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1.
Cell Death Dis ; 13(5): 437, 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513389

RESUMO

Aberrantly synchronized neuronal discharges in the brain lead to epilepsy, a devastating neurological disease whose pathogenesis and mechanism are unclear. SAPAP3, a cytoskeletal protein expressed at high levels in the postsynaptic density (PSD) of excitatory synapses, has been well studied in the striatum, but the role of SAPAP3 in epilepsy remains elusive. In this study, we sought to investigate the molecular, cellular, electrophysiological and behavioral consequences of SAPAP3 perturbations in the mouse hippocampus. We identified a significant increase in the SAPAP3 levels in patients with temporal lobe epilepsy (TLE) and in mouse models of epilepsy. In addition, behavioral studies showed that the downregulation of SAPAP3 by shRNA decreased the seizure severity and that the overexpression of SAPAP3 by recombinant SAPAP3 yielded the opposite effect. Moreover, SAPAP3 affected action potentials (APs), miniature excitatory postsynaptic currents (mEPSCs) and N-methyl-D-aspartate receptor (NMDAR)-mediated currents in the CA1 region, which indicated that SAPAP3 plays an important role in excitatory synaptic transmission. Additionally, the levels of the GluN2A protein, which is involved in synaptic function, were perturbed in the hippocampal PSD, and this perturbation was accompanied by ultrastructural morphological changes. These results revealed a previously unknown function of SAPAP3 in epileptogenesis and showed that SAPAP3 may represent a novel target for the treatment of epilepsy.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Animais , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/patologia , Hipocampo/metabolismo , Humanos , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Densidade Pós-Sináptica/metabolismo , Densidade Pós-Sináptica/patologia , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/metabolismo , Sinapses/metabolismo
2.
Epilepsy Res ; 182: 106915, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35390701

RESUMO

BACKGROUND AND PURPOSE: Epilepsy is a severe neurological and mental disorder, and not all patients adequately respond to the current treatments. Dynamin 1 plays a key role in synaptic endocytosis and the modulation of neurological function. MATERIAL AND METHODS: Cultured hippocampal neurons were used in the study. First, the viability of neurons was determined by the CCK-8 assay after culturing in magnesium-free medium, DMSO, dynasore (dynamin agonist), and PIP2 (dynamin antagonist). Then, the effect of dynasore on seizure activity was evaluated. Next, we tested the levels of phospho-dynamin 1/total dynamin 1 and dynamin 1 mRNA in the control group and four epilepsy groups. Moreover, the uptake of tetramethylrhodamine-dextran in the different groups was measured. RESULTS: Dephospho-dynamin 1 expression was significantly increased in hyperexcitable neurons, while there was no change in total dynamin 1 level. The level of dephospho-dynamin 1 in hyperexcitable neurons was reduced when cultured with dynasore but increased with PIP2 treatment. Activity-dependent bulk endocytosis (ADBE) was upregulated in hyperexcitable neurons. Along with a decrease in dephospho-dynamin 1 level, ADBE was also downregulated with dynasore treatment, while PIP2 did not affect ABDE. The close link between the dephosphorylation status of dynamin 1 and ADBE suggests that ADBE activation depends on dynamin 1 dephosphorylation. CONCLUSION: Dephospho-dynamin 1 triggers ADBE to meet the requirements of high-frequency discharges during epileptic seizures.


Assuntos
Dinamina I , Epilepsia , Dinamina I/genética , Dinamina I/metabolismo , Dinaminas/metabolismo , Endocitose/fisiologia , Epilepsia/metabolismo , Hipocampo/metabolismo , Humanos , Neurônios/metabolismo , Convulsões/metabolismo
3.
Biomed Res Int ; 2022: 1234612, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35445130

RESUMO

The aerial parts of Bupleurum Chinense DC. aromatic oil (BAO) were a well-known Chinese herbal medicine plant extract used to treat epilepsy. This study aimed to explore the therapeutic effect of BAO on kainic acid- (KA-) induced epileptic rats and the possible mechanism of its antiepileptic effect. The composition and content of BAO were analyzed by GC-MS, and BAO was administered orally to alleviate the epileptic behavior induced by KA brain injection. The behavior of epileptic rats was determined by Racine grading criteria. And hematoxylin-eosin staining (HE), Nissl staining, immunohistochemistry, Elisa, Western blot, and other methods were used to study the antiepileptic mechanism of BAO, and the possible mechanism was verified by the epileptic cell model of hippocampal neurons induced by the low-Mg2+ extracellular fluid. BAO was mainly composed of terpenoids and aliphatic compounds. And BAO could improve KA-induced epilepsy-like behavior, neuroinflammation, and neurotransmitter abnormalities in the hippocampus. Furthermore, BAO could regulate the expression of GABA, NMDAR1, Notch1, and MAP2 to improve the symptoms of epilepsy. These results were also validated at the cellular level. These results indicated that BAO could alleviate the epilepsy-like behavior through the action of the Notch/NMDAR/GABA pathway.


Assuntos
Bupleurum , Epilepsia , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Hipocampo/metabolismo , Ácido Caínico/farmacologia , Componentes Aéreos da Planta , Ratos , Ácido gama-Aminobutírico/metabolismo
4.
Proc Natl Acad Sci U S A ; 119(17): e2113675119, 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35439054

RESUMO

SignificanceA child with epilepsy has a previously unreported, heterozygous mutation in KCNA2, the gene encoding KV1.2 proteins. Four KV1.2 assemble into a potassium-selective channel, a protein complex at the neuronal cell surface regulating electrical signaling. KV1.2 subunits assemble with other KV1-family members to form heterotetrameric channels, contributing to neuronal potassium-channel diversity. The most striking consequence of this mutation is preventing KV1.2-subunit trafficking, i.e., their ability to reach the cell surface. Moreover, the mutation is dominant negative, as mutant subunits can assemble with wild-type KV1.2 and KV1.4, trapping them into nontrafficking heterotetramers and decreasing their functional expression. Thus, KV1-family genes' ability to form heterotetrameric channels is a double-edged sword, rendering KV1-family members vulnerable to dominant-negative mutations in a single member gene.


Assuntos
Epilepsia , Membrana Celular/metabolismo , Criança , Epilepsia/genética , Epilepsia/metabolismo , Humanos , Canal de Potássio Kv1.1/genética , Canal de Potássio Kv1.2/genética , Canal de Potássio Kv1.2/metabolismo , Mutação , Potássio/metabolismo , Canais de Potássio/metabolismo
5.
Int J Mol Sci ; 23(7)2022 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-35409261

RESUMO

Posttraumatic epilepsy (PTE) is a major public health concern and strongly contributes to human epilepsy cases worldwide. However, an effective treatment and prevention remains a matter of intense research. The present study provides new insights into the gamma aminobutyric acid A (GABAA)-stabilizing protein ubiquilin-1 (ubqln1) and its regulation in mouse models of traumatic brain injury (TBI) and in vitro epilepsy. We performed label-free quantification on isolated cortical GABAergic interneurons from GAD67-GFP mice that received unilateral TBI and discovered reduced expression of ubqln1 24 h post-TBI. To investigate the link between this regulation and the development of epileptiform activity, we further studied ubqln1 expression in hippocampal and cortical slices. Epileptiform events were evoked pharmacologically in acute brain slices by administration of picrotoxin (PTX, 50 µM) and kainic acid (KA, 500 nM) and recorded in the hippocampal CA1 subfield using Multi-electrode Arrays (MEA). Interestingly, quantitative Western blots revealed significant decreases in ubqln1 expression 1-7 h after seizure induction that could be restored by application of the non-selective monoamine oxidase inhibitor nialamide (NM, 10 µM). In picrotoxin-dependent dose-response relationships, NM administration alleviated the frequency and peak amplitude of seizure-like events (SLEs). These findings indicate a role of the monoamine transmitter systems and ubqln1 for cortical network activity during posttraumatic epileptogenesis.


Assuntos
Lesões Encefálicas Traumáticas , Epilepsia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Lesões Encefálicas Traumáticas/complicações , Modelos Animais de Doenças , Epilepsia/etiologia , Epilepsia/metabolismo , Camundongos , Picrotoxina , Receptores de GABA-A/metabolismo , Convulsões
6.
Prog Neurobiol ; 213: 102267, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35364140

RESUMO

A very high proportion of cases of intellectual disability are genetic in origin and are associated with the occurrence of epileptic seizures during childhood. These two disorders together effect more than 5% of the world's population. One feature linking the two diseases is that learning and memory require the synthesis of new synaptic components and ion channels, while maintenance of overall excitability also requires synthesis of similar proteins in response to altered neuronal stimulation. Many of these disorders result from mutations in proteins that regulate mRNA processing, translation initiation, translation elongation, mRNA stability or upstream translation modulators. One theme that emerges on reviewing this field is that mutations in proteins that regulate changes in translation following neuronal stimulation are more likely to result in epilepsy with intellectual disability than general translation regulators with no known role in activity-dependent changes. This is consistent with the notion that activity-dependent translation in neurons differs from that in other cells types in that the changes in local cellular composition, morphology and connectivity that occur generally in response to stimuli are directly coupled to local synaptic activity and persist for months or years after the original stimulus.


Assuntos
Epilepsia , Deficiência Intelectual , Epilepsia/genética , Epilepsia/metabolismo , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Mutação , Neurônios/fisiologia , Convulsões/metabolismo
7.
Sci Transl Med ; 14(642): eabm5527, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35476595

RESUMO

Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally.


Assuntos
Transtorno Autístico , Epilepsias Mioclônicas , Epilepsia , Morte Súbita Inesperada na Epilepsia , Proteínas tau , Animais , Transtorno Autístico/complicações , Transtorno Autístico/genética , Modelos Animais de Doenças , Epilepsias Mioclônicas/complicações , Epilepsias Mioclônicas/genética , Epilepsia/complicações , Epilepsia/genética , Epilepsia/metabolismo , Síndromes Epilépticas , Humanos , Lactente , Camundongos , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Espasmos Infantis , Proteínas tau/metabolismo
8.
Int J Mol Sci ; 23(5)2022 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-35269897

RESUMO

Preventing epileptogenesis in people at risk is an unmet medical need. Metabotropic glutamate receptors (mGluRs) are promising targets for such therapy. However, drugs acting on mGluRs are not used in the clinic due to limited knowledge of the involvement of mGluRs in epileptogenesis. This study aimed to analyze the changes in gene expression of mGluR subtypes (1-5, 7, 8) in various rat brain regions in the latent and chronic phases of a lithium-pilocarpine model of epilepsy. For this study, multiplex test systems were selected and optimized to analyze mGluR gene expression using RT-qPCR. Region- and phase-specific changes in expression were revealed. During the latent phase, mGluR5 mRNA levels were increased in the dorsal and ventral hippocampus, and expression of group III genes was decreased in the hippocampus and temporal cortex, which could contribute to epileptogenesis. Most of the changes in expression detected in the latent stage were absent in the chronic stage, but mGluR8 mRNA production remained reduced in the hippocampus. Moreover, we found that gene expression of group II mGluRs was altered only in the chronic phase. The study deepened our understanding of the mechanisms of epileptogenesis and suggested that agonists of group III mGluRs are the most promising targets for preventing epilepsy.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Animais , Encéfalo/metabolismo , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/metabolismo , Expressão Gênica , Hipocampo/metabolismo , Humanos , Lítio/farmacologia , Pilocarpina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos
9.
Biomed Pharmacother ; 149: 112846, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35325849

RESUMO

To explore developmental processes of epileptogenesis/ictogenesis and pathophysiology of carbamazepine-resistant epilepsy, we determined effects of high-frequency-oscillation (HFO) on glutamatergic tripartite-synaptic transmission, astroglial expression of connexin43, and intracellular Erk- and Akt-signalling, using genetic rat model (S286L-TG) of autosomal-dominant sleep-related hypermotor epilepsy(ADSHE), which bears rat S286L-mutant Chrna4(corresponding to human S284L-mutant CHRNA4). Artificial physiological ripple- and pathological fast-ripple-burst stimulations use-dependently increased L-glutamate release through connexin43-containing hemichannels by enhancing Erk-signalling alone or both ERK- and Akt-signalling together, respectively. Stimulatory effects of HFO-bursts on astroglial L-glutamate release were enhanced by increasing extracellular K+ levels, Akt- and Erk-signalling-dependently. HFO-bursts also activated connexin43 expression and Akt- and Erk-signallings use-dependently. Extracellular pH elevation enhanced HFO-burst-evoked astroglial L-glutamate release, which was suppressed by therapeutically-relevant concentration of zonisamide via possible carbonic-anhydrase inhibition, but not by that of carbamazepine. Unexpectedly, these responses of S286L-TG to HFO-bursts were almost equal to those of wild-type astrocytes. These results indicated that candidate pathomechanism/pathophysiology of carbamazepine-resistant ADSHE, which enhanced HFO-bursts in S286L-TG neurons may contribute to epileptogenesis/ictogenesis development via activation of connexin43-associated astroglial transmission, which was directly unaffected by mutation, and induced through activated Erk-signalling, followed by Akt-signalling. Therefore, suppression of overexpressed Erk-signalling probably prevents ADSHE onset via indirect inhibition of mutant CHRNA4-associated pathomechanistic developments.


Assuntos
Astrócitos , Epilepsia , Animais , Carbamazepina/metabolismo , Carbamazepina/farmacologia , Conexina 43/genética , Conexina 43/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , Ácido Glutâmico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos
10.
Brain Res ; 1784: 147858, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35245486

RESUMO

Epilepsy is an abnormal brain state that may be induced by synchronous neuronal activation and also abnormalities in energy metabolism or the oxygen supply vascular system. Neurovascular coupling (NVC), the relationship between neuron, capillary, and penetrating artery, remains unexplored on a fine-scale with respect to the pathology process after acute temporal lobe epilepsy (TLE). Here we use two-photon microscopy (TPM) to provide high temporal-spatial resolution imaging to identify changes in NVC during spontaneous and electro-stimulated (ES) states in awake mice. Implantation of a long-term craniotomy window allowed TPM recording of the pathological development after the acute Kainic Acid temporal lobe epilepsy model. Our results provide direct evidence that the capillary and penetrating artery are not correlated to rhythmic neuronal activity during acute epilepsy. During the CSD period, NVC shows a strong correlation. We demonstrate that NVC exhibits nonlinear dynamics after status epilepticus. Furthermore, the vascular correlation to neuronal signals in spontaneous and ES states shows dynamic changes which correlate to the evolution after acute TLE. Understanding NVC in all TLE stages, from the acute through the TLE pathological development, may provide new therapeutic pathways.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Acoplamento Neurovascular , Animais , Encéfalo/fisiologia , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Hipocampo/metabolismo , Ácido Caínico/farmacologia , Camundongos
11.
Int J Mol Sci ; 23(4)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35216493

RESUMO

Epilepsy is one of the most common chronic diseases of the central nervous system (CNS). Treatment of epilepsy remains, however, a clinical challenge with over 30% of patients not responding to current pharmacological interventions. Complicating management of treatment, epilepsy comes with multiple comorbidities, thereby further reducing the quality of life of patients. Increasing evidence suggests purinergic signalling via extracellularly released ATP as shared pathological mechanisms across numerous brain diseases. Once released, ATP activates specific purinergic receptors, including the ionotropic P2X7 receptor (P2X7R). Among brain diseases, the P2X7R has attracted particular attention as a therapeutic target. The P2X7R is an important driver of inflammation, and its activation requires high levels of extracellular ATP to be reached under pathological conditions. Suggesting the therapeutic potential of drugs targeting the P2X7R for epilepsy, P2X7R expression increases following status epilepticus and during epilepsy, and P2X7R antagonism modulates seizure severity and epilepsy development. P2X7R antagonism has, however, also been shown to be effective in treating conditions most commonly associated with epilepsy such as psychiatric disorders and cognitive deficits, which suggests that P2X7R antagonisms may provide benefits beyond seizure control. This review summarizes the evidence suggesting drugs targeting the P2X7R as a novel treatment strategy for epilepsy with a particular focus of its potential impact on epilepsy-associated comorbidities.


Assuntos
Epilepsia/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Convulsões/metabolismo , Animais , Hipocampo/metabolismo , Humanos , Inflamação/metabolismo , Transdução de Sinais/fisiologia
12.
Int J Mol Sci ; 23(3)2022 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-35163267

RESUMO

Type II focal cortical dysplasia (FCD) is a neuropathological entity characterised by cortical dyslamination with the presence of dysmorphic neurons only (FCDIIA) or the presence of both dysmorphic neurons and balloon cells (FCDIIB). The year 2021 marks the 50th anniversary of the recognition of FCD as a cause of drug resistant epilepsy, and it is now the most common reason for epilepsy surgery. The causes of FCD remained unknown until relatively recently. The study of resected human FCD tissue using novel genomic technologies has led to remarkable advances in understanding the genetic basis of FCD. Mechanistic parallels have emerged between these non-neoplastic lesions and neoplastic disorders of cell growth and differentiation, especially through perturbations of the mammalian target of rapamycin (mTOR) signalling pathway. This narrative review presents the advances through which the aetiology of FCDII has been elucidated in chronological order, from recognition of an association between FCD and the mTOR pathway to the identification of somatic mosaicism within FCD tissue. We discuss the role of a two-hit mechanism, highlight current challenges and future directions in detecting somatic mosaicism in brain and discuss how knowledge of FCD may inform novel precision treatments of these focal epileptogenic malformations of human cortical development.


Assuntos
Epilepsia Resistente a Medicamentos/etiologia , Epilepsia/metabolismo , Malformações do Desenvolvimento Cortical do Grupo I/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Encéfalo/metabolismo , Epilepsia Resistente a Medicamentos/genética , Epilepsia Resistente a Medicamentos/fisiopatologia , Epilepsia/etiologia , Epilepsia/genética , Epilepsia/fisiopatologia , Humanos , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical do Grupo I/genética , Malformações do Desenvolvimento Cortical do Grupo I/fisiopatologia , Mutação/genética , Neurônios/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/genética
13.
Neuroscience ; 488: 32-43, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35158016

RESUMO

GDAP2 is a gene highly expressed in the human brain and encodes ganglioside-induced differentiation-associated protein 2 (GDAP2). At present, little is known about the function of GDAP2. In recent years, it has been reported that mutations in the GDAP2 gene may be involved in hereditary cerebellar ataxia. In this study, we first conducted a preliminary study on the effect of GDAP2 overexpression on cultured primary hippocampal neurons in vitro. By analysing neuronal morphology, it was found that the complexity of neurons and the number of dendritic spines increased when GDAP2 was upregulated. The electrophysiological recordings showed that GDAP2 overexpression significantly increased the frequency of mEPSCs, suggesting that GDAP2 overexpression dysregulates excitatory synaptic transmission in cultured primary hippocampal neurons in vitro. On the other hand, behavioural and field-potential recordings of epileptic mouse models showed that GDAP2 overexpression was associated with increased seizure frequency. In summary, this preliminary study suggested that GDAP2 overexpression may have a certain pathogenic effect, providing a new perspective for the study of gene-related diseases such as epilepsy.


Assuntos
Epilepsia , Gangliosídeos , Animais , Epilepsia/metabolismo , Hipocampo/metabolismo , Camundongos , Neurônios/metabolismo , Transmissão Sináptica/fisiologia
14.
Epilepsy Behav ; 129: 108574, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35189481

RESUMO

INTRODUCTION: Mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) is a surgically remediable epilepsy with a relatively high prevalence and psychiatric comorbidities. Depressive disorders may occur in up to 25% of MTLE-HS patients suggesting a common molecular mechanism underlying both conditions. OBJECTIVE: To compare the gene expression comprising serotonin 5HT1A and 5HT2A, noradrenaline (NA) ADRA1A, and ADRA2A receptors in the hippocampus of MTLE-HS patients with and without major depression. METHODS: A cross-sectional study allocated 31 patients in three groups: MTLE-HS without psychiatric diagnosis (MTLE-HS group), MTLE-HS with major depression (MTLE-HS-D group) and a control group consisting of healthy volunteers without any neurological or psychiatric disorders. Demographic and clinical characteristics were compared among groups. Gene expression of receptors were analyzed using general linear mixed models (GLMM), with an unstructured matrix, normal link. RESULTS: The three groups showed a similar distribution regarding age, gender (p > 0.16), history of initial precipitating injury, family history of epilepsy, monthly frequency of seizures, side of hippocampal sclerosis, interictal spike distribution and anti-seizure medications did not differ between MTLE-HS and MTLE-HS-D groups (p > 0.05). We observed a greater expression of the 5HT1A receptor in the control group when compared to the MTLE-HS (P = .004) and MTLE-HS-D (P = .007). Nevertheless, we did not observe any difference when MTLE-HS and MTLE-HS-D groups were compared to the controls for the ADRA1A (P = .931; P = .931), ADRA2A (P = .120; P = .121) and 5HT2A (P = .638; P = .318, respectively) gene expression. CONCLUSION: Mesial temporal lobe epilepsy related to hippocampal sclerosis and MTLE-HS-D patients showed a lowered expression of the 5HT1A receptors when compared with the controls adjusted for age and schooling. Data suggest that temporal lobe epilepsy plasticity may affect serotonin receptors, which may lead to more frequent cases of major depression in this population. More studies comprising wider samples are necessary to confirm these results; they also should investigate serotonin reuptake drugs as an adjuvant therapeutic option for MTLE-HS disorder.


Assuntos
Epilepsia do Lobo Temporal , Epilepsia , Estudos Transversais , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/complicações , Epilepsia do Lobo Temporal/epidemiologia , Epilepsia do Lobo Temporal/genética , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Esclerose/patologia , Serotonina/metabolismo , Lobo Temporal/metabolismo
15.
EBioMedicine ; 76: 103838, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35148983

RESUMO

BACKGROUND: Infantile spasms syndrome (IS) is a type of epilepsy affecting 1.6 to 4.5 per 10,000 children in the first year of life, often with severe lifelong neurodevelopmental consequences. Only two first-line pharmacological treatments currently exist for IS and many children are refractory to these therapies. In such cases, children are treated with the ketogenic diet (KD). While effective in reducing seizures, the diet can result in dyslipidemia over time. METHODS: Employing a neonatal Sprague-Dawley rat model of IS, we investigated how the KD affects hepatic steatosis and its modulation by a defined probiotic blend. A combination of multiple readouts, including malondialdehyde, fatty acid profiles, lipid metabolism-related enzyme mRNA expression, mitochondrial function, histone deacetylase activity, cytokines and chemokines were evaluated using liver homogenates. FINDINGS: The KD reduced seizures, but resulted in severe hepatic steatosis, characterized by a white liver, triglyceride accumulation, elevated malondialdehyde, polyunsaturated fatty acids and lower acyl-carnitines compared to animals fed a control diet. The KD-induced metabolic phenotype was prevented by the co-administration of a blend of Streptococcus thermophilus HA-110 and Lactococcus lactis subsp. lactis HA-136. This probiotic blend protected the liver by elevating pAMPK-mediated signaling and promoting lipid oxidation. The strains further upregulated the expression of caspase 1 and interleukin 18, which may contribute to their hepatoprotective effect in this model. INTERPRETATION: Our results suggest that early intervention with probiotics could be considered as an approach to reduce the risk of hepatic side effects of the KD in children who are on the diet for medically indicated reasons. FUNDING: This study was funded by the Alberta Children's Hospital Research Institute and Mitacs Accelerate Program (IT16942).


Assuntos
Dieta Cetogênica , Epilepsia , Probióticos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Dieta Cetogênica/efeitos adversos , Epilepsia/metabolismo , Humanos , Fígado/metabolismo , Ratos , Ratos Sprague-Dawley
16.
J Integr Neurosci ; 21(1): 15, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164451

RESUMO

Vanillic acid (VA) exhibited antioxidant and neuroprotective properties in some neurodegenerative disorders. So, the current study examined the neuroprotective potential of VA as an antiepileptic agent in pentylenetetrazole (PTZ)-induced epileptic rats and the prospective role of Insulin like growth factor-1 (IGF-1) and nuclear factor-2 erythroid-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in this respect. Thirty male albino rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/Kg, i.p. every other day) for 14 days, and (3) PTZ + VA group: received PTZ and VA (50 mg/Kg daily for 2 weeks). The seizure score and latency were evaluated after PTZ injection. Also, the markers of oxidative stress (malondialdehyde (MDA), catalase, and reduced glutathione (GSH)), histopathological examination, the expression of glial fibrillary acidic protein (GFAP) (a marker of astrocytes) IGF-1, Nrf2, and HO-1 were assessed in the brain tissues by the end of the experiment. PTZ caused significant decrease in seizure latency and significant increase in seizure score by the end of the experiment (p < 0.01). This was associated with significant increase in MDA and GFAP with significant decrease in GSH, total antioxidant capacity (TAC) and IGF-1 in brain tissues compared to normal group (p < 0.01). On the other hand, treatment with VA caused significant attenuation in PTZ-induced seizures which was associated with significant improvement in oxidative stress markers and downregulation in GFAP and upregulation of Nrf2, HO-1 and IGF-1 in CA3 hippocampal region (p < 0.01). VA showed neuroprotective and anti-epileptic effects against PTZ-induced epilepsy which probably might be due to its antioxidant properties and upregulation of Nrf2/HO-1 pathway and IGF-1.


Assuntos
Anticonvulsivantes/farmacologia , Antioxidantes/farmacologia , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Heme Oxigenase (Desciclizante)/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Ácido Vanílico/farmacologia , Animais , Anticonvulsivantes/administração & dosagem , Antioxidantes/administração & dosagem , Convulsivantes/farmacologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Masculino , Pentilenotetrazol/farmacologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Ácido Vanílico/administração & dosagem
17.
J Integr Neurosci ; 21(1): 21, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164457

RESUMO

The current study investigated the effects of stevia extracts on a PTZ-induced epileptic rat model and its potential mechanism. Thirty male Sprague-Dawley rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/kg, i.p. every other day) for 2 weeks, and (3) PTZ+ Stevia group: received PTZ and stevia (200 mg/kg orally daily) for 4 weeks (2 weeks before the start of PTZ treatment and 2 weeks with PTZ administration). The first jerk latency and the seizure score were assessed in rats. Also, brain tissue samples were collected by the end of the experiment, and oxidative stress markers (catalase, MDA, and total antioxidant capacity (TAC)) were measured by biochemical analysis in hippocampal brain homogenates. Also, in the hippocampus, the expression of IL6 and Bcl-2 at the mRNA level and expression of Sirt-1, P53, caspase-3, GFAP, and NF-kB in CA3 hippocampal region by immunohistochemistry was investigated. PTZ substantially increased the seizure score and decreased the seizure latency. Also, PTZ significantly increased MDA, GFAP, IL-6, NF-kB, caspase-3, and p53 and significantly reduced Sirt-1, TAC, and Bcl-2 in hippocampal tissues compared to the control group (p < 0.01). However, Stevia Rebaudiana Bertoni (Stevia R.) significantly attenuated the PTZ-induced seizures, improved oxidative stress markers, downregulated GFAP, IL-6, NF-kB, caspase-3, and p53, and upregulated Sirt-1 and Bcl-2 in the CA3 hippocampal region (p < 0.01). In conclusion, Stevia R. exhibits neuroprotective and antiepileptic actions in PTZ-induced epilepsy due to its antioxidant, anti-apoptotic, and anti-inflammatory effects. Additionally, the Sirt-1 pathway might be involved in the antiepileptic and neuroprotective effects of stevia in PTZ-kindled epileptic rat model.


Assuntos
Anticonvulsivantes/farmacologia , Antioxidantes/farmacologia , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Stevia , Animais , Anticonvulsivantes/administração & dosagem , Antioxidantes/administração & dosagem , Apoptose , Convulsivantes/farmacologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/imunologia , Epilepsia/metabolismo , Hipocampo/imunologia , Hipocampo/metabolismo , Masculino , /metabolismo , Pentilenotetrazol/farmacologia , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Sirtuína 1/efeitos dos fármacos , Sirtuína 1/metabolismo
18.
Int J Mol Sci ; 23(3)2022 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-35163358

RESUMO

Epilepsy is a heterogenous neurological disorder characterized by recurrent unprovoked seizures, mitochondrial stress, and neurodegeneration. Hydrogen sulfide (H2S) is a gasotransmitter that promotes mitochondrial function and biogenesis, elicits neuromodulation and neuroprotection, and may acutely suppress seizures. A major gap in knowledge remains in understanding the role of mitochondrial dysfunction and progressive changes in H2S levels following acute seizures or during epileptogenesis. We thus sought to quantify changes in H2S and its methylated metabolite (MeSH) via LC-MS/MS following acute maximal electroshock and 6 Hz 44 mA seizures in mice, as well as in the early phases of the corneally kindled mouse model of chronic seizures. Plasma H2S was acutely reduced after a maximal electroshock seizure. H2S or MeSH levels and expressions of related genes in whole brain homogenates from corneally kindled mice were not altered. However, plasma H2S levels were significantly lower during kindling, but not after established kindling. Moreover, we demonstrated a time-dependent increase in expression of mitochondrial membrane integrity-related proteins, OPA1, MFN2, Drp1, and Mff during kindling, which did not correlate with changes in gene expression. Taken together, short-term reductions in plasma H2S could be a novel biomarker for seizures. Future studies should further define the role of H2S and mitochondrial stress in epilepsy.


Assuntos
Eletrochoque/efeitos adversos , Epilepsia/metabolismo , Sulfeto de Hidrogênio/sangue , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Animais , Cromatografia Líquida , Modelos Animais de Doenças , Epilepsia/etiologia , Regulação da Expressão Gênica , Excitação Neurológica , Masculino , Metilação , Camundongos , Espectrometria de Massas em Tandem , Fatores de Tempo
19.
Int J Mol Sci ; 23(1)2022 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-35008924

RESUMO

Metabotropic glutamate receptors (mGluRs) are expressed predominantly on neurons and glial cells and are involved in the modulation of a wide range of signal transduction cascades. Therefore, different subtypes of mGluRs are considered a promising target for the treatment of various brain diseases. Previous studies have demonstrated the seizure-induced upregulation of mGluR5; however, its functional significance is still unclear. In the present study, we aimed to clarify the effect of treatment with the selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) on epileptogenesis and behavioral impairments in rats using the lithium-pilocarpine model. We found that the administration of MTEP during the latent phase of the model did not improve survival, prevent the development of epilepsy, or attenuate its manifestations in rats. However, MTEP treatment completely prevented neuronal loss and partially attenuated astrogliosis in the hippocampus. An increase in excitatory amino acid transporter 2 expression, which has been detected in treated rats, may prevent excitotoxicity and be a potential mechanism of neuroprotection. We also found that MTEP administration did not prevent the behavioral comorbidities such as depressive-like behavior, motor hyperactivity, reduction of exploratory behavior, and cognitive impairments typical in the lithium-pilocarpine model. Thus, despite the distinct neuroprotective effect, the MTEP treatment was ineffective in preventing epilepsy.


Assuntos
Epilepsia/metabolismo , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Piridinas/farmacologia , Convulsões , Tiazóis/farmacologia , Animais , Comportamento Animal , Modelos Animais de Doenças , Lítio , Masculino , Neurônios/efeitos dos fármacos , Pilocarpina , Ratos , Ratos Wistar , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores
20.
Brain Res ; 1780: 147800, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35074405

RESUMO

An increasing number of observations have indicated that the activation of inflammatory processes is involved in the pathogenesis of epilepsy. As an effective adjunctive therapy for medically intractable seizures, vagus nerve stimulation (VNS) is thought to interact with the inflammatory process to play an antiepileptic role. In this study, we examined the levels of multiple cytokine in focal brain tissue and peripheral blood to determine whether the antiepileptic effect of chronic VNS is related to the expression of cytokines. We observed that the frequency and duration of seizures significantly decreased in epileptic rats after two weeks of chronic VNS treatment. Pathological staining showed that the number of neural cells in the hippocampus was higher in the Epi + VNS group than in the Epi group, indicating that chronic VNS had a significant neuroprotective effect on epileptic rats. After comparing the expression of 9 cytokines, we found that the levels of the proinflammatory cytokines IL-6, IL-1ß and CXCL-1 in the hippocampus were significantly increased in the Epi group, while these cytokines were significantly decreased in the Epi + VNS group. Moreover, the level of the anti-inflammatory cytokine IL-13 was found to be reduced in Epi rats, while its levels were increased after VNS treatment. However, these changes in cytokine expression were not found in the hypothalamus or peripheral blood. These results suggest that the antiepileptic mechanism of VNS may work by inhibiting the activation of inflammatory processes in the epileptogenic focus.


Assuntos
Quimiocina CXCL1/metabolismo , Epilepsia/metabolismo , Hipocampo/metabolismo , Interleucina-13/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Estimulação do Nervo Vago , Animais , Epilepsia/induzido quimicamente , Cloreto de Lítio , Masculino , Pilocarpina , Ratos , Ratos Sprague-Dawley
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