迷走神经刺激在癫痫治疗中的抗炎作用机制

癫痫是一种由大脑神经元过度兴奋或异常同步放电引起脑部功能障碍的慢性神经疾病,具有反复性、发作性和短暂中枢神经系统功能失常等特征。近年来,研究发现炎症反应的异常激活在癫痫发生和发展过程中起到重要作用,炎症信号分子成为抗癫痫治疗的新靶点。迷走神经刺激(vagus nerve stimulation, VNS)作为辅助疗法通过与抗癫痫药物治疗相结合,可以减少癫痫发作,大量的临床应用表明VNS治疗具有较高的安全性和有效性,然而VNS的作用机制尚不清楚。近年来,人们已经在动物疾病模型和病人中开展了VNS抗炎作用机制的研究,该文对VNS在抗癫痫治疗中外周和中枢神经系统的免疫调节作用机制进行综述。     

肠道微生态在儿童难治性癫痫发病及治疗中的研究进展CSCD

儿童难治性癫痫是一种常见的儿科神经系统疾病。许多临床前及临床证据表明儿童难治性癫痫患者体内优势菌群与健康人相比存在显著差异;抗癫痫干预后难治性癫痫儿童体内肠道菌群分布发生改变;动物粪菌移植实验进一步证实肠道菌群的改变与癫痫发病及抗癫痫疗效存在因果关系。临床上益生菌的添加可能增强抗癫痫疗效,抗生素的使用往往也影响临床的抗癫痫疗效。肠道微生态可能通过内源性机制(如改变神经递质含量等)及外源性机制(如感染和损伤等)改变儿童难治性癫痫患者的代谢、遗传、免疫和感染等。本综述通过总结近年来国内外肠道微生态与儿童癫痫发病和抗癫痫效果的相关研究,阐述肠道微生态在儿童癫痫发病及治疗中的作用并对其可能的作用机制进行探讨。     

血脑屏障上P-糖蛋白与耐药性癫痫关系的研究进展

耐药性癫痫是癫痫治疗的瓶颈。P-糖蛋白通过跨膜外排泵作用阻止抗癫痫药物由血脑屏障入脑发挥期望效应是耐药性癫痫产生的重要原因。本文介绍了耐药性癫痫与血脑屏障上P-糖蛋白的相互关系,对目前提出的调节P-糖蛋白功能,改善耐药性癫痫预后应注意的问题进行说明。安全地调节P-糖蛋白功能到适度可能为耐药性癫痫的治疗带来希望。     

脑血管病继发癫痫66例临床研究

目的:探讨脑血管病与继发性癫痫的关系。方法:对66例脑血管病继发性癫痫作总结分析。结果:早期型癫痫43例,迟发型癫痫23例。病变部位多侵及脑叶(47/66),癫痫以全面发作居多,治疗效果佳。结论:脑血管病是继发性癫痫的重要原因之一,早期型癫痫多不需长期服抗癫痫药,迟发型癫痫多需长期服抗癫痫药,脑血管病急性期癫痫发作组患者死亡率明显高于非癫痫组,癫痫持续状态提示患者病情危重、预后不良。     

儿科抗癫痫药物应用研究进展

儿童癫痫为小儿神经科的常见疾病,临床表现以抽搐为主。近年来,随着医疗技术的发展,以及人们对儿童癫痫的重视,国内外文献对儿科癫痫的治疗报道越来越多,目前,药物治疗仍然是抗癫痫的首选方法,除了运用新型抗癫痫药物外,也有采用中药治疗癫痫的报道,现就近年来儿童癫痫的药物治疗研究作一综述。     

蝎毒对癫痫敏感性和海马GFAP释放的影响

目的和方法 :本工作用海人酸癫痫模型 ,通过对癫痫大鼠蝎毒治疗后行为变化及脑内胶质原纤维酸性蛋白(GFAP)免疫反应活性的检测 ,对蝎毒抗癫痫反复发作的相关脑区及其机制做以初步探讨。结果 :癫痫大鼠蝎毒治疗三周后 ,能明显减少癫痫发作的例数 ,减轻癫痫发作的程度 ,使发作的潜伏期延长 (P <0 .0 5 )。免疫细胞化学的实验显示 ,蝎毒抗癫痫反复发作的相关脑区是海马。 8例蝎毒治疗的大鼠与实验对照组相比 ,有 6例背侧海马GFAP免疫染色明显减轻 ,未见星形胶质细胞增生 ;CA1区无明显神经元缺失 ;而且与空白对照组相比无显著差异。结论 :癫痫大鼠蝎毒治疗三周后 ,能明显减轻癫痫发作的行为 ,抑制海马星形胶质细胞的增生肥大 ,减轻海马神经元受损的程度。蝎毒抑制海马星形胶质细胞增生很可能是蝎毒抗癫痫反复发作的重要机制之一。     

产自东亚钳蝎的钠通道调节剂的抗癫痫/促癫痫作用（英文）

东亚钳蝎(Buthus martensii Karsch, BmK)是治疗癫痫的经典中药之一,已有上千年的历史。从BmK毒液中分离纯化的神经毒素被认为是作用于膜离子通道的主要活性成分。电压门控钠通道(voltage-gated sodium channels, VGSCs)在癫痫发生中起着重要的作用,使其成为重要的癫痫药物靶点。BmK的长链毒素由60～70个氨基酸残基组成,能特异性识别VGSCs,其中用于建立癫痫模型的α-样神经毒素与VGSC受体位点3结合,可诱发鼠类癫痫。而β或β-样神经毒素则与VGSC受体位点4结合,对癫痫模型有显著的抗惊厥作用。本综述旨在阐明BmK多肽作用于VGSCs的抗惊厥或惊厥作用,同时也为抗癫痫药物设计提供潜在的框架。     

去甲肾上腺素通路的研究进展及其在迷走神经电刺激改善难治性癫痫学习记忆中的潜在作用

迷走神经电刺激(vagus nerve stimulation, VNS)对无法手术的耐药难治性癫痫患者能起到较好的抗癫痫效果，目前已被美国FDA批准用于耐药难治性癫痫的临床辅助性治疗。VNS的抗癫痫作用可长期维持，且治疗效果随刺激时间的延长而增加。有研究发现，VNS在减少癫痫发作的同时，还能改善癫痫患者的情绪状态，提高患者的认知能力。去甲肾上腺素能系统参与突触可塑性调节。本文综述了VNS改善难治性癫痫患者学习记忆能力的研究进展，重点讨论了去甲肾上腺素能系统调控突触可塑性变化的相关信号通路，提出VNS激活去甲肾上腺素能系统从而改善患者学习记忆的潜在可能性，为临床癫痫治疗提供新的靶点和思路。     

膜超极化激活离子通道及其靶向抗癫痫药物研究进展

癫痫是一种较为常见的神经系统疾病,主要以大量神经元同步异常放电为特征。目前普遍认为,神经元或神经网络兴奋性和抑制性 电信号传输的失衡,是癫痫发病的最根本原因。现有的抗癫痫药物主要以钠离子通道、钙离子通道、钾离子通道、谷氨酸受体和γ-氨基丁 酸离子通道为靶点,但接受这些药物治疗后,仍有近1/3的病人无法控制癫痫发作。因此,抗癫痫药物的研发亟需新靶点和新思路。许多 研究证据表明,膜超极化激活离子通道的基因突变可以导致遗传型癫痫的发作,且在脑部损伤后,膜超极化激活离子通道会发生表达水平、 通道生物物理学性质及通道亚基构成的改变,从而增加神经元和神经网络兴奋性,促使癫痫发病。故近年来,膜超极化激活离子通道及其 靶向抗癫痫药物研究引起人们广泛关注。综述膜超极化激活离子通道与癫痫发病之间的关系,并探讨以膜超极化激活离子通道为靶点进行 抗癫痫药物开发和治疗的可行性。     

6 Hz角膜点燃癫痫动物模型的研究进展

耐药性癫痫是临床上癫痫防治的重大难题。癫痫动物模型是研究癫痫发病机制及筛选抗癫痫药物和探究药物作用机制的有力工具,6Hz角膜点燃癫痫模型是一种优良的耐药性癫痫动物模型,被美国NIH推荐用于评价新药对抗耐药性癫痫的筛选工具。然而,迄今国内外未见6Hz点燃癫痫动物模型的系统报道,现从该模型的发展历史、制作方法、症状表现、致病机制和应用现状等方面进行综述,以期提供一种探究耐药性癫痫发病机制和筛选耐药性癫痫治疗药物的有力工具和标准模型。     

Temporal arrest

Two patients are presented in which documented periods of asystole were caused by temporal epilepsy. Pacemaker implantation prevented total collapse but episodes of near collapse continued. After institution of anti-epileptic drug treatment both patients are free of symptoms.     

A Mesiotemporal Lobe Epilepsy Mouse Model

Among the different forms of epilepsies, mesiotemporal lobe epilepsy (MTLE) is one of the most common and represents the main pharmaco-resistant form of epilepsy. There is therefore an urgent need to better understand this form of epilepsy to develop better anti-epileptic drugs. Many rodent models are mimicking some aspects of the human temporal lobe epilepsy but only few are addressing most of the human mesiotemporal lobe epilepsy. In this article, we describe the main characteristics of a mouse of model of mesial temporal lobe epilepsy. This model is generated by a single injection of kainic acid into the dorsal hippocampus which reproduces most of the morphological and electrophysiological features of human MTLE in a mouse. This model may help to better understand mesial temporal lobe epilepsy and the development of new therapeutic drugs.     

Mutations in prickle orthologs cause seizures in flies, mice, and humans

Epilepsy is heritable, yet few causative gene mutations have been identified, and thus far no human epilepsy gene mutations have been found to produce seizures in invertebrates. Here we show that mutations in prickle genes are associated with seizures in humans, mice, and flies. We identified human epilepsy patients with heterozygous mutations in either PRICKLE1 or PRICKLE2. In overexpression assays in zebrafish, prickle mutations resulted in aberrant prickle function. A seizure phenotype was present in the Prickle1-null mutant mouse, two Prickle1 point mutant (missense and nonsense) mice, and a Prickle2-null mutant mouse. Drosophila with prickle mutations displayed seizures that were responsive to anti-epileptic medication, and homozygous mutant embryos showed neuronal defects. These results suggest that prickle mutations have caused seizures throughout evolution.     

Feasibility and effects of nurse run clinics for patients with epilepsy in general practice: randomised controlled trial. Epilepsy Care Evaluation Group.

OBJECTIVE: To test the feasibility and effect of nurse run epilepsy clinics in primary care. DESIGN: A randomised controlled trial of nurse run clinics versus "usual care." SETTING: Six general practices in the South Thames region. SUBJECTS: 251 patients aged over 15 years who were taking anti-epileptic drugs or had a diagnosis of epilepsy and an attack in the past two years who met specified inclusion criteria and had responded to a questionnaire. MAIN OUTCOME MEASURES: Questionnaire responses and recording of key variables extracted from the clinical records before and after the intervention. RESULTS: 127 patients were randomised to a nurse run clinic, of whom 106 (83%) attended. The nurse wrote 28 letters to the general practitioners suggesting changes in epilepsy management. For this intervention group compared with the usual care group there was a highly significant improvement in the level of advice recorded as having been given on drug compliance, adverse drug effects, driving, alcohol intake, and self help groups. CONCLUSIONS: Nurse run clinics for patients with epilepsy were feasible and well attended. Such clinics can significantly improve the level of advice and drug management recorded.     

Reciprocal Changes in Phosphorylation and Methylation of Mammalian Brain Sodium Channels in Response to Seizures

Voltage-gated sodium (Nav) channels initiate action potentials in brain neurons and are primary therapeutic targets for anti-epileptic drugs controlling neuronal hyperexcitability in epilepsy. The molecular mechanisms underlying abnormal Nav channel expression, localization, and function during development of epilepsy are poorly understood but can potentially result from altered posttranslational modifications (PTMs). For example, phosphorylation regulates Nav channel gating, and has been proposed to contribute to acquired insensitivity to anti-epileptic drugs exhibited by Nav channels in epileptic neurons. However, whether changes in specific brain Nav channel PTMs occur acutely in response to seizures has not been established. Here, we show changes in PTMs of the major brain Nav channel, Nav1.2, after acute kainate-induced seizures. Mass spectrometry-based proteomic analyses of Nav1.2 purified from the brains of control and seizure animals revealed a significant down-regulation of phosphorylation at nine sites, primarily located in the interdomain I-II linker, the region of Nav1.2 crucial for phosphorylation-dependent regulation of activity. Interestingly, Nav1.2 in the seizure samples contained methylated arginine (MeArg) at three sites. These MeArgs were adjacent to down-regulated sites of phosphorylation, and Nav1.2 methylation increased after seizure. Phosphorylation and MeArg were not found together on the same tryptic peptide, suggesting reciprocal regulation of these two PTMs. Coexpression of Nav1.2 with the primary brain arginine methyltransferase PRMT8 led to a surprising 3-fold increase in Nav1.2 current. Reciprocal regulation of phosphorylation and MeArg of Nav1.2 may underlie changes in neuronal Nav channel function in response to seizures and also contribute to physiological modulation of neuronal excitability.     

New insights on the potential anti-epileptic effect of metformin: Mechanistic pathway

Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well-controlled disease by anti-epileptic agents (AEAs) in about 69%. However, 30%–40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA-approved drugs that have an anti-seizure activity to the anti-epileptic regimen is logical. The anti-diabetic agent metformin has anti-seizure activity. Nevertheless, the underlying mechanism of the anti-seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti-seizure activity by triggering adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain-derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti-seizure mechanism of metformin. Also, metformin reduces α-synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.     

Vitamin B6 in Plasma and Cerebrospinal Fluid of Children

Background

Over the past years, the essential role of vitamin B6 in brain development and functioning has been recognized and genetic metabolic disorders resulting in functional vitamin B6 deficiency have been identified. However, data on B6 vitamers in children are scarce.

Materials and Methods

B6 vitamer concentrations in simultaneously sampled plasma and cerebrospinal fluid (CSF) of 70 children with intellectual disability were determined by ultra performance liquid chromatography-tandem mass spectrometry. For ethical reasons, CSF samples could not be obtained from healthy children. The influence of sex, age, epilepsy and treatment with anti-epileptic drugs, were investigated.

Results

The B6 vitamer composition of plasma (pyridoxal phosphate (PLP) > pyridoxic acid > pyridoxal (PL)) differed from that of CSF (PL > PLP > pyridoxic acid > pyridoxamine). Strong correlations were found for B6 vitamers in and between plasma and CSF. Treatment with anti-epileptic drugs resulted in decreased concentrations of PL and PLP in CSF.

Conclusion

We provide concentrations of all B6 vitamers in plasma and CSF of children with intellectual disability (±epilepsy), which can be used in the investigation of known and novel disorders associated with vitamin B6 metabolism as well as in monitoring of the biochemical effects of treatment with vitamin B6.     

The genetic and molecular basis of epilepsy

In the past decade, studies of large families in which epilepsy has been inherited in an autosomal dominant fashion have revealed several mutated genes, most of which encode ion channel subunits. Despite these exciting findings, only a few families with similar phenotypes have mutations in these known genes. More frustrating has been the genetic research into idiopathic epilepsies with complex inheritance. Although these forms are more common than those with Mendelian inheritance, their unknown mode of inheritance, phenotypic heterogeneity and the uncertainty of the genetic overlap among syndrome subtypes have hampered gene mapping. New techniques of molecular analysis could help the dissection of genes for epilepsies with complex inheritance. Hopefully, in the near future, successful genetic studies will make possible the discovery of new and more-targeted anti-epileptic drugs.     

Post-Treatment with Voltage-Gated Na+ Channel Blocker Attenuates Kainic Acid-Induced Apoptosis in Rat Primary Hippocampal Neurons

Injection of rats with kainic acid (KA), a non-N-methyl-D-aspartate (NMDA) type glutamate receptor agonist, induces recurrent (delayed) convulsive seizures and subsequently hippocampal neurodegeneration, which is reminiscent of human epilepsy. The protective effect of anti-epileptic drugs on seizure-induced neuronal injury is well known; however, molecular basis of this protective effect has not yet been elucidated. In this study, we investigated the effect and signaling mediators of voltage-gated Na(+) channel blockers (Lamotrigine, Rufinamide, Oxcarbazepine, Valproic Acid, and Zonisamide) on KA-induced apoptosis in rat primary hippocampal neurons. Exposure of hippocampal neurons to 10 μM KA for 24 h caused significant increases in morphological and biochemical features of apoptosis, as determined by Wright staining and ApopTag assay, respectively. Analyses showed increases in expression and activity of cysteine proteases, production of reactive oxygen species (ROS), intracellular free [Ca(2+)], and Bax:Bcl-2 ratio during apoptosis. Cells exposed to KA for 15 min were then treated with Lamotrigine, Rufinamide, Oxcarbazepine, Valproic Acid, or Zonisamide. Post-treatment with one of these anti-epileptic drugs (500 nM) attenuated production of ROS and prevented apoptosis in hippocampal neurons. Lamotrigine, Rufinamide, and Oxcarbazepine appeared to be less protective when compared with Valproic Acid or Zonisamide. This difference may be due to blockade of T-type Ca(2+) channels also by Valproic Acid and Zonisamide. Our findings thus suggest that the anti-epileptic drugs that block both Na(+) channels and Ca(2+) channels are significantly more effective than agents that block only Na(+) channels for attenuating seizure-induced hippocampal neurodegeneration.