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OBJECTIVE: This study aims to investigate the difference between epilepsy comorbid with and without cognitive dysfunction. METHOD: Participants were classified into patients with epilepsy comorbid cognitive dysfunction (PCCD) and patients with epilepsy without comorbid cognitive dysfunction (nPCCD). Microstate analysis was applied based on 20-channel electroencephalography (EEG) to detect the dynamic changes in the whole brain. The coverage, occurrence per second, duration, and transition probability were calculated. RESULT: The occurrence per second and the coverage of microstate B in the PCCD group were higher than that of the nPCCD group. Coverage in microstate D was lower in the PCCD group than in the nPCCD group. In addition, the PCCD group has a higher probability of A to B and B to A transitions and a lower probability of A to D and D to A transitions. CONCLUSION: Our research scrutinizes the disparities observed within EEG microstates among epilepsy patients both with and without comorbid cognitive dysfunction. SIGNIFICANCE: EEG microstate analysis offers a novel metric for assessing neuropsychiatric disorders and supplies evidence for investigating the mechanisms and the dynamic change of epilepsy comorbid cognitive dysfunction.
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Encéfalo , Disfunção Cognitiva , Eletroencefalografia , Epilepsia , Humanos , Masculino , Feminino , Epilepsia/complicações , Epilepsia/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Adulto , Encéfalo/fisiopatologia , Adulto Jovem , Pessoa de Meia-Idade , Adolescente , Testes NeuropsicológicosRESUMO
OBJECTIVE: Our primary objective is to verify whether 5-HTR6 is involved in the development of mossy fiber sprouting (MFS), and to determine how the progression of MFS is affected by 5-HTR6. METHODS: A total of 90 male adult Sprague-Dawley rats were allocated into either the control group (n=36) or the epileptic group (n=54). Status epilepticus (SE) of rats was induced by the intraperitoneal (i.p.) injection of LiCl-pilocarpine. We conducted our experiments in two stages. The first stage involves equally dividing 36 epileptic rats into three groups with treatments of none, 5-HTR6 antagonist SB-27104 (SB) and vehicle DMSO. Then behavior and electroencephalogram (EEG) of rats were monitored by video-EEG. The second stage involves dividing 126 epileptic rats into seven groups with treatments of none, 10% DMSO, SB (100 µg/kg), Fyn antagonist PP2 (50 µg/kg), p-ERK1/2 antagonist PD-98059 (30 µg/kg), SB (100 µg/ kg) + PP2 (50 µg/kg); SB (100 µg/kg) + PD-98059 (30 µg/kg). We also treated 18 rats in the control group of the first stage with 100 µg/kg 5-HTR6 agonist WAY-181187 (WAY). MFS of rats was detected through the approach of Timm's staining. Finally, expressions of 5-HTR6, Fyn, p-ERK1/2 and GAP-3 were qualified and semi-quantified via western blotting or RT-PCR. RESULTS: Induction of SE could stimulate formation of MFS and increased GAP-43 expressions. Expressions of 5-HTR6, Fyn and p-ERK1/2 were also up-regulated with increasing time after establishment of SE models. The development of MFS was remarkably inhibited by SB, PP2 and PD. Compared to the single antagonist, such an inhibitory effect was enhanced by SB+PD or SB+PP. Moreover, treatment of healthy rats with WAY would contribute to up-regulated Fyn and p-ERK1/2 expressions, as well as development of MFS (P < 0.05). Suppression of Fyn triggered a down-regulating trend of p-ERK1/2 (P < 0.05), however, suppressed p-ERK1/2 did not have such a significant effect on Fyn expression. CONCLUSION: HTR6 may affect the progression of MFS by activating both p-ERK1/2 and Fyn, which further modulate the expression of GAP-43.
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Epilepsia/fisiopatologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Receptores de Serotonina/metabolismo , Animais , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Flavonoides/farmacologia , Proteína GAP-43/genética , Proteína GAP-43/metabolismo , Masculino , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Agonistas Muscarínicos/farmacologia , Pilocarpina/toxicidade , Proteínas Proto-Oncogênicas c-fyn/antagonistas & inibidores , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia , Tiazóis/farmacologia , Fatores de Tempo , Triptaminas/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Objective: Epilepsy is a common neurological disorder characterized by recurrent epilepsy episodes. As a non-pharmacological treatment, the ketogenic diet has been widely applied in treating epilepsy. However, the exact therapeutic mechanism of the ketogenic diet for epilepsy remains unclear. This study investigates the molecular mechanisms of the ketogenic diet in regulating fatty acid metabolism and activating the ADCY3-initiated cAMP signaling pathway to enhance neuronal inhibition and thereby treat epilepsy. Methods and results: Meta-analysis reveals that the ketogenic diet is superior to the conventional diet in treating epilepsy. Animal experiments demonstrate that the ketogenic diet is more effective than the conventional diet in treating epilepsy, with the best results achieved using the classic ketogenic diet. Transcriptome sequencing analysis identifies six essential genes, among which ADCY3 shows increased expression in the ketogenic diet. In vivo experiments confirm that the activation of the cAMP-PKA signaling pathway by ADCY3 enhances neuronal inhibition and improves epilepsy control. Conclusion: Clinical observations indicate that the ketogenic diet improves patient epilepsy episodes by regulating the ADCY3-initiated cAMP signaling pathway.
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Background: Drug-resistant epilepsy (DRE) patients exhibit aberrant large-scale brain networks. Perampanel may be a therapeutic option for controlling seizures in these patients. Objective: We aim to explore the differences of resting-state electroencephalogram (EEG) microstate in perampanel-responsive and non-responsive DRE patients. Design: Retrospective study. Methods: Clinical data were collected from DRE patients who received perampanel treatment at the Fujian Medical University Union Hospital from June 2020 to September 2021, with a minimum follow-up of 6 months. Patients were classified into three groups based on the extent of reduction in seizure frequency: non-responsive (seizure reduction <50%), responsive (seizure reduction >50% but not seizure-free), and seizure-free. Resting-state EEG data sets of all participants were subjected to EEG microstate analysis. The study comprehensively compared the mean duration, frequency per second, and temporal coverage of each microstate among the three groups. Results: A total of 76 perampanel-treated DRE patients were categorized into three groups based on their response to treatment: non-responsive (n = 20), responsive (n = 36), and seizure-free (n = 20), according to the degree of seizure frequency reduction. The results of EEG microstate analysis revealed no statistically significant distinctions in frequency, duration, and coverage of microstate D in these DRE patients. However, the seizure-free group showed significantly increased duration and coverage of microstate A, frequency and coverage of microstate B, and significantly decreased duration, frequency, and coverage of microstate C when compared with the other groups. Conclusion: Microstate A, B, and D is associated with the sensorimotor network, visual network, salience network, and attention network, respectively. This study demonstrates statistically significant differences in the sensorimotor, visual, and salience networks, but not in the attention network, between perampanel-responsive and non-responsive DRE patients.
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The human iPS cell line, hiPS-RTT (FJMUi002-A), is derived from peripheral blood mononuclear cells (PBMCs) from a 12-year-old female RTT patient carrying a heterozygous p. R133C (c.397C > T) mutation in the MeCP2 gene. The hiPS-RTT cell line was generated by non-integrative reprogramming vectors encoding OCT3/4, SOX2, KLF4, and c-MYC and was free of genomically integrated reprogramming genes. The hiPS-RTT cell line had a normal karyotype, expressed pluripotency markers, and had capacity to form three germ layers in vitro and in vivo, which offering a useful resource to study the pathogenesis and treatment strategies of RTT.
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Células-Tronco Pluripotentes Induzidas , Síndrome de Rett , Criança , Feminino , Humanos , Diferenciação Celular , Linhagem Celular , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares , Mutação/genética , Síndrome de Rett/genéticaRESUMO
BACKGROUND: Recent studies have shown that mTOR signaling plays an important role in synaptic plasticity. However, the function of S6K1, the mechanistic target of rapamycin kinase complex 1 (mTORC1) substrate, in epilepsy remains unknown. AIMS: Our present study aimed to explore the mechanism by which S6K1 is involved in chronic epilepsy. METHODS: First, immunostaining was used to measure neurite length and complexity in kainic acid (KA)-treated primary cultured neurons treated with PF-4708671, a highly selective S6K1 inhibitor. We obtained evidence for the role of S6K1 in protecting and promoting neuronal growth and development in vitro. Next, to explore the function and mechanism of the S6K1 inhibitor in epilepsy, a pilocarpine-induced chronic epileptic rat model was established. In vivo electrophysiology (including local field potentiation in CA1 and long-term potentiation), depression/anxiety-like behavior tests, and Golgi staining were performed to assess seizure behavior, power spectral density, depression/anxiety-like behavior, and synaptic plasticity. Furthermore, western blotting was applied to explore the potential molecular mechanisms. RESULTS: We found that inhibition of S6K1 expression significantly decreased seizures and depression-like behavior and restored power at low frequencies (1-80 Hz), especially in the delta, theta, and alpha bands, in chronic epileptic rats. In addition, PF-4708671 reversed the LTP defect in hippocampal CA3-CA1 and corrected spine loss and dendritic pathology. CONCLUSION: In conclusion, our data suggest that inhibition of S6K1 attenuates seizures and depression in chronic epileptic rats via the rescue of synaptic structural and functional deficits. Given the wide range of physiological functions of mTOR, inhibition of its effective but relatively simple functional downstream molecules is a promising target for the development of drugs for epilepsy.
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Depressão , Epilepsia , Ratos , Animais , Depressão/tratamento farmacológico , Depressão/etiologia , Convulsões , Epilepsia/patologia , Potenciação de Longa Duração/fisiologia , Serina-Treonina Quinases TOR/metabolismo , HipocampoRESUMO
Background: Epilepsy is one of the most prevalent serious brain disorders globally, impacting over 70 million individuals. Observational studies have increasingly recognized the impact of plasma lipidome on epilepsy. However, establishing a direct causal link between plasma lipidome and epilepsy remains elusive due to inherent confounders and the complexities of reverse causality. This study aims to investigate the causal relationship between specific plasma lipidome and epilepsy, along with their intermediary mediators. Methods: We conducted a two-sample Mendelian randomization (MR) and mediation MR analysis to evaluate the causal effects of 179 plasma lipidomes and epilepsy, with a focus on the inflammatory cytokine as a potential mediator based on the genome-wide association study. The primary methodological approach utilized inverse variance weighting, complemented by a range of other estimators. A set of sensitivity analyses, including Cochran's Q test, I 2 statistics, MR-Egger intercept test, MR-PRESSO global test and leave-one-out sensitivity analyses was performed to assess the robustness, heterogeneity and horizontal pleiotropy of results. Results: Our findings revealed a positive correlation between Phosphatidylcholine (18:1_18:1) levels with epilepsy risk (OR = 1.105, 95% CI: 1.036-1.178, p = 0.002). Notably, our mediation MR results propose Tumor necrosis factor ligand superfamily member 12 levels (TNFSF12) as a mediator of the relationship between Phosphatidylcholine (18,1_18:1) levels and epilepsy risk, explaining a mediation proportion of 4.58% [mediation effect: (b = 0.00455, 95% CI: -0.00120-0.01030), Z = 1.552]. Conclusion: Our research confirms a genetic causal relationship between Phosphatidylcholine (18:1_18:1) levels and epilepsy, emphasizing the potential mediating role of TNFSF12 and provide valuable insights for future clinical investigations into epilepsy.
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Objective: The objective of this study was to identify the factors that affect the efficacy of added perampanel for the treatment of drug-resistant epilepsy (DRE), and to develop a reliable nomogram to predict the benefit of this addition. Methods: A retrospective clinical analysis was conducted on DRE patients who received perampanel treatment and who were followed up for at least 6 months from January 2020 and September 2023 at the Epilepsy Center of Fujian Medical University Union Hospital. Data from January 2020 to December 2021 were used as development dataset to build model, while the data from January 2022 to September 2023 were used as validation dataset for internal validation. The predictive factors that affected the efficacy of perampanel as DRE treatment were included in the final multivariate logistic regression model, and a derived nomogram was established. Results: A total of 119 DRE patients who received perampanel treatment were included in this study (development datasets: n = 76; validation data: n = 43). Among them, 72.3% (n = 86) showed a 50% or greater reduction in seizure frequency after perampanel treatment. Of all the parameters of interest, sex, age, history of generalized tonic-clonic seizures, and the number of antiseizure medications were identified as significant predictors for estimating the benefit of adding perampanel for the treatment of DRE. A model incorporating these four variables was developed, and a nomogram was constructed to calculate the probability of benefit of adding perampanel using the model coefficients. The C-index of the predictive model was 0.838, and the validation C-index was 0.756. The goodness-of-fit test showed good calibration of the model (p = 0.920, 0.752 respectively). Conclusion: The proposed nomogram has significant clinical potential for predicting the probability of benefit of perampanel as DRE treatment. This nomogram can be used to identify DRE patients who could benefit from the early addition of perampanel to their treatment regimen.
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Current epidemiological and experimental studies have indicated the overlapping genetic foundation of epilepsy and depression. However, the detailed pleiotropic genetic etiology and neurobiological pathways have not been well understood, and there are many variants with underestimated effect on the comorbidity of the two diseases. Utilizing genome-wide association study (GWAS) summary statistics of epilepsy (15,212 cases and 29,677 controls) and depression (170,756 cases and 329,443 controls) from large consortia, we assessed the integrated gene-based association with both diseases by Multimarker Analysis of Genomic Annotation (MAGMA) and Fisher's meta-analysis. On the one hand, shared genes with significantly altered transcripts in Gene Expression Omnibus (GEO) data sets were considered as possible pleiotropic genes. On the other hand, the pathway enrichment analysis was conducted based on the gene lists with nominal significance in the gene-based association test of each disease. We identified a total of two pleiotropic genes (CD3G and SLCO3A1) with gene expression analysis validated and interpreted twenty-five common biological process supported with literature mining. This study indicates the potentially shared genes associated with both epilepsy and depression based on gene expression, meta-data analysis, and pathway enrichment strategy along with traditional GWAS and provides insights into the possible intersecting pathways that were not previously reported.
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Epilepsia , Estudo de Associação Genômica Ampla , Depressão/genética , Epilepsia/genética , Pleiotropia Genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Many studies report predictions for cognitive function but there are few predictions in epileptic patients; therefore, we established a workflow to efficiently predict outcomes of both the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) in outpatients with epilepsy. Data from 441 outpatients with epilepsy were included; of these, 433 patients met the 12 clinical characteristic criteria and were divided into training (n = 304) and experimental (n = 129) groups. After descriptive statistics were analyzed, cross-validation was used to select the optimal model. The random forest (RF) algorithm was combined with the redundancy analysis (RDA) algorithm; then, optimal feature selection and resampling were carried out after removing linear redundancy information. The features that contributed more to multiple outcomes were selected. Finally, the external traceability of the model was evaluated using the follow-up data. The RF algorithm was the best prediction model for both MMSE and MoCA outcomes. Finally, seven markers were screened by overlapping the top ten important features for MMSE ranked by RF modeling, those ranked for MoCA ranked by RF modeling, and those for both assessments ranked by RDA. The optimal combination of features were namely, sex, age, age of onset, seizure frequency, brain MRI abnormalities, epileptiform discharge in EEG and usage of drugs. which was the most efficient in predicting outcomes of MMSE, MoCA, and both assessments.
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Disfunção Cognitiva/diagnóstico , Epilepsia , Aprendizado de Máquina , Adulto , Biomarcadores , Encéfalo/diagnóstico por imagem , Epilepsia/patologia , Epilepsia/terapia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Pacientes Ambulatoriais , Prognóstico , Fatores de Risco , Convulsões , Resultado do TratamentoRESUMO
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with neuronal cell inclusions composed of neurofilaments and other abnormal aggregative proteins as pathological hallmarks. Approximately 90% of patients have sporadic cases (sALS), and at least 4 genes, i.e. C9orf72, SOD1, FUS and TARDBP, have been identified as the main causative genes, while many others have been proposed as potential risk genes. However, these mutations could explain only ~ 10% of sALS cases. The neurofilament polypeptides encoded by NEFH, NEFM, and NEFL are promising protein biomarkers for ALS and other degenerative diseases. However, whether the genetic variants of these genes were associated with ALS remain ambiguous. METHODS: Here, we used PCR-Sanger to sequence the exons of these three genes in a cohort of 371 sALS patients and 711 healthy controls (Phase I) and validated the risk variant in another 300 sALS patients and 1076 controls (Phase II). RESULTS: A total of 92 variants were identified, including 36 rare heterozygous variants in NEFH, 27 in NEFM, and 16 in NEFL, and only rs568759161 (p.Ser787Arg) in NEFH reached nominal statistical power (P = 0.02 at Phase I, P = 0.009 at Phase II) in the case-control comparison. Together, the Phase I and II studies showed the significantly higher frequency of the variant in cases (9/1342, 0.67%) than in controls (2/3574, 0.07%) (OR 12.06; 95% CI 2.60-55.88; P = 0.0003). No variants passed multiple testing in the discovery cohort, but rs568759161 was associated with ALS in a replication cohort. CONCLUSIONS: Our results confirmed that NEFH Ser787Arg is a novel sALS risk variant in Chinese subjects, but NEFM and NEFL were not associated with sALS. These data may have implications for genetic counselling and for understanding the pathogenesis of sALS.
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Esclerose Lateral AmiotróficaRESUMO
OBJECTIVE: To analyze factors for cognitive impairment in epileptic patients. METHODS: A total of 257 epileptic patients completed clinical memory scale (CMS) and 70 of them were further surveyed with mini-mental state examination (MMSE), Montreal cognitive assessment (MoCA), digital symbol test (DSy), verbal fluency test, digit span test (DSp), Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD). Monadic linear related analysis and multiple stepwise regression analysis were performed to evaluate the potential factors for cognitive impairment. RESULTS: Educational level was correlated with scores of cognitive tests (p < .01), with a difference between the junior high school group and senior high school group (p < .01 or p < .05). Seizure frequency was negatively correlated with CMS scores (p < .01), with a difference between the group with a seizure frequency of less than once a year and other groups (p < .01). The kind of antiepileptic drugs (AEDs) was negatively correlated with CMS scores (p < .01), with a difference between the single-drug group and the group taking more than two kinds of AEDs (p < .01). Depression scores were negatively correlated with MMSE, MoCA, DSy, DSp (p < .01 or p < .05), disease duration negatively with DSy (p < .01), and age negatively with MoCA (p < .05). Seizure type was correlated with DSy, and general seizure fared worse in the tests than other seizure types (p < .05). CONCLUSION: Educational level, seizure frequency, kinds of AEDs and depression can affect the cognitive function of epileptic patients. High educational level, good seizure control, single-drug treatment and healthy psychological state are protective factors for cognitive function of epileptic patients.
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Anticonvulsivantes/uso terapêutico , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Epilepsia/complicações , Adolescente , Adulto , Criança , Disfunção Cognitiva/psicologia , Escolaridade , Epilepsia/tratamento farmacológico , Epilepsia/psicologia , Feminino , Humanos , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Risco , Adulto JovemRESUMO
Recent studies have documented that reduced M-current promotes epileptogenesis and attenuates synaptic remodeling. Neurite growth is closely related to the level of 5-HT6 receptor (5-HT6R) in the central nervous system. However, little research is available regarding the relation between 5-HT6R and M-current and the role of 5-HT6R in M-current regulation. Herein, we found that the expression of 5-HT6R was notably increased and the expression of KNCQ2/3, the main components of the M channel, was decreased in a time-dependent manner in pilocarpine-induced chronic epileptic hippocampus. Interestingly, antagonism of 5-HT6R by SB271046 upregulated the expression of KCNQ2 but not KCNQ3. SB271046 greatly alleviated excitatory/inhibitory imbalance and improved the impaired LTP in the chronic epileptic hippocampus. Further mechanism exploration revealed that the above effects of SB271046 can be reversed by the M-channel inhibitor XE991, which also confirmed that SB271046 can indeed improve abnormal M current. These data indicate that the antagonism of 5-HT6R may decrease the excitability of hippocampal pyramidal neurons in chronic epileptic rats and improve the impaired long-term potentiation by upregulating the expression of KCNQ2 in the M-channel.
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Cognitive impairment is a common comorbidity in patients with temporal lobe epilepsy (TLE) that severely affects patients' quality of life. Also, serotonin 5-hydroxytryptamine 6 (5-HT6) receptor plays an important role in cognition. This study aimed to investigate effects of 5-HT6 receptor on learning-memory capacities in epileptic rats. Total of 36 adult Sprague-Dawley (SD) rats were divided into vehicle (n = 6) and epileptic group (n = 30). Status epilepticus (SE) was induced via systemic injection of pilocarpine. Epileptic group was sub-divided into vehicle, 10, 20, and 30 µg SB-271046 groups, six mice per group. Learning-memory performance of rats was evaluated by using Y maze and Morris water maze test. 5-HT6 receptor expression was examined using immunostaining and Western blot. The other six rats were used to make epileptic model and Jab-1/p-c-Jun were detected. Results showed that frequency of spontaneous recurrent seizures (SRSs) was significantly decreased in pilocarpine-induced epileptic rats that treated with SB-271046. Alternation rate and new arm percentage were decreased in epileptic rats compared to control. The 5-day mean latency was prolonged in epileptic rats compared to control rats. During retention stage, mean latency, number of target crossings, and percentage of time spent in target zone were decreased in epileptic rats, but not in those treated with SB-271046. The number of apoptotic neurons was significantly increased in epileptic rats, which was decreased by SB-271046. 5-HT6 expression was significantly increased in hippocampus and cortex following recurrent seizures. Jab-1 level was decreased after SB-271046 administration. p-c-Jun level was elevated in epileptic rats and decreased in a dose-dependent manner after the SB-271046 administration. In conclusion, the over-expression of 5-HT6 receptor and activated Jab-1/p-c-Jun plays an important role in pilocarpine-induced seizures and learning-memory impairment.
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Complexo do Signalossomo COP9/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Aprendizagem em Labirinto , Transtornos da Memória/metabolismo , Peptídeo Hidrolases/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Receptores de Serotonina/metabolismo , Convulsões/metabolismo , Estado Epiléptico/metabolismo , Animais , Transtornos da Memória/etiologia , Pilocarpina/toxicidade , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/genética , Convulsões/etiologia , Transdução de Sinais , Estado Epiléptico/etiologiaRESUMO
OBJECT: To study memory impairment mechanisms of the medial temporal lobe epilepsy (MTLE) by analyzing the functional connectivity (FC) through resting state functional magnetic resonance imaging (rs-fMRI). METHODS: Rs-fMRI data were acquired from 13 patients with left MTLE and 11 patients with right MTLE. Another 13 healthy volunteers were selected as controls. The altered FC pattern between the unilateral hippocampus and other regions of the brain in MTLE patients was compared to that of the normal control group. Then the correlation between the strength of FC and the clinical memory scale scores in patients with MTLE was determined. RESULTS: The scores of the following check points of MTLE patients including point to memory, recognition of nonsense figure, associative learning, the image free recall, portrait characteristic recall and memory quotient were significantly lower than those in the normal group (all P<0.05). The scores of point to memory and recognition of nonsense figure were different between R-MTLE and L-MTLE patients. Different correlations between the strength of FC and the clinical memory scale scores were detected between R-MTLE and L-MTLE patients. CONCLUSIONS: The memory function of patients with MTLE was impaired. Patients with L-MTLE showed lower score on pure verbal memory test and those with R-MTLE showed weaker performance on pure visual memory test. Patients with MTLE showed extensive abnormal FC between hippocampus and particular encephalic regions.
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Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/fisiopatologia , Memória/fisiologia , Adulto , Mapeamento Encefálico , Eletroencefalografia , Epilepsia do Lobo Temporal/psicologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , DescansoRESUMO
Anti-platelet treatments, an effective anti-thrombotic therapy, are widely used in non-cardioembolic ischemic stroke or transient ischemic attack (TIA), including aspirin, cilostazol, clopidogrel, and other mono or dual therapies, while the optimal choice remains uncertain. All the literatures of 38 eligible randomized control trials were searched in PubMed, Embase, and China National Knowledge Internet (CNKI) without language limitation. And, nine anti-platelet therapies were assessed, including aspirin, clopidogrel, cilostazol, ticlopidine, triflusal, terutroban, sarpogrelate, dipyridamole plus aspirin, and clopidogrel plus aspirin. Additionally, we extract data of composite vascular events, major bleeding, ischemic stroke, intracranial hemorrhage, and all-cause death, as indicators of efficacy and safety. And among them, composite vascular events were the primary outcome. The binary outcomes were expressed as odds ratios (ORs) with corresponding 95 % confidence intervals (CIs). Both traditional meta-analysis and network meta-analysis were performed. Besides, for each outcome, the rank order was applied to reflect the superiority of every therapy compared with others, using the surface under the cumulative ranking curve (SUCRA). A cluster analysis was also conducted. Through the network meta-analysis, the synthesized data shows that cilostazol performed best on composite vascular events compared with placebo (OR = 0.62, 95 % CI 0.46-0.83) and aspirin (OR = 0.71, 95 % CI 0.53-0.95). In terms of ischemic stroke, clopidogrel plus aspirin seems the optimal, and it has significant difference between placebo (OR = 0.53, 95 % CI 0.35-0.74) and aspirin (OR = 0.75, 95 % CI 0.61-0.95). Meanwhile, cilostazol is also the first rank in major bleeding, especially when it is in contrast to aspirin (OR = 0.13, 95 % CI 0.02-0.70) and clopidogrel plus aspirin (OR = 0.09, 95 % CI 0.01-0.50). There is no significant difference among these nine treatments and placebo, as to all-cause death and intracranial hemorrhage. According to the cluster analysis, cilostazol can be the best choice with comprehensive assessment of composite vascular events, ischemic stroke and major bleeding. Based on this network meta-analysis, cilostazol was recommended as the optimal choice with good performance in both efficacy and safety for patient with ischemic stroke or TIA among nine anti-platelet therapies.
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Isquemia Encefálica/tratamento farmacológico , Ataque Isquêmico Transitório/tratamento farmacológico , Inibidores da Agregação Plaquetária/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Acidente Vascular Cerebral/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Plaquetas/fisiologia , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Quimioterapia Combinada , Humanos , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Resultado do TratamentoRESUMO
The aim of the present study was to investigate the role of paroxetine intervention in epilepsy, and its association with the expression of serotonin transporter (SERT) and hippocampal apoptosis. Thirty adult male Sprague Dawley rats were divided into control vehicle (n=6) and epileptic (n=24) groups. Status epilepticus (SE) was induced via systemic injection of pilocarpine, and seizure activity was monitored via video electroencephalogram. The epileptic group was then randomly divided into two groups; Four weeks following SE induction, paroxetine (5 mg/kg/day; SE + paroxetine group) or normal saline (SE group) was intraperitoneally injected for 4 weeks. Brain tissue was collected to evaluate apoptosis via terminal deoxynucleotidyl transferase dUTP nickend labeling. SERT, Bcell lymphoma2 (Bcl2) and brain derived neurotropic factor (BDNF) expression levels were evaluated by western blotting, and miR16 expression was evaluated by reverse transcriptionquantitative polymerase chain reaction. Paroxetine did not affect the mortality of the pilocarpineinduced chronic epileptic rats. Spontaneous recurrent seizures (SSRs) were observed 728 days following SE induction. The frequency and stage of the SSRs were reduced by paroxetine administration. Apoptotic cells were observed in the epileptic hippocampus. Following paroxetine intervention, the staining intensity and number of apoptotic cells were significantly decreased. Expression levels of BDNF and Bcl2 were lower in the SE group compared with the vehicle group. The former was not altered by paroxetine injection; however, the latter was increased. In the SE group, SERT expression was not altered in the raphe nucleus but was decreased in the hippocampus. Following paroxetine administration, SERT expression was decreased in the raphe nucleus and increased in the hippocampus. In the SE group, miR16 expression was decreased in the raphe nucleus and increased in the hippocampus. Following paroxetine administration, miR16 expression was not altered in the raphe nucleus but was reduced in the hippocampus. In conclusion, the seizures and hippocampal apoptosis observed in chronic epileptic rats were alleviated by paroxetine treatment. This effect may be associated with the reduced Bcl2 and BDNF expression and the modulation of SERT expression. The alterations in miR16 expression may provide a potential explanation for the modulation of apoptosis; however, further research is required to determine the complete underlying molecular mechanism.
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Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Paroxetina/administração & dosagem , Pilocarpina/efeitos adversos , Animais , Comportamento Animal , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Epilepsia/tratamento farmacológico , Hipocampo/metabolismo , Hipocampo/patologia , Imuno-Histoquímica , Masculino , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismoRESUMO
We analyzed the dynamic concentration change of serotonin (5-HT) and its main metabolite 5-hydroxyindoleacetic acid (5-HIAA) within the epileptic hippocampus in rats. Seizure was induced by systemic injection of pilocarpine (320mg/kg, i.p.). Using electroencephalography (EEG) recordings, we found that primary seizure discharge was induced 30min after pilocarpine administration and that recurrent discharge peaked 14d after the onset of status epilepticus (SE). The extracellular fluid in the hippocampus was sampled by microdialysis from conscious animals at various time points before and after SE. The concentrations of 5-HT and 5-HIAA in the samples were measured by high-performance liquid chromatography and electrochemical detection (HPLC-ECD). Interestingly, 5-HT levels in the hippocampus were dramatically increased within the 30min following SE. This reversed to basal level by 4d after SE and continued to drop to 48% at 7d and 28% of basal level 14d after SE. Accordingly, a marked increase of 5-HIAA in the hippocampus appeared at 2d after SE, then gradually declined to levels below baseline. To identify serotonergic neurons in the raphe nuclei (a major source of 5-HT release in the brain), brain sections were immunostained for tryptophan hydroxylase (TPH). The number of TPH positive neurons and the intensity of TPH staining significantly decreased at 28d after SE. These data suggest that pilocarpine induces depletion of 5-HT in the hippocampus and significantly compromise serotonergic neurons in the raphe nuclei. The loss of serotonergic function may play a significant role in the pathophysiology of epilepsy.
Assuntos
Encéfalo/metabolismo , Epilepsia/metabolismo , Serotonina/metabolismo , Doença Aguda , Animais , Doença Crônica , Eletroencefalografia , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Hipocampo/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Pilocarpina , Núcleos da Rafe/metabolismo , Ratos , Neurônios Serotoninérgicos/metabolismoRESUMO
OBJECTIVE: To investigate the relationship between serotonin (5-HT) and epilepsy and the mechanism of learning-memory in pilocarpine (PILO)-induced epileptic rats after 5,7-dihydroxytryptamine (5,7-DHT) microinjection in median raphe nucleus. METHODS: Adult S D rats were randomly divided into 3 groups: PILO group, PILO+ 5,7-DHT group, vehicle control group; PILO group was divided into two groups by status epilepticus (SE): PILO + SE group and PILO - SE group. The rats' seizures and cortex electroencephalography (EEG) were observed by video EEG. The rats' spatial learning-memory was evaluated by Morris water maze. Finally, serotonergic neuron in raphe nuclei was observed by immunohistochemistry. RESULTS: After treatment of 5,7-DHT (PILO + 5,7-DHT group), the success rate, the mortality and the frequency of chronic spontaneous seizures in pilocarpine-induced epilepsy model were all improved. Compared with the control group, the number of serotonergic neuron in raphe nuclei was decrease in PILO + SE group (P < 0.05). Moreover, it's extremely decrease in PILO + 5,7-DHT group (P < 0.01). Compared with control group, the mean escape latency was prolonged, the times of crossing target was decreased and the retention time in target zone was shortened in PILO + SE group (P < 0.05), but there was no significant difference between PILO + SE group and PILO + 5,7-DHT group. CONCLUSION: Depletion of serotonin may facility the rats' epileptic seizures, but we could not interpret which may cause epileptic rats' cognitive deficit.
Assuntos
5,7-Di-Hidroxitriptamina/toxicidade , Epilepsia/psicologia , Aprendizagem em Labirinto , Memória , Serotonina/metabolismo , Animais , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Masculino , Pilocarpina/efeitos adversos , Núcleos da Rafe , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To observe the dynamics of hippocampal release of glutamate (Glu) and gamma-aminobutyric acid (GABA) in epilepsy (TLE) after administration with high frequency stimulation (HFS). METHODS: The SD were divided into four groups (n =10): (1) Control group (KB) the rats were injected intraperitoneally with saline 0.9%. (2) Kainic acid (KA) group: the rats were injected with KA. (3) Pseudo-deep brain stimulation (DBS) group: the KA-induced rats were implanted with rheophores alone. (4) DBS group: KA induced-rats with DBS in hippocampal epileptic foci. We then collected hippocampal extracellular fluid by microdialysis and the levels of Glu and GABA were measured by high-performance liquid chromatography (HPLC) and fluorescence detection. RESULTS: There was no difference in the baseline of Glu and GABA in the four groups. In contrast, a significant increase in the content of Glu and GABA was shown in the three periods of KA-kindled seizures. Electrical stimulation of hippocampus resulted in a decrease of hippocampal Glu contents, while there was no change in GABA contents. Additionally, HFS of hippocampus normalized the Glu/GABA ratio in the chronic period of seizures. CONCLUSION: The high frequency stimulation of epileptic foci may protect against seizures by modulating the extracellular release of hippocampal Glu.