Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
1.
Neurochem Int ; 176: 105727, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38555055

RESUMO

Temporal lobe epilepsy (TLE), the most common type of drug-resistant epilepsy, severely affects quality of life. However, the underlying mechanism of TLE remains unclear and deserves further exploration. Sorbs2, a key synaptic regulatory protein, plays an important role in the regulation of synaptic transmission in the mammalian brain. In this study, we aimed to investigate the expression pattern of Sorbs2 in a kainic acid (KA)-induced TLE mouse model and in patients with TLE to further determine whether Sorbs2 is involved in seizure activity and to explore the potential mechanism by which Sorbs2 affects seizures in this TLE mouse model. First, we found that the expression of Sorbs2 was obviously increased in the hippocampus and cortex of a TLE mouse model and in the temporal cortex of TLE patients, indicating an abnormal expression pattern of Sorbs2 in TLE. Importantly, subsequent behavioral analyses and local field potential (LFP) analyses of a TLE mouse model demonstrated that the downregulation of hippocampal Sorbs2 could prolong the latency to spontaneous recurrent seizures (SRSs) and protect against SRSs. We also found that the knockdown of Sorbs2 in the hippocampus could decrease excitatory synaptic transmission in pyramidal neurons (PNs) in the hippocampal CA1 region and reduce the expression levels of the AMPAR subunits GluA1 and GluA2. Thus, we speculated that Sorbs2 may promote epileptogenesis and the development of TLE by affecting AMPAR-mediated excitatory synaptic transmission in PNs in the CA1 region. Therefore, reducing the expression of hippocampal Sorbs2 could restrain epileptogenesis and the development of TLE.


Assuntos
Epilepsia do Lobo Temporal , Proteínas de Ligação a RNA , Receptores de AMPA , Convulsões , Transmissão Sináptica , Animais , Feminino , Humanos , Masculino , Camundongos , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/induzido quimicamente , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Ácido Caínico/farmacologia , Ácido Caínico/toxicidade , Camundongos Endogâmicos C57BL , Receptores de AMPA/metabolismo , Convulsões/metabolismo , Convulsões/induzido quimicamente , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo
2.
Glia ; 72(6): 1082-1095, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38385571

RESUMO

Information exchange between neurons and astrocytes mediated by extracellular vesicles (EVs) is known to play a key role in the pathogenesis of central nervous system diseases. A key driver of epilepsy is the dysregulation of intersynaptic excitatory neurotransmitters mediated by astrocytes. Thus, we investigated the potential association between neuronal EV microRNAs (miRNAs) and astrocyte glutamate uptake ability in epilepsy. Here, we showed that astrocytes were able to engulf epileptogenic neuronal EVs, inducing a significant increase in the glutamate concentration in the extracellular fluid of astrocytes, which was linked to a decrease in glutamate transporter-1 (GLT-1) protein expression. Using sequencing and gene ontology (GO) functional analysis, miR-181c-5p was found to be the most significantly upregulated miRNA in epileptogenic neuronal EVs and was linked to glutamate metabolism. Moreover, we found that neuronal EV-derived miR-181c-5p interacted with protein kinase C-delta (PKCδ), downregulated PKCδ and GLT-1 protein expression and increased glutamate concentrations in astrocytes both in vitro and in vivo. Our findings demonstrated that epileptogenic neuronal EVs carrying miR-181c-5p decrease the glutamate uptake ability of astrocytes, thus promoting susceptibility to epilepsy.


Assuntos
Epilepsia , Vesículas Extracelulares , MicroRNAs , Humanos , Astrócitos/metabolismo , Proteína Quinase C-delta/metabolismo , Epilepsia/genética , Epilepsia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neurônios/metabolismo , Vesículas Extracelulares/metabolismo , Ácido Glutâmico/metabolismo , Sistema X-AG de Transporte de Aminoácidos/metabolismo
3.
Mol Cell Neurosci ; 128: 103915, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38143048

RESUMO

BACKGROUND: The EphB receptor tyrosine kinase family participates in intricate signaling pathways that orchestrate neural networks, guide neuronal axon development, and modulate synaptic plasticity through interactions with surface-bound ephrinB ligands. Additionally, Kalirin, a Rho guanine nucleotide exchange factor, is notably expressed in the postsynaptic membrane of excitatory neurons and plays a role in synaptic morphogenesis. This study postulates that Kalirin may act as a downstream effector of EphB3 in epilepsy. This investigation focuses on understanding the link between EphB3 and epilepsy. MATERIALS AND METHODS: Chronic seizure models using LiCl-pilocarpine (LiCl/Pilo) and pentylenetetrazol were developed in rats. Neuronal excitability was gauged through whole-cell patch clamp recordings on rat hippocampal slices. Real-time PCR determined Kalirin's mRNA expression, and Western blotting was employed to quantify EphB3 and Kalirin protein levels. Moreover, dendritic spine density in epileptic rats was evaluated using Golgi staining. RESULTS: Modulation of EphB3 functionality influenced acute seizure severity, latency duration, and frequency of spontaneous recurrent seizures. Golgi staining disclosed an EphB3-driven alteration in dendritic spine density within the hippocampus of epileptic rats, underscoring its pivotal role in the reconfiguration of hippocampal neural circuits. Furthermore, our data propose Kalirin as a prospective downstream mediator of the EphB3 receptor. CONCLUSIONS: Our findings elucidate that EphB3 impacts the action potential dynamics in isolated rat hippocampal slices and alters dendritic spine density in the inner molecular layer of epileptic rat hippocampi, likely through Kalirin-mediated pathways. This hints at EphB3's significant role in shaping excitatory circuit loops and recurrent seizure activity via Kalirin.


Assuntos
Epilepsia , Neurônios , Ratos , Animais , Ratos Sprague-Dawley , Estudos Prospectivos , Neurônios/metabolismo , Epilepsia/metabolismo , Convulsões/metabolismo
4.
J Neurointerv Surg ; 2023 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-37586821

RESUMO

BACKGROUND: While statins have been widely used in patients with large-artery atherosclerotic stroke, their effectiveness in patients with cardioembolic large vessel occlusion (CE-LVO) undergoing endovascular treatment (EVT) remains unclear. This study aimed to evaluate whether combining statin therapy with EVT could improve clinical outcomes in patients with acute ischemic stroke caused by CE-LVO in the anterior circulation. METHODS: We performed a retrospective screening on patients with CE-LVO in the anterior circulation who underwent EVT in 27 hospitals across China between 2018 and 2021. The primary outcome measure was functional independence, defined as a 90-day modified Rankin Scale (mRS) score of 0 to 2. Safety outcomes included 90-day mortality and symptomatic intracranial hemorrhage (sICH). RESULTS: A total of 510 patients with CE-LVO in the anterior circulation undergoing EVT were included in this study. Of these, 404 (79.2%) patients received statin treatment (statin group), while 106 (20.8%) did not (non-statin group). Statin treatment was significantly associated with improved functional independence (adjusted OR (aOR) 2.072, 95% CI 1.197 to 3.586, P=0.009). Moreover, statin use was associated with a lower rate of 90-day mortality (aOR 0.343, 95% CI 0.197 to 0.596, P<0.001) and a lower rate of sICH (aOR 0.153, 95% CI 0.072 to 0.325, P<0.001). CONCLUSION: Statin treatment was associated with improved clinical outcomes and reduced risks of mortality and sICH in patients with CE-LVO in the anterior circulation undergoing EVT.

5.
Curr Neurovasc Res ; 20(3): 354-361, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37488759

RESUMO

BACKGROUND: Contrast extravasation (CE) on brain non-contrast computed tomography (NCCT) after endovascular therapy (EVT) is commonly present in patients with acute ischemic stroke (AIS). Substantial uncertainties remain about the relationship between the spatial location of CE and symptomatic intracranial hemorrhage (sICH). Therefore, this study aimed to evaluate this association. METHODS: We performed a retrospective screening on consecutive patients with AIS due to LVO (AIS-LVO) who had CE on NCCT immediately after EVT for anterior circulation large vessel occlusion (LVO). We used the Alberta stroke program early CT Score (ASPECTS) scoring system to estimate the spatial location of CE. Multivariable logistic regression was performed to achieve the risk factors of sICH. RESULTS: In this study, 115 of 153 (75.1%) anterior circulation AIS-LVO patients had CE on NCCT. After excluding 9 patients, 106 patients were enrolled in the final analysis. In multivariate regression analysis, atrial fibrillation (AF) (adjusted OR [aOR] 6.833, 95% confidence interval [CI] 1.331-35.081, P = 0.021) and CE-ASPECTS (aOR 0.602, 95% CI 0.411-0.882 P = 0.009) were associated with sICH. In subgroup analysis, CE at the internal capsule (IC) region was an independent risk factor for sICH (aOR 5.992, 95% CI 1.010-35.543 P < 0.05). These and conventional variables were incorporated as a predict model, with AUC of 0.899, demonstrating good discrimination and calibration for sICH in this study cohort. CONCLUSION: The spatial location of CE on NCCT immediately after EVT was an independent and strong risk factor for sICH in acute ischemic stroke patients.


Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/cirurgia , AVC Isquêmico/complicações , Estudos Retrospectivos , Isquemia Encefálica/complicações , Resultado do Tratamento , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/etiologia , Acidente Vascular Cerebral/etiologia , Procedimentos Endovasculares/efeitos adversos
6.
CNS Neurosci Ther ; 29(11): 3644-3656, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37302990

RESUMO

INTRODUCTION: Annexin A2 (ANXA2) participates in the pathology of a variety of diseases. Nevertheless, the impact of ANXA2 on epilepsy remains to be clarified. AIMS: Hence, the study aimed at investigating the underlying role of ANXA2 in epilepsy through behavioral, electrophysiological, and pathological analyses. RESULTS: It was found that ANXA2 was markedly upregulated in the cortical tissues of temporal lobe epilepsy patients (TLE), kainic acid (KA)-induced epilepsy mice, and in a seizure-like model in vitro. ANXA2 silencing in mice suppressed first seizure latency, number of seizures, and seizure duration in behavioral analysis. In addition, abnormal brain discharges were less frequent and shorter in the hippocampal local field potential (LFP) record. Furthermore, the results showed that the frequency of miniature excitatory postsynaptic currents was decreased in ANXA2 knockdown mice, indicating that the excitatory synaptic transmission is reduced. Co-immunoprecipitation (COIP) experiments demonstrated that ANXA2 interacted with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit GluA1. Moreover, ANXA2 knockdown decreased GluA1 expression on the cell surface and its phosphorylation onserine 831 and serine 845, related to the decreased phosphorylation levels mediated by protein kinases A and C (PKA and PKC). CONCLUSIONS: This study covers a previously unknown and key function of ANXA2 in epilepsy. These findings indicate that ANXA2 can regulate excitatory synaptic activity mediated by AMPAR subunit GluA1 to improve seizure activity, which can provide novel insights for the treatment and prevention of epilepsy.


Assuntos
Anexina A2 , Epilepsia , Humanos , Camundongos , Animais , Fosforilação , Anexina A2/genética , Anexina A2/metabolismo , Receptores de AMPA/metabolismo , Epilepsia/metabolismo , Convulsões/induzido quimicamente , Convulsões/metabolismo
7.
Epilepsy Behav ; 139: 109064, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36640483

RESUMO

PURPOSE: This study aimed to summarize the clinical characteristics and explore the risk factors for cerebral cavernous malformation (CCM)-related epilepsy (CRE). METHODS: We retrospectively analyzed the clinical data of patients with CCM in our cerebral vascular malformations database. Descriptive statistics were used to present the clinical characteristics of CRE patients. Patients were divided into a CRE and a non-CRE group according to clinical presentation. Binary logistic regression analysis was used to analyze the risk factors of CRE. RESULTS: A total of 199 patients with CCM confirmed by postoperative pathological examination were enrolled, 93 of whom were diagnosed with CRE, and 34 patients had drug-resistant epilepsy. The most common seizure type of CRE patients was focal to bilateral tonic-clonic seizure (FBTCS), followed by focal impaired awareness motor seizure. All CCM lesions were supratentorial, 97.8% of which involved the cerebral cortex, 86.0% of lesions had hemosiderin rim, and 50.5% of lesions were located in the temporal lobe. Binary logistic regression analysis indicated that CCM diagnosis age ≤ 44 years (odds ratio [OR] 2.79, p = 0.010), temporal lobe lesion location (OR = 9.07, p = 0.042), medial temporal lobe lesion (OR = 14.09, p = 0.002), cortical involvement of the lesion (OR = 32.77, p = 0.010), and hemosiderin rim around the lesion (OR = 16.48, p = 0.001) significantly increased the risk of CRE. CONCLUSIONS: The most common seizure type of CRE was FBTCS. Those whose CCM diagnosis age was ≤ 44 years, having a temporal lobe lesion location, especially the medial temporal lobe lesion, cortical involvement, and hemosiderin rim around the lesion had a higher risk of developing CRE.


Assuntos
Epilepsia , Hemangioma Cavernoso do Sistema Nervoso Central , Humanos , Adulto , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/cirurgia , Estudos Retrospectivos , Hemossiderina , Resultado do Tratamento , Epilepsia/epidemiologia , Epilepsia/etiologia , Epilepsia/cirurgia , Convulsões/complicações , Fatores de Risco
8.
Cell Death Dis ; 12(10): 936, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642320

RESUMO

Although many studies have explored the mechanism of epilepsy, it remains unclear and deserves further investigation. Vezatin has been reported to be a synaptic regulatory protein involved in regulating neuronal synaptic transmission (NST). However, the role of vezatin in epilepsy remains unknown. Therefore, the aims of this study are to investigate the underlying roles of vezatin in epilepsy. In this study, vezatin expression was increased in hippocampal tissues from pilocarpine (PILO)-induced epileptic mice and a Mg2+-free medium-induced in vitro seizure-like model. Vezatin knockdown suppressed seizure activity in PILO-induced epileptic mice. Mechanistically, vezatin knockdown suppressed AMPAR-mediated synaptic events in epileptic mice and downregulated the surface expression of the AMPAR GluA1 subunit (GluA1). Interestingly, vezatin knockdown decreased the phosphorylation of GluA1 at serine 845 and reduced protein kinase A (PKA) phosphorylation; when PKA phosphorylation was suppressed by H-89 (a selective inhibitor of PKA phosphorylation) in vitro, the effects of vezatin knockdown on reducing the phosphorylation of GluA1 at serine 845 and the surface expression of GluA1 were blocked. Finally, we investigated the pattern of vezatin in brain tissues from patients with temporal lobe epilepsy (TLE), and we found that vezatin expression was also increased in patients with TLE. In summary, the vezatin expression pattern is abnormal in individuals with epilepsy, and vezatin regulates seizure activity by affecting AMPAR-mediated NST and the surface expression of GluA1, which is involved in PKA-mediated phosphorylation of GluA1 at serine 845, indicating that vezatin-mediated regulation of epileptic seizures represents a novel target for epilepsy.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Receptores de AMPA/metabolismo , Convulsões/metabolismo , Sinapses/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Epilepsia/metabolismo , Epilepsia/patologia , Potenciais Pós-Sinápticos Excitadores , Técnicas de Silenciamento de Genes , Hipocampo/metabolismo , Lentivirus/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neurônios/metabolismo , Neurônios/patologia , Fosforilação , Fosfosserina/metabolismo , Pilocarpina , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/patologia , Transdução de Sinais
9.
BMJ Open ; 11(7): e044917, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34233968

RESUMO

OBJECTIVE: Contrast extravasation (CE) after endovascular therapy (EVT) is commonly present in acute ischaemic stroke (AIS) patients. Substantial uncertainties remain about the relationship between CE and the outcomes of EVT in patients with AIS. Therefore, we aimed to evaluate this association. DESIGN: A systematic review and meta-analysis of published studies were performed. DATA SOURCE: We systematically searched the Medline and Embase databases for relevant clinical studies. The last literature search in databases was performed in June 2020. ELIGIBILITY CRITERIA FOR STUDY SELECTION: We included studies exploring the associations between CE and the outcomes of EVT in patients with AIS undergoing EVT. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted relevant information and data from each article independently. We pooled ORs with CIs using a random-effects meta-analysis to calculate the associations between CE and outcomes of EVT. The magnitude of heterogeneity between estimates was quantified with the I2 statistic with 95% CIs. RESULTS: Fifteen observational studies that enrolled 1897 patients were included. Patients with CE had higher risks of poor functional outcome at discharge (2.38, 95% CI 1.45 to 3.89 p=0.001; n=545) and poor functional outcome at 90 days (OR 2.16, 95% CI 1.20 to 3.90; n=1194). We found no association between CE and in-hospital mortality (OR 0.95, 95% CI 0.27 to 3.30; n=376) or 90-day mortality (OR 1.38, 95% CI 0.81 to 2.36; n=697) after EVT. Moreover, CE was associated with higher risks of post-EVT intracranial haemorrhage (ICH) (OR 6.68, 95% CI 3.51 to 12.70; n=1721) and symptomatic ICH (OR 3.26, 95% CI 1.97 to 5.40; n=1092). CONCLUSIONS: This systematic review and meta-analysis indicates that in patients with AIS undergoing EVT, CE is associated with higher risks of unfavourable functional outcomes and ICH. Thus, we should pay more attention to CE in patients with AIS undergoing EVT.


Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/terapia , Procedimentos Endovasculares/efeitos adversos , Humanos , Acidente Vascular Cerebral/terapia , Resultado do Tratamento
10.
CNS Drugs ; 35(7): 717-726, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34019256

RESUMO

BACKGROUND: Several real-world observational studies have investigated the association between statin treatment and outcomes of cardioembolic stroke. However, substantial uncertainties remain about this association. OBJECTIVE: We aimed to perform a systematic review and meta-analysis to determine the effect of statin treatment on the outcomes of cardioembolic stroke. METHODS: We systematically searched the PubMed and Embase databases for relevant clinical studies. Pooled relative risks (RRs) and 95% confidence intervals (CIs) with a random-effects model were used to assess the outcomes of interest. RESULTS: A total of 18 observational studies published between 2009 and 2020 were included. No randomized clinical trial was found. Compared with non-statin treatment, statin treatment was not associated with a decreased risk of stroke recurrence in patients with cardioembolic stroke [PWCS] (RR, 0.93; 95% CI 0.82-1.06). However, compared with non-statin treatment, statin treatment was associated with a lower risk of all-cause death (RR, 0.59; 95% CI 0.49-0.73) and better functional outcomes (RR, 0.67; 95% CI 0.47-0.97) in PWCS. There was no significant association between statin treatment and major bleeding event risk in PWCS (RR, 0.35; 95% CI 0.06-2.16). Compared with non-statin treatment, statin treatment was not associated with a decreased risk of coronary atherosclerotic disease in PWCS (RR, 1.04; 95% CI 0.96-1.11). CONCLUSIONS: Although the use of statins does not enhance the prevention of stroke recurrence in PWCS, statin treatment is associated with improved clinical outcomes in PWCS. Statins play a beneficial role in the treatment of cardioembolic stroke.


Assuntos
AVC Embólico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Avaliação de Resultados em Cuidados de Saúde/métodos , AVC Embólico/tratamento farmacológico , AVC Embólico/mortalidade , AVC Embólico/prevenção & controle , Humanos , Mortalidade , Estudos Observacionais como Assunto , Resultado do Tratamento
11.
Front Neurol ; 12: 602037, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897580

RESUMO

Background: Cerebral small vessel disease (SVD) is prevalent in the population, especially among elderly individuals. Substantial uncertainties remain about the clinical relevance of SVD with outcomes of mechanical thrombectomy (MT) in acute ischemic stroke (AIS). Objectives: This systematic review and meta-analysis was performed to evaluate the association between SVD and clinical outcomes in patients with AIS undergoing MT. Methods: We systematically searched the Medline, Embase, and Cochrane databases for relevant clinical studies. The exposure of SVD mainly included leukoaraiosis, cerebral microbleeds (CMBs), and lacunes. The pooled OR was used to calculate the association between each subtype of SVD and outcomes of MT. The primary outcome was poor functional outcome, which was defined as a modified Rankin Scale score (mRS) ≥3 at 90 days after MT. The secondary outcomes included mortality at 90 days, in-hospital mortality, intracranial hemorrhage (ICH) and symptomatic intracranial hemorrhage (sICH), successful recanalization and futile recanalization (FR), early neurological improvement, and early neurological deterioration (END) after MT. Results: Overall, 20 studies with 5,189 patients with AIS undergoing MT were included. High leukoaraiosis burden (HLB) at baseline was associated with increased risks of poor functional outcome at 90 days (OR 2.70, 95% CI 2.01-3.63; p < 0.001; 10 studies; n = 2,004), in-hospital mortality (OR 4.06, 95% CI 1.48-11.13; p = 0.006; 2 studies; n = 314), FR (OR 5.00, 95% CI 2.86-8.73; p < 0.001; 3 studies; n = 493), and END (OR 2.65, 95% CI 1.09-6.45; 1 study; n = 273) after MT. HLB (VSS 3-4 or FS ≥ 2) at baseline was not associated with mortality at 90 days, ICH, or sICH after MT. CMBs at baseline were found to be associated with increased risks of poor functional outcome at 90 days (OR 1.84, 95% CI 1.17-2.90; p = 0.008; 2 studies; n = 1,924) after MT. We found no association between the presence of lacunes and poor functional outcome at 90 days after MT. Conclusions: In patients with AIS undergoing MT, HLB and CMBs were associated with increased risks of unfavorable outcomes after MT.

12.
Seizure ; 83: 63-69, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33096458

RESUMO

PURPOSE: The magnitude of association between statin use and post-stroke seizures (PSS) risk remains unclear. Therefore, the aim of this meta-analysis was to evaluate this issue. METHODS: We systematically searched electronic libraries, including Medline, Embase, and Cochrane databases, for relevant clinical studies. The main outcome was the risk of early PSS and the risk of post-stroke epilepsy (PSE). The pooled relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were used to calculate the association between statin treatment and risks of early PSS and PSE. RESULTS: A total of 7 articles met our inclusion criteria and were included. For early PSS risk, statin use was associated with a lower risk of early PSS (RR 0.36, 95% CI 0.25-0.53; p < 0.001). Subgroup analyses based on the prescribing timing of statins showed that pre-stroke statin use was not associated with the risk of early PSS; post-stroke statin use was associated with a lower risk of early PSS (RR 0.37, 95% CI 0.25-0.54; p < 0.001). For PSE risk, statin use was associated with a lower risk of PSE (RR 0.62, 95% CI 0.42-0.92; p = 0.017). Further subgroup analyses based on the prescribing timing of statins indicated that pre-stroke statin use was not associated with the risk of PSE; post-stroke statin use was associated with a lower risk of PSE (RR 0.59, 95% CI 0.49-0.70; p < 0.001). CONCLUSIONS: Statin treatment, especially the post-statin treatment, was associated with lower risks of early PSS and PSE.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Epilepsia/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Convulsões/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Isquemia Encefálica/complicações , Humanos , Risco , Acidente Vascular Cerebral/complicações
13.
Neurochem Res ; 45(9): 1997-2008, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32419121

RESUMO

The number of γ-aminobutyric acid type A receptors (GABAARs) expressed on the surface membrane and at synaptic sites is implicated in the enhanced excitation of neuronal circuits and abnormal network oscillations in epilepsy. Huntingtin-associated protein 1 (HAP1), a key mediator of pathological alterations in protein trafficking, directly interacts with GABAARs and facilitates their recycling back to synapses after internalization from the surface; thus, HAP1 regulates the strength of inhibitory synaptic transmission. Here, we show that HAP1 modulates epileptic seizures by regulating GABAAR function in patients with temporal lobe epilepsy (TLE) and in the pentylenetetrazol (PTZ)-induced epileptic model. We demonstrate that GABAARß2/3 and HAP1 expression are decreased and that the HAP1-GABAARß2/3 complex is disrupted in the epileptic rat brain. We found that HAP1 upregulation exerts antiepileptic activity in the PTZ-induced seizure and that these changes are associated with increased surface GABAARß2/3 expression and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). This study provides evidence that hippocampal HAP1 is linked to GABAARs in evoking seizures and suggests that this mechanism is involved in epileptic seizures in the brain, representing a potential therapeutic target for epilepsy.


Assuntos
Epilepsia do Lobo Temporal/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Receptores de GABA-A/metabolismo , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Epilepsia do Lobo Temporal/induzido quimicamente , Feminino , Antagonistas GABAérgicos/farmacologia , Técnicas de Inativação de Genes , Humanos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Proteínas do Tecido Nervoso/genética , Pentilenotetrazol , Picrotoxina/farmacologia , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos , Adulto Jovem
14.
Cell Death Dis ; 10(11): 825, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672961

RESUMO

C-X-C motif chemokine receptor 7 (CXCR7), which mediates the immune response in the brain, was recently reported to regulate neurological functions. However, the role of CXCR7 in epilepsy remains unclear. Here, we found that CXCR7 was upregulated in the hippocampal dentate gyrus (DG) of mice subjected to kainic acid (KA)-induced epilepsy and in the brain tissues of patients with temporal lobe epilepsy. Silencing CXCR7 in the hippocampal DG region exerted an antiepileptic effect on the KA-induced mouse model of epilepsy, whereas CXCR7 overexpression produced a seizure-aggravating effect. Mechanistically, CXCR7 selectively regulated N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic neurotransmission in hippocampal dentate granule cells by modulating the cell membrane expression of the NMDAR subunit2A, which requires the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Thus, CXCR7 may regulate epileptic seizures and represents a novel target for antiepileptic treatments.


Assuntos
Epilepsia do Lobo Temporal/genética , Receptores CXCR/genética , Receptores de N-Metil-D-Aspartato/genética , Convulsões/genética , Sinapses/genética , Animais , Giro Denteado/metabolismo , Giro Denteado/patologia , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Ácido Caínico/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Convulsões/patologia , Sinapses/patologia
15.
Exp Neurol ; 304: 41-57, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29481784

RESUMO

Endophilin A1 is a member of the endophilin A family and is primarily expressed in the central nervous system. Endophilin A1 can mediate neuronal excitability by regulating neuronal synaptic plasticity, which indicates that the protein may be involved in epilepsy. However, to date, its role in epilepsy remains unclear. To explore the role of endophilin A1 in epilepsy, we aimed to investigate the expression patterns of endophilin A1 in patients with temporal lobe epilepsy (TLE) and in a pentylenetetrazole (PTZ)-kindled epileptic mouse model and to conduct behavioral and electrophysiological analyses after lentivirus-mediated knockdown of endophilin A1 in the hippocampus of epileptic mice. This study found that the expression of endophilin A1 was significantly up-regulated in the temporal neocortex of TLE patients and in the hippocampus and adjacent temporal cortex of the PTZ-kindled epileptic mouse model. Behavioral analyses indicated that knockdown of endophilin A1 in the mouse hippocampus increased the latency of the first seizure and reduced the frequency and duration of seizure activity. Whole-cell patch-clamp recordings of pyramidal neurons in the hippocampal CA3 area indicated that knockdown of endophilin A1 in the mouse hippocampus resulted in a reduced frequency of action potentials and decreased amplitudes of miniature excitatory postsynaptic currents (mEPSCs) and evoked AMPA-dependent EPSCs. Moreover, western blotting analysis showed that the surface expression of the AMPAR GluR2 subunit was also decreased after endophilin A1 knockdown, and co-immunoprecipitation indicated an association between endophilin A1 and AMPAR GluR2 in the mouse hippocampus. Further, when AMPARs were activated by CX546, the antiepileptic function of endophilin A1 knockdown was decreased. Based on these results, endophilin A1 plays a critical role in epilepsy, and its suppression in the mouse hippocampus can restrain neuronal excitability and seizure activity via regulating AMPARs.


Assuntos
Aciltransferases/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Receptores de AMPA/metabolismo , Animais , Convulsivantes/toxicidade , Modelos Animais de Doenças , Feminino , Humanos , Excitação Neurológica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pentilenotetrazol/toxicidade , Convulsões/metabolismo
16.
Sci Rep ; 7(1): 6550, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28747763

RESUMO

Whether very early mobilization (VEM) improves outcomes in stroke patients and reduces immobilization-related complications (IRCs) is currently unknown. The objective of this systematic review and meta-analysis was to evaluate the efficacy and safety of VEM in acute stroke patients following admission. Medline, Embase, and Cochrane Central Register of Controlled Trials databases were searched for randomized controlled trials (RCTs) that examined the efficacy or safety of VEM in patients with acute stroke. VEM was defined as out of bed activity commencing within 24 or 48 hours after the onset of stroke. A total of 9 RCTs with 2,803 participants were included. Upon analysis, VEM was not associated with favorable functional outcomes (modified Ranking Scale: 0-2) at 3 months [relative risk (RR): 0.96; 95% confidence interval (CI): 0.86-1.06]; VEM did not reduce the risk of IRCs during follow up. With respect to safety outcomes, VEM was not associated with a higher risk of death (RR: 1.04; 95% CI: 0.52-2.09) and did not increase the risk of neurological deterioration or incidence of falls with injury. In conclusion, pooled data from RCTs concluded that VEM is not associated with beneficial effects when carried out in patients 24 or 48 hours after the onset of a stroke.


Assuntos
Deambulação Precoce/efeitos adversos , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/terapia , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Acidente Vascular Cerebral/mortalidade , Análise de Sobrevida , Resultado do Tratamento
17.
J Am Heart Assoc ; 6(7)2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28743788

RESUMO

BACKGROUND: Inconsistent findings have been obtained for previous studies evaluating the association between antihypertensive medication (AHM) adherence and the risk of stroke. This dose-response meta-analysis was designed to investigate the association between AHM adherence and stroke risk. METHODS AND RESULTS: MEDLINE and Embase databases were systematically searched to identify relevant studies. The quantification of adherence to AHM was calculated as the percentage of the sum of days with AHM actually taken divided by the total number of days in a specific period. Summary relative risks (RR) and 95% CIs were estimated using a random-effects model. Stratified and dose-response analyses were also performed. A total of 18 studies with 1 356 188 participants were included. The summary RR of stroke for the highest compared with the lowest AHM adherence level was 0.73 (95% CI, 0.67-0.79). Stratified by stroke subtype, a higher AHM adherence was associated with lower risks of ischemic stroke (RR, 0.74; 95% CI, 0.69-0.79) and hemorrhagic stroke (RR, 0.55; 95% CI, 0.42-0.72). Moreover, both fatal (RR, 0.51; 95% CI, 0.36-0.73) and nonfatal stroke (RR, 0.52; 95% CI, 0.28-0.94) were lower in participants with higher AHM adherence. The results of a dose-response analysis indicated that a 20% increment in AHM adherence level was associated with a 9% lower risk of stroke (RR, 0.91; 95% CI, 0.86-0.96). CONCLUSIONS: Higher AHM adherence is dose-dependently associated with a lower risk of stroke in patients with hypertension.


Assuntos
Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Isquemia Encefálica/prevenção & controle , Hipertensão/tratamento farmacológico , Hemorragia Intracraniana Hipertensiva/prevenção & controle , Adesão à Medicação , Acidente Vascular Cerebral/prevenção & controle , Idoso , Isquemia Encefálica/etiologia , Isquemia Encefálica/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Hemorragia Intracraniana Hipertensiva/etiologia , Hemorragia Intracraniana Hipertensiva/fisiopatologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Proteção , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia , Fatores de Tempo , Resultado do Tratamento
18.
Discov Med ; 23(127): 221-234, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28595035

RESUMO

The mechanism of epilepsy-induced axonal impairment is poorly understood. N-methyl-D-aspartate receptors (NMDARs) play important roles in epilepsy and mediate structural and functional axonal impairment. GSK-3ß and Cdk5 affect axons and are regulated by NMDARs, while their roles in epilepsy-induced axonal impairment are unclear. We demonstrated that axonal impairment is characterized by neurofilament heavy (NFH) reduction, amyloid precursor protein (APP) accumulation, and increased tau phosphorylation accompanied by a decrease of total tau in temporal lobe epilepsy (TLE) patients and pentylenetetrazol (PTZ)-kindled rats. Inhibiting NMDARs using memantine and ifenprodil alleviated NFH reduction and APP accumulation, decreased Cdk5 expression, and inhibited the activity of GSK-3ß in the white matter of PTZ-kindled rats. Inhibiting GSK-3ß and Cdk5 using lithium chloride and roscovitine also alleviated axonal impairment induced by PTZ. Therefore, axonal impairment in TLE may be mediated by NMDAR via GSK-3ß and Cdk5. In addition, inhibiting either NMDARs or GSK-3ß lowered the relative tau phosphorylation level by reversing the decrease of total tau without affecting phosphorylated tau S396 and T231. Meanwhile inhibiting Cdk5 lowered the tau phosphorylation level by reducing phosphorylated tau without affecting total tau, indicating a possible role of GSK-3ß in NMDAR-mediated tau phosphorylation in epilepsy.


Assuntos
Axônios/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas tau/metabolismo , Adulto , Animais , Axônios/patologia , Epilepsia do Lobo Temporal/patologia , Feminino , Humanos , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley
19.
Seizure ; 48: 79-88, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28441631

RESUMO

PURPOSE: Some studies have suggested that BAFF and BAFFR are highly expressed in the central nervous system (CNS) and participate in inflammatory and immune associated diseases. However, whether BAFF and BAFFR are involved in the pathogenesis of epilepsy remains unknown. This study aimed to investigate the expression of BAFF and BAFFR proteins in the brains of patients with temporal lobe epilepsy (TLE) and in a pilocarpine-induced rat model of TLE to identify possible roles of the BAFF-BAFFR signaling pathway in epileptogenesis. METHODS: Real-time quantitative polymerase chain reaction (RT-qPCR), western blot, immunohistochemistry, and double-immunofluorescence were performed in this study. RESULTS: The results showed that BAFF and BAFFR expression levels were markedly up-regulated in intractable TLE patients and TLE rats. Moreover, BAFF and BAFFR proteins mainly highly expressed in the membranes and cytoplasms of the dendritic marker MAP2 in the cortex and hippocampus. CONCLUSION: Therefore, the significant increased in BAFF and BAFFR protein expression in both TLE patients and rats suggest that BAFF and BAFFR may play important roles in regulating the pathogenesis of epilepsy.


Assuntos
Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Epilepsia/induzido quimicamente , Adolescente , Adulto , Animais , Western Blotting , Química Encefálica , Criança , Modelos Animais de Doenças , Epilepsia/metabolismo , Feminino , Imunofluorescência , Humanos , Masculino , Pilocarpina/farmacologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima , Adulto Jovem
20.
Int J Nanomedicine ; 12: 2443-2456, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28408816

RESUMO

Spinal cord injury (SCI) commonly leads to lifelong disability due to the limited regenerative capacity of the adult central nervous system. Nanomicelles can be used as therapeutic systems to provide effective treatments for SCI. In this study, a novel triblock monomethyl poly(ethylene glycol)-poly(l-lactide)-poly(trimethylene carbonate) copolymer was successfully synthesized. Next, polymeric nanomicelles loaded with zonisamide (ZNS), a Food and Drug Administration-approved antiepileptic drug, were prepared and characterized. The ZNS-loaded micelles (ZNS-M) were further utilized for the treatment of SCI in vitro and in vivo. The obtained ZNS-M were ~50 nm in diameter with good solubility and dispersibility. Additionally, these controlled-release micelles showed significant antioxidative and neuron-protective effects in vitro. Finally, our results indicated that ZNS-M treatment could promote motor function recovery and could increase neuron and axon density in a hemisection SCI model. In summary, these results may provide an experimental basis for the use of ZNS-M as a clinically applicable therapeutic drug for the treatment of SCI in the future.


Assuntos
Sistemas de Liberação de Medicamentos , Isoxazóis/uso terapêutico , Micelas , Nanopartículas/química , Polímeros/química , Traumatismos da Medula Espinal/tratamento farmacológico , Doença Aguda , Animais , Antioxidantes/farmacologia , Axônios/efeitos dos fármacos , Axônios/patologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Morte Celular/efeitos dos fármacos , Cromatografia em Gel , Dioxanos/síntese química , Dioxanos/química , Portadores de Fármacos , Liberação Controlada de Fármacos , Imageamento por Ressonância Magnética , Camundongos , Poliésteres/síntese química , Poliésteres/química , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Espectroscopia de Prótons por Ressonância Magnética , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X , Zonisamida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...