seizures in mice as well as interactions between ranolazine and classical antiepileptic drugs in this model of epilepsy. Types of pharmacodynamic interactions were established by isobolographic analysis of obtained data. The main findings of the study were that ranolazine behaves like an antiseizure drug in the MES test. Moreover, ranolazine interacted antagonistically with carbamazepine, phenytoin, and phenobarbital in the proportions of 1:3 and 1:1. These interactions occurred pharmacodynamic, since ranolazine did not change the brain levels of antiepileptic drugs measured in the fluorescence polarization immunoassay. Ranolazine and its combinations with carbamazepine, phenytoin, and phenobarbital did not impair motor coordination evaluated in the chimney test. Unfortunately, an attempt to conduct a passive avoidance task (evaluating long-term memory) resulted in ranolazine-induced delayed lethality. In conclusion, ranolazine exhibits clear-cut anticonvulsant properties in the MES test but interacts antagonistically with some antiepileptic drugs. The obtained results need confirmation in clinical studies. The mechanisms of ranolazine-induced toxicity require specific explanation.


Assuntos
Anticonvulsivantes , Epilepsia , Animais , Camundongos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Ranolazina/farmacologia , Ranolazina/uso terapêutico , Fenitoína/farmacologia , Interações Medicamentosas , Convulsões/tratamento farmacológico , Convulsões/etiologia , Epilepsia/tratamento farmacológico , Carbamazepina/farmacologia , Fenobarbital/farmacologia , Encéfalo , Eletrochoque/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Aprendizagem da Esquiva
13.
Int J Mol Sci ; 23(24)2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36555823

RESUMO

The use of Cannabis for medicinal purposes has been documented since ancient times, where one of its principal cannabinoids extracted from Cannabis sativa, cannabidiol (CBD), has emerged over the last few years as a promising molecule with anti-seizure potential. Here, we present an overview of recent literature pointing out CBD's pharmacological profile (solubility, metabolism, drug-drug interactions, etc.,), CBD's interactions with multiple molecular targets as well as advances in preclinical research concerning its anti-seizure effect on both acute seizure models and chronic models of epilepsy. We also highlight the recent attention that has been given to other natural cannabinoids and to synthetic derivatives of CBD as possible compounds with therapeutic anti-seizure potential. All the scientific research reviewed here encourages to continue to investigate the probable therapeutic efficacy of CBD and its related compounds not only in epilepsy but also and specially in drug-resistant epilepsy, since there is a dire need for new and effective drugs to treat this disease.


Assuntos
Canabidiol , Canabinoides , Cannabis , Epilepsia , Humanos , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Canabidiol/metabolismo , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Cannabis/metabolismo
14.
Int J Mol Sci ; 23(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36430153

RESUMO

Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH3 lactotrophs. RFM increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary GH3 lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca2+-activated K+ channels (BKCa channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BKCa channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na+ current (INa) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of KCa1.1 channels with amino acid residues, thereby functionally affecting BKCa channels' activity. This study is the first to present evidence that, in addition to inhibiting the INa, RFM effectively modifies the IK(Ca), which suggests that it has an impact on neuronal function and excitability.


Assuntos
Anticonvulsivantes , Triazóis , Anticonvulsivantes/farmacologia , Simulação de Acoplamento Molecular , Triazóis/farmacologia , Íons
15.
Epilepsy Behav ; 137(Pt A): 108964, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36343532

RESUMO

INTRODUCTION: Acetate has been shown to have neuroprotective and anti-inflammatory effects. It is oxidized by astrocytes and can thus provide auxiliary energy to the brain in addition to glucose. Therefore, we hypothesized that it may protect against seizures, which is investigated here by feeding glyceryl triacetate (GTA), to provide high amounts of acetate without raising sodium or acid levels. METHOD: CD1 male mice were fed controlled diets with or without GTA for up to three weeks. Body weights, blood glucose levels, plasma short-chain fatty acid levels, and other hematological parameters were monitored. Seizure thresholds were determined in 6 Hz and maximal electroshock seizure threshold (MEST) tests. Antioxidant capacities were evaluated in the cerebral cortex and plasma using a ferric reducing antioxidant power (FRAP) assay and Trolox equivalent antioxidant capacity assay. RESULTS: Body weight gain was similar with both diets with and without GTA in two experiments. Glyceryl triacetate-fed groups showed 2-3- and 1.6-fold increased acetate and propionate levels in plasma, respectively. Glucose levels were unaltered in blood collected from the tail tip but increased in trunk blood. No differences were found in the activity of cerebral cortex acetyl-CoA synthetase. In the 6 Hz threshold test, seizure thresholds were lower by 3 mA and 2.4 mA after 8 and 14 days, respectively, in the GTA compared to the control diet-fed group, but showed no difference on day 16, showing that GTA has small, but inconsistent proconvulsant effects in this model. In MEST tests, a slightly increased seizure threshold (1 mA) was found on day 19 in the GTA-fed group, but not in another experiment on day 21. There were no differences in antioxidant capacity in plasma or cortex between the two groups. CONCLUSION: Glyceryl triacetate feeding showed no antioxidant effects nor beneficial changes in acute electrical seizure threshold mouse models, despite its ability to increase plasma acetate levels.


Assuntos
Anticonvulsivantes , Convulsões , Animais , Camundongos , Masculino , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Relação Dose-Resposta a Droga , Convulsões/tratamento farmacológico , Eletrochoque , Modelos Animais de Doenças , Acetatos/uso terapêutico , Glucose
16.
Bioorg Med Chem Lett ; 77: 129042, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36332884

RESUMO

Triazine-linked triazole compounds (4a-j) were designed, synthesized, and then examined for their anticonvulsant abilities. Compounds 4e, 4f, 4g, 4i, and 4j displayed significant anticonvulsant activity in both maximum electroshock seizure (MES) and pentylenetetrazole (PTZ) induced seizure during the preliminary screening. The phase II anticonvulsant activity statistics revealed that compounds 4e, 4f, 4g, 4i, and 4j demonstrated excellent activity as compared to the conventional drugs methaqualone and valproate, supporting the potential of these triazine-linked triazole analogues as novel anticonvulsant agents. To take use of the findings, computational parameters including docking analysis and drug-likeness prediction were carried out. Molecular modelling studies supported the essential pharmacophoric information that the structure activity relationship offered. The triazine-linked triazole analogues that were investigated might be viewed as helpful models for future research and derivatization.


Assuntos
Anticonvulsivantes , Triazinas , Humanos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/química , Simulação de Acoplamento Molecular , Triazinas/farmacologia , Pentilenotetrazol , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Eletrochoque , Triazóis , Relação Estrutura-Atividade , Estrutura Molecular
17.
Biomed Pharmacother ; 156: 113938, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36411625

RESUMO

Valproic acid (VPA) is a widely used antiepileptic drug, and the herbal extract of Gastrodia elata exerts an anticonvulsant effect. However, few studies have investigated the pharmacokinetic and pharmacodynamic interactions between G. elata extract and VPA. We hypothesize that G. elata extract increases the VPA levels in the brain and enhances the antiepileptic effects of VPA, and this synergistic effect is mediated by transporters at the bloodbrain barrier (BBB). We performed microdialysis on pilocarpine-induced epileptic model rats in vivo to investigate this hypothesis. The results demonstrated that cotreatment with G. elata extract and VPA ameliorated drug-resistant epilepsy by increasing the VPA levels in the brain. In addition, G. elata extract and VPA exerted synergistic anticonvulsive effects to decrease the seizure severity by protecting neurons in the hippocampus and altering the DOPAC and 5-HT levels. However, these phenomena were partially blocked by the organic anion transporter peptide (OATP) inhibitor cyclosporine A (CsA; 20 mg/kg, i.p.), which demonstrated that the increase in the VPA level in the brain was modulated by the transporter OATP. This study provides a comprehensive strategy for assessing the interaction between traditional medicines and conventional antiepileptic drugs in a status epilepticus animal model.


Assuntos
Gastrodia , Fármacos Neuroprotetores , Transportadores de Ânions Orgânicos , Animais , Ratos , Ácido Valproico/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico
18.
Biomolecules ; 12(11)2022 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-36359013

RESUMO

The recently obtained cryo-electron microscopy structure (PDB code: 7SK2) of the human γ-aminobutyric acid transporter type 1 (hGAT-1) in complex with the antiepileptic drug, tiagabine, revealed a rather unexpected binding mode for this inhibitor in an inward-open state of the transporter. The simultaneously released crystal structures of the modified dopamine transporter with mutations mimicking hGAT-1 indicated an alternative binding mode for the tiagabine analogues that were found to block the transporter in an outward-open state, which is more consistent with the results of previous biological and molecular modeling studies. In view of the above discrepancies, our study compares different hypothetical tiagabine binding modes using classical and accelerated molecular dynamics simulations, as well as MM-GBSA free binding energy (dG) calculations. The results indicate that the most stable and energetically favorable binding mode of tiagabine is the one where the nipecotic acid fragment is located in the main binding site (S1) and the aromatic rings are arranged within the S2 site of the hGAT-1 transporter in an outward-open state, confirming the previous molecular modelling findings. The position of tiagabine bound to hGAT-1 in an inward-open state, partially within the intracellular release pathway, was significantly less stable and the dG values calculated for this complex were higher. Furthermore, analysis of the cryo-electron map for the 7SK2 structure shows that the model does not appear to fit into the map optimally at the ligand binding site. These findings suggest that the position of tiagabine found in the 7SK2 structure is rather ambiguous and requires further experimental verification. The identification of the main, high-affinity binding site for tiagabine and its analogues is crucial for the future rational design of the GABA transporter inhibitors.


Assuntos
Anticonvulsivantes , Simulação de Dinâmica Molecular , Humanos , Tiagabina , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Microscopia Crioeletrônica , Anticonvulsivantes/farmacologia
19.
Ceska Slov Farm ; 71(5): 224-233, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36443027

RESUMO

The anticonvulsant spectrum of the original promising anticonvulsant N-[(2,4-dichlorophenyl) methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl) acetamide was studied. The compound had a pronounced anticonvulsant effect, significantly reducing the mortality of mice in models of seizures induced by pentylenetetrazole, picrotoxin, strychnine, and caffeine. In the thiosemicarbazideinduced seizure model, the test compound did not reduce mortality. The obtained results indicated that the mechanism of anticonvulsant action involved GABA-ergic (effective in models of pentylenetetrazole and picrotoxin-induced seizures), glycinergic (efficiency in the strychnine model of paroxysms), and adenosinergic (effectiveness in the model of caffeine induced seizures). Molecular docking of a promising anticonvulsant to anticonvulsant biotargets follow the mechanisms of chemo-induced seizures, namely GABA, glycine, and adenosine receptors type A2A, GABAAT, and BCAT enzymes. The conformity between in vivo and in silico studies results was revealed.


Assuntos
Anticonvulsivantes , Pentilenotetrazol , Animais , Camundongos , Anticonvulsivantes/farmacologia , Picrotoxina , Estricnina , Espectro de Ação , Cafeína , Simulação de Acoplamento Molecular , Acetamidas/farmacologia , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Ácido gama-Aminobutírico
20.
Int Rev Neurobiol ; 167: 217-249, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36427956

RESUMO

Epilepsy is one of the most common neurological diseases globally, afflicting approximately 50 million people worldwide. While many antiepileptic drugs exist, an estimated one-third of individuals do not respond to available medications. The high fat, low carbohydrate ketogenic diet (KD) has been used to treat refractory epilepsy in cases when existing antiepileptic drugs fail. However, there are many variations of the KD, each of which varies greatly in its efficacy and side effects. Increasing evidence suggests that interactions between the KD and gut microbiome may modulate the effects of the diet on host physiology. Herein, we review existing evidence of microbiome differences in epileptic individuals compared to healthy controls. We highlight in particular both clinical and animal studies revealing effects of the KD on the composition and function of the microbiome, as well as proof-of-concept animal studies that implicate the microbiome in the antiseizure effects of the KD. We further synthesize findings suggesting that variations in clinical KD formulations may differentially influence host physiology and discuss the gut microbial interactions with specific dietary factors that may play a role. Overall, understanding interactions between the gut microbiota and specific nutritional components of clinical KDs could reveal foundational mechanisms that underlie the effectiveness, variability, and side effects of different KDs, with the potential to lead to precision nutritional and microbiome-based approaches to treat refractory epilepsy.


Assuntos
Dieta Cetogênica , Epilepsia Resistente a Medicamentos , Epilepsia , Microbioma Gastrointestinal , Animais , Microbioma Gastrointestinal/fisiologia , Anticonvulsivantes/farmacologia , Epilepsia/terapia
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