辛醇预处理对红藻氨酸诱导的癫疒间大鼠海马神经元凋亡和胶质纤维酸性蛋白表达的影响

目的观察缝隙连接阻断剂辛醇预处理对红藻氨酸(KA)诱导的癫疒间大鼠海马神经元凋亡和胶质纤维酸性蛋白(GFAP)表达的影响。方法 160只雄性SD大鼠随机分为KA组、辛醇组、生理盐水(NS)组和二甲基亚砜(DMSO)组,应用KA右侧杏仁核注射制作癫疒间大鼠模型;制模前30 min辛醇组腹腔注射辛醇溶液;制模后3 h、6 h、12 h、24 h和7 d应用原位末端标记(TUNEL)法和免疫组化染色法分别检测各组大鼠海马CA3区TUNEL和GFAP阳性细胞数。结果 KA组制模后6 h海马CA3区有TUNEL阳性细胞表达,并逐渐增多,7 d达高峰;辛醇组制模后在6 h～7 d TUNEL阳性细胞数明显少于KA组(均P<0.01);KA组海马CA3区GFAP阳性细胞数随时间而逐渐增多,各时间点明显多于辛醇组(均P<0.01)。结论辛醇神经保护作用的机制可能与抑制细胞缝隙连接间通讯,切断凋亡信号传播,以减少神经元凋亡有关。     

迷走神经刺激对红藻氨酸致癫癎大鼠海马及齿状回NMDAR1的影响

目的:利用红藻氨酸(kainate,KA)致大鼠复杂部分性发作模型,观察海马及齿状回等易损脑区N-甲基-D-门冬氨酸受体1亚单位(NMDAR_1)的变化,以期进一步探明迷走神经刺激治疗癫(疒间)的作用机制。方法:免疫细胞化学法。结果:正常大鼠NMDAR_1阳性结构可见于海马各区及齿状回;KA给药后1h海马CA1、CA3、齿状回NMDAR_1的密度开始增高;3h达高峰,以后逐渐下降,24h后基本恢复正常;预先给予左侧迷走神经电刺激治疗的大鼠相应脑区NMDAR_1密度较KA致(疒间)组明显降低,具有统计学差异。结论:迷走神经刺激抑制癫(疒间)发作可能是通过降低易损脑区神经元NMDAR_1活性而发挥作用的。     

海藻氨酸致癎大鼠中海马谷氨酸转运体功能的研究

目的　研究海藻氨酸(KA)致疒间大鼠海马谷氨酸转运体(GluTs)功能的变化,进一步探讨GluTs 参与癫疒间发生的机制。方法　60只Wistar大鼠随机分为KA组和对照组,每组再按点燃后4h、24h、48h、5 d、7d不同时点随机分为5个亚组,分别测定不同时点海马突触颗粒和海马组织切片对3H L 谷氨酸的摄取 量,观察GluTs于点燃后不同时点的活性。结果　KA组点燃后海马突触颗粒GluTs功能在各时点均降低(均 P<0.01),海马组织切片GluTs功能在点燃后初期上升而后下降(P<0.05)。结论　KA可引起海马GluTs 功能的变化,其可能与癫疒间的发生及易感性的形成有关。     

辛醇预处理对红藻氨酸诱导的癫(癎)大鼠海马神经元凋亡和胶质纤维酸性蛋白表达的影响

目的 观察缝隙连接阻断剂辛醇预处理对红藻氨酸(KA)诱导的癫(癎)大鼠海马神经元凋亡和胶质纤维酸性蛋白(GFAP)表达的影响.方法 160只雄性SD大鼠随机分为KA组、辛醇组、生理盐水(NS)组和二甲基亚砜(DMSO)组,应用KA右侧杏仁核注射制作癫(癎)大鼠模型;制模前30 min辛醇组腹腔注射辛醇溶液;制模后3h、6h、12 h、24 h和7d应用原位末端标记(TUNEL)法和免疫组化染色法分别检测各组大鼠海马CA3区TUNEL和GFAP阳性细胞数.结果 KA组制模后6h海马CA3区有TUNEL阳性细胞表达,并逐渐增多,7d达高峰;辛醇组制模后在6 h～7 d TUNEL阳性细胞数明显少于KA组(均P＜0.01);KA组海马CA3区GFAP阳性细胞数随时间而逐渐增多,各时间点明显多于辛醇组(均P＜0.01).结论 辛醇神经保护作用的机制可能与抑制细胞缝隙连接间通讯,切断凋亡信号传播,以减少神经元凋亡有关.     

癫大鼠海马区囊泡锚定蛋白Ⅰ的表达及突触超微结构的改变

目的观察大鼠癫发作后海马区囊泡锚定蛋白Ⅰ(synapsinⅠ)的表达和突触超微结构的变化,探讨突触功能、形态可塑性与癫的关系。方法用锂匹罗卡品制作癫疒间大鼠模型,应用免疫组化法观察致疒间后急性期、静止期和慢性期synapsinⅠ在海马的表达;应用电镜和图像处理软件观察海马突触超微结构。结果癫疒间组大鼠海马区synapsinⅠ的表达于致疒间后3h减弱;6h和12h达高峰,与对照组比较差异有显著性(P<0.05～0.01);24h恢复正常并持续到60d。致疒间后3h突触后致密物质厚度(PSD)和突触数密度(Nv)无显著改变;6hPSD增高,Nv降低;7d、30dPSD恢复正常,Nv增高。结论synapsinⅠ的高表达和PSD的增高可能与急性期癫疒间持续状态的维持有关;synapsinⅠ的正常表达和PSD的正常可能是静止期内癫疒间不发作的原因之一;慢性期Nv的增加是自发性发作出现的物质基础。     

氯化锂-匹罗卡品致(疒间)大鼠脑髓鞘转录因子的表达及其意义

目的探讨氯化锂-匹罗卡品致疒间大鼠脑髓鞘转录因子1(MyT1)的表达及其意义.方法给SD大鼠先后腹腔注射氯化锂、匹罗卡品,制成癫疒间动物模型;用免疫荧光组化法检测癫疒间大鼠癫疒间发作后不同时间大脑皮质和海马CA1区MyT1阳性细胞数.结果与对照组相比,癫疒间后1 d组大鼠海马CA1区MyT1阳性细胞数显著减少(P＜0.05),癫疒间后其他各时间组大鼠脑皮质和海马CA1区MyT1阳性细胞数均有明显的增加,其中癫疒间后7 d组MyT1阳性细胞数最多(P＜0.01,P＜0.05).结论氯化锂-匹罗卡品致疒间大鼠早期大脑MyT1表达增加,并有时程性变化.     

癫大鼠血清、海马组织中神经元特异性烯醇化酶和S-100β蛋白的变化及其临床意义

目的探讨红藻氨酸(KA)诱导癫疒间大鼠血清及海马组织中神经元特异性烯醇化酶(NSE)和S100β蛋白(S100β)的变化及其临床意义。方法180只Wistar大鼠随机分为对照组、KA组和卡马西平(CBZ)组,后两组再按癫疒间发作后1h、4h、12h、24h、48h和72h不同时点分为6个亚组。以放射免疫法(RIA)和酶联免疫吸附试验(ELISA)分别测定大鼠血清和海马匀浆液中NSE和S100β的变化。结果癫疒间发作72h内,血清和海马匀浆液中NSE和S100β的含量是一个动态变化过程,且呈同步变化的趋势,在12h时均达到峰值。在4～48h时,KA组和CBZ组的二者含量均明显高于对照组(P<0.05～0.01)。结论癫疒间发作后NSE和S100β的含量升高,二者可作为癫疒间发作后脑组织损伤的一个参考指标。     

实验性癫痫大鼠发作后海马γ-氨基丁酸B受体亚单位的表达及其激动剂的影响

目的 观察海人酸(KA)诱导的实验性癫疒间(EP)大鼠发作后海马γ-氨基丁酸B受体(GABABR)亚单位mRNA表达及其激动剂巴氯芬的影响.方法 运用原位杂交法检测各实验组大鼠EP发作后及巴氯芬干预后海马区GABABR亚单位GAR1a及GAR2 mRNA表达.结果 KA致疒间早期(6～12 h)2种亚单位mRNA表达水平广泛下降,至1 d仍明显低于对照组(均P<0.05),但齿状回(DG)区mRNA表达开始回升,3 d后表达水平已明显高于对照组(P<0.05),而CA1与CA3区表达仍维持低水平(均P<0.05),但其表达水平渐向对照组水平恢复.巴氯芬干预后亚单位表达明显下降的时间点延迟,且表达水平明显高于非干预的致疒间组(P<0.05～0.01).结论 致疒间鼠2种亚单位表达下降后又上调为颞叶EP的内源性自我保护机制;巴氯芬促进2种亚单位表达,增强GABA抑制作用,有利于控制EP,为筛选针对GABABR亚单位的抗疒间药提供新途径.     

匹罗卡品致疒间大鼠海马GAP-43与TrkB基因表达及其意义

目的探讨生长相关蛋白(GAP-43)和脑源性神经营养因子(BDNF)受体TrkB基因在匹罗卡品致疒间大鼠海马的表达及其意义.方法应用原位杂交组织化学方法研究匹罗卡品(PILO)致疒间大鼠海马GAP-43及TrkB mRNA表达的变化.结果匹罗卡品致癫疒间持续状态后3～6小时,海马齿状回颗粒细胞、CA3区及CA1区锥体细胞层TrkB mRNA表达显著高于对照组(P<0.01或0.05);在慢性期第7～30天,呈现第2次表达增强.致疒间后6～12小时,正常状态下并不表达GAP-43的大鼠海马颗粒细胞其GAP-43 mRNA表达较对照组显著增高(P<0.01),24小时～7天表达减少,在癫疒间慢性期表达再次高于对照组.结论 GAP-43及TrkB是颞叶癫疒间病理基础--海马苔藓纤维出芽的重要分子机制;BDNF对苔藓纤维的作用部分是通过GAP-43实现的.     

海人酸致癎大鼠海马CA_3区神经元线粒体与细胞核损伤及caspase-3表达的研究

目的观察海人酸(KA)诱导的癫疒间持续状态(SE)大鼠海马CA3区神经元线粒体与细胞核超微结构的损伤及caspase-3表达的变化。方法用KA诱导大鼠SE 2 h。分别于SE终止后第3 h、12 h、24 h取海马CA3区制作切片,光镜下观察神经元的变化,电镜下观察线粒体和细胞核的超微结构;免疫组化方法检测相同部位caspase-3的表达变化。结果光镜下SE后24 h神经元出现排列散乱、胞体皱缩、胞浆红染以及胞核固缩。电镜下SE后3 h,可见线粒体嵴肿胀及膜的崩解;SE后24 h细胞核染色质明显边聚。Caspase-3平均阳性细胞数及灰度值于SE后12 h较正常对照组显著增加(均P<0.05);24 h出现极显著增加(均P<0.01)。结论SE后早期海马神经元线粒体损伤可能是神经元损伤的关键环节。     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.